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1.
Zhonghua Shao Shang Za Zhi ; 36(8): 651-657, 2020 Aug 20.
Artigo em Chinês | MEDLINE | ID: mdl-32829603

RESUMO

Objective: To investigate the effects and mechanism of mitochondrial transcription factor A (TFAM) and cytochrome c oxidase (COX) pathway in the energy production of hypoxic cardiomyocytes of rats regulated by tumor necrosis factor receptor associated protein 1 (TRAP1). Methods: The cardiomyocytes were isolated from 135 neonatal Sprague-Dawley rats (aged 1-3 d) and cultured for the following experiments. (1) Cells were collected and divided into normoxia blank control (NBC) group, hypoxia blank control (HBC) group, hypoxia+ TRAP1 over-expression control (HTOC) group, and hypoxia+ TRAP1 over-expression (HTO) group according to the random number table (the same grouping method below), with 1 bottle in each group. Cells in NBC group were cultured routinely, cells in HBC group were cultured in hypoxic condition for 6 hours after routine culture, cells in HTOC and HTO groups were respectively added with TRAP1 over-expression empty virus vector and TRAP1 over-expression adenovirus vector virus suspension for transfection for 48 hours after routine culture and then cultured in hypoxic condition for 6 hours. The protein expression of TFAM of cells in each group was detected by Western blotting. (2) Cells were collected and divided into NBC, HBC, HTOC, HTO, HTO+ TFAM interference control (HTOTIC), and HTO+ TFAM interference (HTOTI) groups, with 1 well in each group. Cells in the former 4 groups were dealt with the same methods as the corresponding groups in experiment (1). Cells in HTOTIC and HTOTI groups were respectively added with TFAM interference empty virus vector and TFAM interference adenovirus vector virus suspension for transfection for 48 hours, and the other processing methods were the same as those in HTO group. The content of ATP of cells in each group was determined by ATP determination kit and microplate reader, and the COX activity of cells in each group was determined by COX activity assay kit and microplate reader. (3) Cells were collected and divided into NBC group, normoxia+ sodium azide (NSA) group, HBC group, and hypoxia+ sodium azide (HSA) group, with 1 well in each group. Cells in NBC and HBC groups were respectively dealt with the same methods as the corresponding groups in experiment (1). Cells in NSA and HSA groups were respectively added with 32 nmol sodium azide at 30 min before experiment or hypoxia, and then cells in HSA group were cultured in hypoxic condition for 6 hours. The content of ATP was determined by the same method as above. The above three experiments were repeated for three times. Data were statistically analyzed with one-way analysis of variance and least significant difference test. Results: (1) Compared with that in NBC group, the protein expression of TFAM of cells in HBC group was significantly decreased (P<0.01). Compared with that in HBC group or HTOC group, the protein expression of TFAM of cells in HTO group was significantly increased (P<0.01). (2) Compared with 0.552±0.041 and 1.99±0.15 in NBC group, the COX activity (0.270±0.044) and ATP content (1.09±0.11) of cells in HBC group were significantly decreased (P<0.01). Compared with 0.269±0.042 and 1.17±0.12 in HBC group and those in HTOC group, the COX activity (0.412±0.032 and 0.404±0.016) and ATP content (1.75±0.06 and 1.69±0.07) of cells in HTO and HTOTIC groups were significantly increased (P<0.01). Compared with those in HTO and HTOTIC groups, the COX activity (0.261±0.036) and ATP content (1.23±0.07) of cells in HTOTI group were significantly decreased (P<0.01). (3) Compared with that in NBC group, the ATP content of cells in NSA and NBC groups was significantly decreased (P<0.01). Compared with that in HBC group, the ATP content of cells in HSA group was significantly decreased (P<0.01). Conclusions: TRAP1 can increase the COX activity of cardiomyocytes by raising the expression of TFAM, and finally alleviate the impairment in energy production of cardiomyocytes caused by hypoxia.


Assuntos
Miócitos Cardíacos , Animais , Proteínas de Ligação a DNA , Complexo IV da Cadeia de Transporte de Elétrons , Proteínas de Choque Térmico HSP90 , Hipóxia , Proteínas Mitocondriais , Ratos , Ratos Sprague-Dawley , Receptores do Fator de Necrose Tumoral , Fatores de Transcrição
2.
Mol Immunol ; 124: 25-34, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32497752

RESUMO

Tumor necrosis factor receptor superfamily (TNFRSF) is an ancient protein superfamily. By binding to tumor necrosis factor (TNF), it can participate in inflammatory response, apoptosis, lymphocyte homeostasis and tissue development. Seven TNFR members have previously been identified in lampreys but detailed functions of TNFR members are not yet to be resolved. Here, we demonstrate some of the distinguishing features of TNFR10-like member which belongs to TNFRSF. The immunohistochemical results indicate that the TNFR10-like protein is abundant in vascular epithelial cells of the lamprey typhlosole and gills. The expression of tnfr10-like gene has a significantly increased at transcription level after Vibrio anguillarum, Staphylococcus aureus and Poly (I:C) stimulation. Notably, TNFR10-like is specifically expressed in the granulocytes of lamprey peripheral blood and supraneural body. Besides, overexpression tnfr10-like gene in HEK-293 T cells cause a decrease in cell activity and able to activate nuclear transcription factor-κB (NF-κB). Together, these results imply that L-TNFR10-like may play a vital role as a potential marker in lamprey granulocytes and may also be involved in regulation of immune response mediated by itself.


