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1.
Cancer Treat Rev ; 88: 102058, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32619864

RESUMO

Soft tissue sarcomas constitute 1% of adult malignant tumors. They are a heterogeneous group of more than 50 different histologic types. Isolated limb perfusion is an established treatment strategy for locally advanced sarcomas. Since its adoption for sarcomas in 1992, after the addition of TNFα, few modifications have been done and although indications for the procedure are essentially the same across centers, technical details vary widely. The procedures mainly involves a 60 min perfusion with melphalan and TNFα under mild hyperthermia, achieving a limb preservation rate of 72-96%; with an overall response rates from 72 to 82.5% and an acceptable toxicity according to the Wieberdink scale. The local failure rate is 27% after a median follow up of 14-31 months compared to 40% of distant recurrences after a follow up of 12-22 months. Currently there is no consensus regarding the benefit of ILP per histotype, and the value of addition of radiotherapy or systemic treatment. Further developments towards individualized treatments will provide a better understanding of the population that can derive maximum benefit of ILP with the least morbidity.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Quimioterapia do Câncer por Perfusão Regional/métodos , Sarcoma/tratamento farmacológico , Neoplasias de Tecidos Moles/tratamento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Quimioterapia do Câncer por Perfusão Regional/efeitos adversos , Quimioterapia do Câncer por Perfusão Regional/tendências , Ensaios Clínicos Fase II como Assunto , Extremidades/irrigação sanguínea , Extremidades/patologia , Humanos , Hipertermia Induzida/métodos , Melfalan/administração & dosagem , Melfalan/efeitos adversos , Ensaios Clínicos Controlados Aleatórios como Assunto , Sarcoma/patologia , Neoplasias de Tecidos Moles/patologia , Fator de Necrose Tumoral alfa/administração & dosagem , Fator de Necrose Tumoral alfa/efeitos adversos
2.
Ann Rheum Dis ; 79(5): 566-572, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32161058

RESUMO

OBJECTIVES: To investigate whether tumour necrosis factor alpha inhibitors (TNFis) are associated with an increased risk of neuroinflammatory diseases among patients with arthritic diseases. METHODS: Cohorts of patients with rheumatoid arthritis (RA, n=25 796), psoriatic arthritis (PsA, n=8586) and ankylosing spondylitis (AS, n=9527) who initiated a TNFi treatment year 2000-2017 were identified from nationwide clinical rheumatology registers in Sweden and Denmark. Information on demyelinating disease and inflammatory neuropathy diagnoses was retrieved from prospective linkage to National Patients Register. A Cox proportional hazard model was used to estimate HRs and 95% CI comparing TNFi exposed and non-exposed, by disease and country. RESULTS: Among 111 455 patients with RA, we identified 270 (Sweden) and 51 (Denmark) events (all types of neuroinflammatory diseases combined), corresponding to crude incidence rates (per 1000 person-years) of 0.37 (Sweden) and 0.39 (Denmark) in TNFi-treated patients vs 0.39 (Sweden) and 0.28 (Denmark) in unexposed patients, and an age-sex-calendar-period-adjusted HR (95% CI) of 0.97 (0.72 to 1.33) (Sweden) and 1.45 (0.74 to 2.81) (Denmark) in TNFi exposed compared with non-exposed patients. For a total of 64 065 AS/PsA patients, the corresponding numbers were: 196 and 32 events, crude incidence rates of 0.59 and 0.87 in TNFi-treated patients vs 0.40 and 0.19 in unexposed patients, and HRs of 1.50 (1.07 to 2.11) and 3.41 (1.30 to 8.96), for Sweden and Denmark, respectively. For multiple sclerosis, the patterns of HRs were similar. CONCLUSIONS: Use of TNFi in AS/PsA, but not in RA, was associated with increased risk of incident neuroinflammatory disease, though the absolute risk was below one in 1000 patients/year.


Assuntos
Artrite Psoriásica/tratamento farmacológico , Artrite Reumatoide/tratamento farmacológico , Doenças Desmielinizantes/induzido quimicamente , Sistema de Registros , Espondilite Anquilosante/tratamento farmacológico , Inibidores do Fator de Necrose Tumoral/efeitos adversos , Idoso , Artrite Psoriásica/diagnóstico , Artrite Reumatoide/diagnóstico , Estudos de Coortes , Doenças Desmielinizantes/epidemiologia , Dinamarca , Feminino , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Doenças do Sistema Nervoso/induzido quimicamente , Doenças do Sistema Nervoso/epidemiologia , Prognóstico , Modelos de Riscos Proporcionais , Estudos Retrospectivos , Medição de Risco , Espondilite Anquilosante/diagnóstico , Suécia , Inibidores do Fator de Necrose Tumoral/administração & dosagem , Fator de Necrose Tumoral alfa/efeitos adversos , Fator de Necrose Tumoral alfa/antagonistas & inibidores
3.
Internist (Berl) ; 61(3): 313-320, 2020 Mar.
Artigo em Alemão | MEDLINE | ID: mdl-31965234

RESUMO

A 78-year-old woman with rheumatoid arthritis on TNF-α inhibitor, methotrexate and prednisolone presented with severe but unspecific symptoms such as leg weakness, shivering, bifrontal headache, nausea and staggering. The broad range of differential diagnoses lead to intricate and time-consuming diagnostic procedures. Serology, magnetic resonance imaging and microbiological investigations represent important steps to make the final diagnosis of cerebral toxoplasmosis. Both diagnostic approach and therapy require close cooperation of different disciplines. Therapies of rheumatoid arthritis as well as of toxoplasmosis are based on a long-term treatment and could be associated with numerous harmful side effects. Continuous monitoring and permanent adjustment of therapy regimes are therefore mandatory.


Assuntos
Antirreumáticos/uso terapêutico , Artrite Reumatoide/tratamento farmacológico , Encéfalo/diagnóstico por imagem , Imunossupressores/uso terapêutico , Metotrexato/uso terapêutico , Infecções Oportunistas/diagnóstico , Prednisolona/uso terapêutico , Toxoplasmose Cerebral/