Assuntos
Proteínas de Peixes/imunologia , Granulócitos/imunologia , Lampreias/imunologia , Receptores do Fator de Necrose Tumoral/imunologia , Sequência de Aminoácidos , Animais , Proteínas de Peixes/genética , Células HEK293 , Humanos , Lampreias/genética , Filogenia , Receptores do Fator de Necrose Tumoral/genética
3.
Medicine (Baltimore) ; 99(18): e19967, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32358369

RESUMO

The present study aimed to investigate the association between the expressions of serum progranulin (PGRN) and serum soluble Oxford 40 ligand (sOX40L) and determine their clinical significances in primary Sjögren's syndrome (pSS).The present study included a total of 68 patients with pSS and 50 healthy controls. Demographic data and clinical basic information were collected. Enzyme-linked immunosorbent assay (ELISA) was performed to determine serum levels of PGRN, sOX40L and interleukins. Spearman's correlation coefficient and Mann-Whitney U test were used to determine the correlation between PGRN, and sOX40L and the association between PGRN and sOX40L and disease activity and disease severity.Serum interleukin (IL)-4, IL-6, IL-10, PGRN, and sOX40L levels were significantly higher in pSS patients as compared to the healthy controls. A positive correlation was observed between PGRN and sOX40L. Patients with elevated levels of PGRN or sOX40L exhibited higher disease activity compared to those with lower levels. Patients with III to IV stages of pSS or multiple system damage showed higher serum levels of PGRN and sOX40L.Elevated serum PGRN, and sOX40L levels were relevant with disease activity and severity in patients with pSS.


Assuntos
Progranulinas/sangue , Receptores do Fator de Necrose Tumoral/sangue , Síndrome de Sjogren/fisiopatologia , Adulto , Ensaio de Imunoadsorção Enzimática , Feminino , Humanos , Interleucinas/biossíntese , Interleucinas/sangue , Masculino , Pessoa de Meia-Idade , Progranulinas/biossíntese , Estudos Prospectivos , Receptores do Fator de Necrose Tumoral/biossíntese , Índice de Gravidade de Doença , Síndrome de Sjogren/sangue , Fatores Socioeconômicos
4.
PLoS Pathog ; 16(2): e1008361, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-32101593

RESUMO

Monocytes exist in two major populations, termed Ly6Chi and Ly6Clow monocytes. Compared to Ly6Chi monocytes, less is known about Ly6Clow monocyte recruitment and mechanisms involved in the recruitment of this subset. Furthermore, the role of Ly6Clow monocytes during infections is largely unknown. Here, using intravital microscopy, we demonstrate that Ly6Clow monocytes are predominantly recruited to the brain vasculature following intravenous infection with Cryptococcus neoformans, a fungal pathogen causing meningoencephalitis. The recruitment depends primarily on the interaction of VCAM1 expressed on the brain endothelium with VLA4 expressed on Ly6Clow monocytes. Furthermore, TNFR signaling is essential for the recruitment through enhancing VLA4 expression on Ly6Clow monocytes. Interestingly, the recruited Ly6Clow monocytes internalized C. neoformans and carried the organism while crawling on and adhering to the luminal wall of brain vasculature and migrating to the brain parenchyma. Our study reveals a substantial recruitment of Ly6Clow monocytes to the brain and highlights important properties of this subset during infection.


Assuntos
Criptococose/imunologia , Monócitos/imunologia , Molécula 1 de Adesão de Célula Vascular/metabolismo , Animais , Encéfalo/imunologia , Criptococose/metabolismo , Cryptococcus neoformans/metabolismo , Cryptococcus neoformans/patogenicidade , Modelos Animais de Doenças , Feminino , Integrina alfa4beta1/metabolismo , Masculino , Meningoencefalite/metabolismo , Meningoencefalite/microbiologia , Camundongos , Camundongos Endogâmicos C57BL , Monócitos/metabolismo , Micoses/metabolismo , Receptores do Fator de Necrose Tumoral/metabolismo , Transdução de Sinais
5.
Ann N Y Acad Sci ; 1460(1): 43-56, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31423598

RESUMO

Type 1 diabetes mellitus (T1DM) is an autoimmune disease characterized by insulin deficiency, and patients with diabetes have an increased risk of bone fracture and significantly impaired fracture healing. Proinflammatory cytokine tumor necrosis factor-alpha is significantly upregulated in diabetic fractures and is believed to underlie delayed fracture healing commonly observed in diabetes. Our previous genetic screen for the binding partners of progranulin (PGRN), a growth factor-like molecule that induces chondrogenesis, led to the identification of tumor necrosis factor receptors (TNFRs) as the PGRN-binding receptors. In this study, we employed several in vivo models to ascertain whether PGRN has therapeutic effects in diabetic fracture healing. Here, we report that deletion of PGRN significantly delayed bone fracture healing and aggravated inflammation in the fracture models of mice with T1DM. In contrast, recombinant PGRN effectively promoted diabetic fracture healing by inhibiting inflammation and enhancing chondrogenesis. In addition, both TNFR1 proinflammatory and TNFR2 anti-inflammatory signaling pathways are involved in PGRN-stimulated diabetic fracture healing. Collectively, these findings illuminate a novel understanding concerning the role of PGRN in diabetic fracture healing and may have an application in the development of novel therapeutic intervention strategies for diabetic and other types of impaired fracture healing.


Assuntos
Diabetes Mellitus Experimental/patologia , Diabetes Mellitus Tipo 1/patologia , Consolidação da Fratura/efeitos dos fármacos , Progranulinas/farmacologia , Animais , Condrogênese/efeitos dos fármacos , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Deleção de Genes , Humanos , Inflamação/patologia , Camundongos , Progranulinas/deficiência , Proteínas Proto-Oncogênicas c-akt/metabolismo , Receptores do Fator de Necrose Tumoral/metabolismo , Proteínas Recombinantes/farmacologia , Transdução de Sinais/efeitos dos fármacos , Serina-Treonina Quinases TOR/metabolismo , Fator de Necrose Tumoral alfa/metabolismo
6.
Fish Shellfish Immunol ; 96: 336-349, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31759079

RESUMO

Tumor necrosis factor receptor superfamilies (TNFRSF) are one of essential cytokines and can trigger inflammation, apoptosis, participating lymphocyte homeostasis and tissue development in vertebrates. To gain insights into the evolution and characterization of tnfr genes in lamprey, a jawless vertebrate, we performed a genome-wide and transcriptome survey and identified 7 tnfr genes in the lamprey (Lethenteron reissneri) database. Based on the molecular phylogenetic analysis, 7 L-tnfr genes are divided into three different clusters, and multiple members of tnfr genes family have appeared in lamprey. Meanwhile, protein domains and motifs analysis reveals that TNFRSF are conserved and have typical cysteine-rich domains (CRDs). Synteny results indicates that the L-tnfr neighborhood genes have taken place great changes compared to jawed vertebrates. Real-time quantitative results demonstrate that tnfr gene family plays an important role in the immune defense. This study has a new understanding for origin and evolution of the tnfr gene family in different vertebrates.


Assuntos
Evolução Molecular , Proteínas de Peixes/genética , Lampreias/genética , Família Multigênica , Receptores do Fator de Necrose Tumoral/genética , Animais , Lampreias/metabolismo , Filogenia , Sintenia , Transcriptoma
7.
Dis Markers ; 2019: 8154926, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31827644

RESUMO

The cancer stem cell model is considered as a putative cause of resistance to chemotherapy and disease recurrence in malignant tumors. In this study, we tested the hypothesis that the response to neoadjuvant/perioperative chemotherapy correlates with the expression of four different putative cancer stem cell markers of gastric cancer (GC), i.e., LGR5, FZD7, TROY, and MIST1. The expression of LGR5, FZD7, TROY, and MIST1 was assessed by immunohistochemistry in 119 perioperatively treated GCs including pretherapeutic biopsies, resected primary GCs, and corresponding nodal and distant metastases. All four markers were detected in our cohort with variable prevalence and histoanatomical distributions. Few tumor cells expressed TROY. LGR5, FZD7, and MIST1 were coexpressed in 41.2% and completely absent in 6.2%. The prevalence of LGR5- and FZD7-positive GCs was higher and of TROY-positive GCs lower in perioperatively treated GCs compared with treatment-naïve tumors. LGR5, FZD7, and MIST1 in the primary tumors correlated significantly with their expression in the corresponding lymph node metastasis. An increased expression of LGR5 in primary GC correlated significantly with tumor regression. The expression of MIST1 in lymph node metastases correlated significantly with the number of lymph node metastases as well as overall and tumor-specific survival. FZD7 did not correlate with any clinicopathological patient characteristic. Our study on clinical patient samples shows that GCs may coexpress independently different stem cell markers; that neoadjuvant/perioperative treatment of GC significantly impacts on the expression of stem cell markers, which cannot be predicted by the analysis of pretherapeutic biopsies; and that their expression and tumor biological effect are heterogeneous and have to be viewed as a function of histoanatomical distribution.


Assuntos
Adenocarcinoma/secundário , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Receptores Frizzled/metabolismo , Receptores Acoplados a Proteínas-G/metabolismo , Receptores do Fator de Necrose Tumoral/metabolismo , Neoplasias Gástricas/patologia , Adenocarcinoma/tratamento farmacológico , Adenocarcinoma/metabolismo , Biomarcadores Tumorais/metabolismo , Quimioterapia Adjuvante/mortalidade , Estudos de Coortes , Feminino , Seguimentos , Humanos , Metástase Linfática , Masculino , Pessoa de Meia-Idade , Terapia Neoadjuvante/mortalidade , Células-Tronco Neoplásicas/efeitos dos fármacos , Células-Tronco Neoplásicas/metabolismo , Células-Tronco Neoplásicas/patologia , Assistência Perioperatória , Prognóstico , Neoplasias Gástricas/tratamento farmacológico , Neoplasias Gástricas/metabolismo , Taxa de Sobrevida
8.
Physiol Rep ; 7(24): e14315, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31872577

RESUMO

BACKGROUND: The immune system generates inflammatory responses through cytokines like Interleukin 6 (IL-6) and the Tumor Necrosis Factor alpha (TNF α); these cytokines mediate cellular responses aided by the presence of soluble receptors such as: Soluble Interleukin 6 Receptor (sIL6R) and Soluble Tumor Necrosis Factor Receptors Type 1 and 2 (sTNFR1, sTNFR2); the literature is limited about the relationship between this cytokines and the role of its soluble receptors. OBJECTIVES: This study is to determine a possible relationship between specific inflammatory markers and their soluble receptors with the autonomic nervous system's activity and body composition. METHODS: 27 subjects (13 men of 19.3 ± 1.6 years old and 14 women of 19.1 ± 1.7 years old) were evaluated. Body composition, autonomic nervous system activity and plasma concentration of inflammatory markers IL-6, TNF α, sIL6R, sTNFR1 and sTNFR2 were measured using bio-impedance, heart rate variability and ELISA respectively. RESULTS: A positive association between body-fat percentage and the sIL6R (0.47, p = .013) as well as inverse relationship between muscular mass and the sIL6R (-0.45, p = .019) were found. The sIL6R was also positively correlated with sympathetic activity markers: Relation LF/HF (0.52, p = .006), cardiac sympathetic index (0.45, p = .008), and cardiac vagal index (-0.44, p = .022). CONCLUSION: This study suggested that the IL-6 trans-signaling involving both the soluble receptor, sIL6R, and gp130 membrane co-receptor could produce inflammatory responses that generate an impact on the autonomic nervous system, possibly due to its direct action on the hypothalamus, the solitary tract nucleus, or the heart.


Assuntos
Sistema Nervoso Autônomo/fisiologia , Composição Corporal , Receptores de Interleucina-6/sangue , Adolescente , Feminino , Humanos , Interleucina-6/sangue , Masculino , Receptores do Fator de Necrose Tumoral/sangue , Fator de Necrose Tumoral alfa/sangue , Adulto Jovem
9.
Reprod Biol ; 19(4): 329-339, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31757605

RESUMO

During an inflammatory process of the testis, the network of somatic, immune, and germ cell interactions is altered leading to organ dysfunction. In testicular biopsies of infertile men, spermatogenesis impairment is associated with reduced spermatogonia proliferation, increased number of immune cells, and content of pro-inflammatory cytokines. TNFα-TNFR and nitric oxide (NO)-NO synthase systems are up-regulated in models of testicular damage and in human testis with maturation arrest. The purpose of this study was to test the hypothesis that TNFα-TNFR system and NO alter the function of spermatogonia in the inflamed testis. We studied the effect of TNFα and NO on GC-1 spermatogonia cell cycle progression and death by flow cytometry. GC-1 cells expressed TNFR1 and TNFR2 (immunofluorescence). TNFα (10 and 50 ng/ml) and DETA-Nonoate (0.5 and 2 mM), a NO releaser, increased the percentage of cells in S-phase of the cell cycle and reduced the percentage in G1, inducing also cell apoptosis. TNFα effect was not mediated by oxidative stress unlike NO, since the presence of N-acetyl-l-cysteine (2.5 and 5.0 mM) prevented NO induced cell cycle arrest and death. GC-1 spermatogonia overpass NO induced cell cycle arrest but no TNFα, since after removal of NO, spermatogonia progressed through the cell cycle. We propose TNFα and NO might contribute to impairment of spermatogenesis by preventing adequate functioning of the spermatogonia population. Our results showed that TNFα and NO impaired spermatogonia cell cycle, inducing GC-1 arrest in the S phase.


Assuntos
Inflamação/fisiopatologia , Óxido Nítrico/fisiologia , Espermatogônias/fisiologia , Fator de Necrose Tumoral alfa/fisiologia , Apoptose , Ciclo Celular , Linhagem Celular , Humanos , Masculino , Estresse Oxidativo , Receptores do Fator de Necrose Tumoral/metabolismo , Espermatogênese
10.
Adv Exp Med Biol ; 1189: 53-84, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31758531

RESUMO

Costimulatory signals initiated by the interaction between the tumor necrosis factor (TNF) ligand and cognate TNF receptor (TNFR) superfamilies promote clonal expansion, differentiation, and survival of antigen-primed CD4+ and CD8+ T cells and have a pivotal role in T-cell-mediated adaptive immunity and diseases. Accumulating evidence in recent years indicates that costimulatory signals via the subset of the TNFR superfamily molecules, OX40 (TNFRSF4), 4-1BB (TNFRSF9), CD27, DR3 (TNFRSF25), CD30 (TNFRSF8), GITR (TNFRSF18), TNFR2 (TNFRSF1B), and HVEM (TNFRSF14), which are constitutive or inducible on T cells, play important roles in protective immunity, inflammatory and autoimmune diseases, and tumor immunotherapy. In this chapter, we will summarize the findings of recent studies on these TNFR family of co-signaling molecules regarding their function at various stages of the T-cell response in the context of infection, inflammation, and cancer. We will also discuss how these TNFR co-signals are critical for immune regulation and have therapeutic potential for the treatment of T-cell-mediated diseases.


Assuntos
Receptores do Fator de Necrose Tumoral/metabolismo , Transdução de Sinais , Linfócitos T/citologia , Fator de Necrose Tumoral alfa/metabolismo , Humanos , Imunoterapia , Ativação Linfocitária , Neoplasias
11.
Adv Exp Med Biol ; 1189: 85-133, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31758532

RESUMO

T-cell receptor (TCR)-mediated antigen-specific stimulation is essential for initiating T-cell activation. However, signaling through the TCR alone is not sufficient for inducing an effective response. In addition to TCR-mediated signaling, signaling through antigen-independent co-stimulatory or co-inhibitory receptors is critically important not only for the full activation and functional differentiation of T cells but also for the termination and suppression of T-cell responses. Many studies have investigated the signaling pathways underlying the function of each molecular component. Co-stimulatory and co-inhibitory receptors have no kinase activity, but their cytoplasmic region contains unique functional motifs and potential phosphorylation sites. Engagement of co-stimulatory receptors leads to recruitment of specific binding partners, such as adaptor molecules, kinases, and phosphatases, via recognition of a specific motif. Consequently, each co-stimulatory receptor transduces a unique pattern of signaling pathways. This review focuses on our current understanding of the intracellular signaling pathways provided by co-stimulatory and co-inhibitory molecules, including B7:CD28 family members, immunoglobulin, and members of the tumor necrosis factor receptor superfamily.


Assuntos
Antígenos CD28/metabolismo , Ativação Linfocitária , Receptores de Antígenos de Linfócitos T/metabolismo , Transdução de Sinais , Linfócitos T/citologia , Humanos , Imunoglobulinas/metabolismo , Receptores do Fator de Necrose Tumoral/metabolismo
12.
Sci Signal ; 12(605)2019 10 29.
Artigo em Inglês | MEDLINE | ID: mdl-31662485

RESUMO

iRhom2 is an essential cofactor for ADAM17, the metalloprotease that sheds both the proinflammatory cytokine tumor necrosis factor-α (TNF-α) and TNF receptors (TNFRs) from the cell surface. In this issue of Science Signaling, Sundaram et al. demonstrate a protective role for iRhom2 in promoting ADAM17-mediated shedding of TNFRs in hepatic stellate cells, which reduces TNFR signaling and liver fibrosis in response to injury.


Assuntos
Colestase , Receptores do Fator de Necrose Tumoral , Proteína ADAM17 , Humanos , Cirrose Hepática , Transdução de Sinais , Fator de Necrose Tumoral alfa
13.
J Immunol ; 203(7): 1766-1775, 2019 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-31484730

RESUMO

Proinflammatory macrophages and miR-155 are increased in patients with rheumatoid arthritis (RA). We studied membrane TNF (mTNF) expression on blood monocytes, polarization into macrophages, miR-155 expression, and the effect of anti-TNF on these biomarkers in RA patients. Sixty-seven RA patients and 109 controls (55 healthy, 54 with spondyloarthritis and connective tissue diseases) were studied. Monocytes were isolated and differentiated into macrophages with or without anti-TNF. mTNF expression was increased on monocytes from RA patients, but not from other inflammatory diseases, correlated with disease activity. Under human serum AB or M-CSF, only monocytes from RA had a defect of differentiation into M2-like macrophages and had a propensity for preferential maturation toward M1-like macrophages that contributed to synovial inflammation. This defect was correlated to mTNF expression and was partially reversed by monoclonal anti-TNF Abs but not by the TNF soluble receptor. miR-155 was increased in M2-macrophages except in adalimumab-treated patients. Transfection of healthy monocytes with miR-155 induced a decrease in M2-like markers, and transfection of RA monocytes with antagomir-155 allowed restoration of M2-like polarization. Defect in differentiation of monocytes into M2-like-macrophages linked to increased miR-155 and correlated with increased mTNF on monocytes could play a key role in RA pathogenesis. Monoclonal anti-TNF Abs but not the TNF soluble receptor partially restored this defect.


Assuntos
Artrite Reumatoide/imunologia , Diferenciação Celular/imunologia , Ativação de Macrófagos , Macrófagos/imunologia , MicroRNAs/imunologia , Monócitos/imunologia , Adulto , Idoso , Antirreumáticos/administração & dosagem , Artrite Reumatoide/tratamento farmacológico , Artrite Reumatoide/patologia , Feminino , Humanos , Macrófagos/patologia , Masculino , Pessoa de Meia-Idade , Monócitos/patologia , Receptores do Fator de Necrose Tumoral/imunologia , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Fator de Necrose Tumoral alfa/imunologia
14.
J Investig Clin Dent ; 10(4): e12469, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31541512

RESUMO

AIM: To study the expression of tumor necrosis factor-like weak inducer of apoptosis (TWEAK) and fibroblast growth factor-inducible immediate early response protein 14 (Fn14) in oral squamous cell carcinoma (OSCC), to elucidate the possible role of TWEAK-Fn14 in OSCC development. METHODS: Immunohistochemistry for TWEAK-Fn14 was performed on 61 oral mucosal samples: healthy oral mucosa (HOM; N = 15); oral dysplastic lesions (ODL; N = 15); and OSCC (N = 31). Extent of staining (ES) and immunoreactive score (IRS) were assessed. The data was statistically analyzed. RESULTS: All OSCC expressed TWEAK, and the Fn14 expression was noted in 90% of OSCC. A significant difference in the TWEAK and Fn14 expression was noted among the groups. ES and IRS of TWEAK-Fn14 significantly increased in OSCC compared with ODL and HOM. ES of TWEAK was significantly higher than Fn14 in all 3 groups. ES of TWEAK-Fn14 was significantly higher at the invasive tumor front (ITF) than in the whole tumor. TWEAK-Fn14 showed a significant association with clinicopathological parameters of prognostic significance. CONCLUSION: Findings suggest that TWEAK and Fn14 may participate in the growth and progression of OSCC. Increased expression of TWEAK-Fn14 at the ITF may facilitate increased proliferation, altered differentiation and invasion.


Assuntos
Carcinoma de Células Escamosas , Neoplasias Bucais , Apoptose , Fatores de Crescimento de Fibroblastos , Humanos , Receptores do Fator de Necrose Tumoral , Receptor de TWEAK
15.
Int J Mol Sci ; 20(18)2019 Sep 11.
Artigo em Inglês | MEDLINE | ID: mdl-31514326

RESUMO

In mammals, leptin and tumor-necrosis factor (TNF) are prominent interacting adipokines mediating appetite control and insulin sensitivity. While TNF pleiotropically functions in immune defense and cell survival, leptin is largely confined to signaling energy stores in adipocytes. Knowledge about the function of avian leptin and TNF is limited and they are absent or lowly expressed in adipose, respectively. Employing radiation-hybrid mapping and FISH-TSA, we mapped TNF and its syntenic genes to chicken chromosome 16 within the major histocompatibility complex (MHC) region. This mapping position suggests that avian TNF has a role in regulating immune response. To test its possible interaction with leptin within the immune system and beyond, we compared the transcription patterns of TNF, leptin and their cognate receptors obtained by meta-analysis of GenBank RNA-seq data. While expression of leptin and its receptor (LEPR) were detected in the brain and digestive tract, TNF and its receptor mRNAs were primarily found in viral-infected and LPS-treated leukocytes. We confirmed leptin expression in the duodenum by immunohistochemistry staining. Altogether, we suggest that whereas leptin and TNF interact as adipokines in mammals, in birds, they have distinct roles. Thus, the interaction between leptin and TNF may be unique to mammals.


Assuntos
Galinhas/genética , Mapeamento Cromossômico , Digestão , Regulação da Expressão Gênica , Leptina/genética , Mamíferos/genética , Transdução de Sinais , Fator de Necrose Tumoral alfa/metabolismo , Animais , Linhagem Celular , Galinhas/metabolismo , Duodeno/metabolismo , Feminino , Leptina/metabolismo , Metáfase/genética , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Mapeamento de Híbridos Radioativos , Receptores para Leptina/metabolismo , Receptores do Fator de Necrose Tumoral/genética , Receptores do Fator de Necrose Tumoral/metabolismo , Sintenia/genética , Fator de Necrose Tumoral alfa/genética
16.
World Neurosurg ; 132: e99-e108, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31518751

RESUMO

BACKGROUND: High cholesterol has been correlated with a greater risk of cerebrovascular diseases. Whether pre-existing high cholesterol exacerbates traumatic brain injury (TBI), and whether treatment with the cholesterol-lowering agent simvastatin has neuroprotective effects, especially anti-neuroinflammatory effects, after TBI are not well investigated. METHODS: Five-week-old male Sprague-Dawley rats were fed a high-fat diet for 8 weeks to induce hypercholesterolemia. Anesthetized male Sprague-Dawley rats were divided into 5 groups, including the sham-operated control, TBI control, and TBI with simvastatin treatment (4 mg/kg, 10 mg/kg, or 20 mg/kg) groups. Simvastatin was intraperitoneally injected at 0, 24, and 48 hours after TBI. Motor function was measured using an inclined plane. Neuronal apoptosis (maker Neu-N, terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling), tumor necrosis factor-α expression in microglia (marker OX42) and astrocytes (marker glial fibrillary acidic protein), and Tumor necrosis factor-alpha receptor (TNFR) 1 and TNFR2 expression in neurons in the ischemic cortex were investigated using an immunofluorescence assay. All of the parameters were measured on the third day after TBI. RESULTS: TBI significantly increased the serum levels of cholesterol. The TBI-induced motor deficit was significantly attenuated by 4, 10, and 20 mg/kg simvastatin therapy on the third day after TBI. TBI-induced neuronal TNFR1 activation and apoptosis, as well as tumor necrosis factor-α expression in astrocytes in the ischemic cortex, were significantly attenuated by simvastatin, particularly when 20 mg/kg was administered. Simultaneously, the serum cholesterol remained high despite simvastatin treatment. CONCLUSIONS: The neuroprotection effects of simvastatin on the pre-existing hypercholesterolemia during TBI in rats may be related to its anti-neuroinflammatory effects but not to its cholesterol-lowing effects.


Assuntos
Anticolesterolemiantes/uso terapêutico , Lesões Encefálicas Traumáticas/complicações , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Hipercolesterolemia/tratamento farmacológico , Hipercolesterolemia/etiologia , Fármacos Neuroprotetores/uso terapêutico , Sinvastatina/uso terapêutico , Animais , Lesões Encefálicas Traumáticas/psicologia , Colesterol/sangue , Ativação de Macrófagos/efeitos dos fármacos , Masculino , Desempenho Psicomotor/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Receptores do Fator de Necrose Tumoral/biossíntese , Fator de Necrose Tumoral alfa/sangue
17.
Oncogene ; 38(49): 7433-7446, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31427736

RESUMO

The ligands for the natural killer group 2 (NKG2D) protein render tumor cells susceptible to NKG2D-dependent immune cell attack. However, cancer cells escape from immune surveillance by downregulating NKG2D ligands. We previously discovered that engagement of activated CD8+ T cells and tumor cells induces NKG2D ligands on tumor cells, but the underlying mechanism remains to be defined. Both in vivo mouse tumor models and in vitro cell assays were performed to study the downstream signaling. Our results supported the notion that, upon engagement with the cognate receptors, CD137 ligand and CD40 initiates activation of nuclear factor-kappa B (NF-κB) signaling in tumor cells even in the absence of CD8+ T cells. Like tumor and CD8+ T cell contact-dependent NKG2D ligand induction, this CD137L/CD40-mediated signaling activation was associated with elevated levels of acetyltransferase P300/CBP-associated factor (PCAF), whereas inhibition of phosphorylated NF-κB abrogated PCAF induction. Although stimulation of CD137L/CD40-mediated signaling is vital, inflammatory cytokines, including interferon gamma (IFNγ) and TNFα, also facilitate NKG2D ligand-induced immune surveillance via both facilitating T-cell chemotaxis and CD137L/CD40 induced NF-κB/PCAF activation. Collectively, our results unveil a novel mechanism of NKG2D ligand upregulation involving reverse signaling of CD40 and CD137L on tumor cells which, along with inflammatory cytokines IFNγ and TNFα, stimulate downstream NF-κB and PCAF activation. Understanding this mechanism may help in development of induced NKG2D ligand-dependent T-cell therapy against cancers.


Assuntos
Linfócitos T CD8-Positivos/imunologia , NF-kappa B/metabolismo , Subfamília K de Receptores Semelhantes a Lectina de Células NK/metabolismo , Neoplasias/imunologia , Neoplasias/metabolismo , Fatores de Transcrição de p300-CBP/metabolismo , Animais , Linfócitos T CD8-Positivos/metabolismo , Citocinas/metabolismo , Humanos , Células Matadoras Naturais/imunologia , Células Matadoras Naturais/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , NF-kappa B/genética , Subfamília K de Receptores Semelhantes a Lectina de Células NK/genética , Neoplasias/genética , Proteínas Associadas à Matriz Nuclear/genética , Proteínas Associadas à Matriz Nuclear/metabolismo , Proteínas de Transporte Nucleocitoplasmático/genética , Proteínas de Transporte Nucleocitoplasmático/metabolismo , Receptores do Fator de Necrose Tumoral/genética , Receptores do Fator de Necrose Tumoral/metabolismo , Transdução de Sinais , Células Tumorais Cultivadas , Fatores de Transcrição de p300-CBP/genética
18.
Commun Biol ; 2: 317, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31453381

RESUMO

There is a growing interest in therapeutically targeting the inflammatory response that underlies age-related chronic diseases including obesity and type 2 diabetes. Through integrative small RNA sequencing, we show the presence of conserved plant miR159a and miR156c in dried nuts having high complementarity with the mammalian TNF receptor superfamily member 1a (Tnfrsf1a) transcript. We detected both miR159a and miR156c in exosome-like nut nanovesicles (NVs) and demonstrated that such NVs reduce Tnfrsf1a protein and dampen TNF-α signaling pathway in adipocytes. Synthetic single-stranded microRNAs (ss-miRs) modified with 2'-O-methyl group function as miR mimics. In plants, this modification naturally occurs on nearly all small RNAs. 2'-O-methylated ss-miR mimics for miR156c and miR159a decreased Tnfrsf1a protein and inflammatory markers in hypertrophic as well as TNF-α-treated adipocytes and macrophages. miR156c and miR159a mimics effectively suppress inflammation in mice, highlighting a potential role of plant miR-based, single-stranded oligonucleotides in treating inflammatory-associated metabolic diseases.


Assuntos
Adipócitos/metabolismo , Dessecação , Nozes/genética , RNA de Plantas/genética , Receptores do Fator de Necrose Tumoral/metabolismo , Células 3T3-L1 , Adipócitos/efeitos dos fármacos , Tecido Adiposo/patologia , Animais , Citocinas/metabolismo , Feminino , Regulação da Expressão Gênica de Plantas/efeitos dos fármacos , Glucose/metabolismo , Células HEK293 , Humanos , Hipertrofia , Inflamação/genética , Inflamação/patologia , Insulina/farmacologia , Camundongos , Camundongos Endogâmicos C57BL , MicroRNAs/genética , MicroRNAs/metabolismo , Nanopartículas/química , Nanopartículas/ultraestrutura , Células RAW 264.7 , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , RNA de Plantas/metabolismo
19.
Prostate ; 79(14): 1589-1596, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31376183

RESUMO

BACKGROUND: Molecular studies have tried to address the unmet need for prognostic biomarkers in prostate cancer (PCa). Some gene expression tests improve upon clinical factors for prediction of outcomes, but additional tools for accurate prediction of tumor aggressiveness are needed. METHODS: Based on a previously published panel of 23 gene transcripts that distinguished patients with metastatic progression, we constructed a prediction model using independent training and testing datasets. Using the validated messenger RNAs and Gleason score (GS), we performed model selection in the training set to define a final locked model to classify patients who developed metastatic-lethal events from those who remained recurrence-free. In an independent testing dataset, we compared our locked model to established clinical prognostic factors and utilized Kaplan-Meier curves and receiver operating characteristic analyses to evaluate the model's performance. RESULTS: Thirteen of 23 previously identified gene transcripts that stratified patients with aggressive PCa were validated in the training dataset. These biomarkers plus GS were used to develop a four-gene (CST2, FBLN1, TNFRSF19, and ZNF704) transcript (4GT) score that was significantly higher in patients who progressed to metastatic-lethal events compared to those without recurrence in the testing dataset (P = 5.7 × 10-11 ). The 4GT score provided higher prediction accuracy (area under the ROC curve [AUC] = 0.76; 95% confidence interval [CI] = 0.69-0.83; partial area under the ROC curve [pAUC] = 0.008) than GS alone (AUC = 0.63; 95% CI = 0.56-0.70; pAUC = 0.002), and it improved risk stratification in subgroups defined by a combination of clinicopathological features (ie, Cancer of the Prostate Risk Assessment-Surgery). CONCLUSION: Our validated 4GT score has prognostic value for metastatic-lethal progression in men treated for localized PCa and warrants further evaluation for its clinical utility.


Assuntos
Biomarcadores Tumorais/genética , Proteínas de Ligação ao Cálcio/genética , Metástase Neoplásica/genética , Neoplasias da Próstata/genética , Receptores do Fator de Necrose Tumoral/genética , Cistatinas Salivares/genética , Fatores Genéricos de Transcrição/genética , Idoso , Humanos , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Metástase Neoplásica/patologia , Prognóstico , Neoplasias da Próstata/patologia , RNA Mensageiro/análise , Curva ROC , Medição de Risco , Sensibilidade e Especificidade
20.
Commun Biol ; 2: 293, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31396573

RESUMO

The tumour necrosis factor alpha (TNFα) superfamily of proteins are critical in numerous biological processes, such as in development and immunity. Eiger is the sole TNFα member described in arthropods such as in the important model organism Drosophila. To date there are no structural data on any Eiger protein. Here we present the structure of the TNF domain of Eiger from the fall armyworm Spodoptera frugiperda (SfEiger) to 1.7 Å from a serendipitously obtained crystal without prior knowledge of the protein sequence. Our structure confirms that canonical trimerization is conserved from ancestral TNFs and points towards a mode of receptor engagement. Furthermore, we observe numerous surface histidines on SfEiger, potentially acting as pH switches following internalization into endosomes. Our data contributes to the genome annotation of S. frugiperda, a voracious agricultural pest, and can serve as a basis for future structure-function investigations of the TNF system in related arthropods such as Drosophila.


Assuntos
Endossomos/metabolismo , Proteínas de Insetos/metabolismo , Receptores do Fator de Necrose Tumoral/metabolismo , Spodoptera/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Animais , Cristalografia por Raios X , Proteínas de Insetos/química , Simulação de Dinâmica Molecular , Conformação Proteica , Receptores do Fator de Necrose Tumoral/química , Transdução de Sinais , Relação Estrutura-Atividade , Propriedades de Superfície , Fator de Necrose Tumoral alfa/química
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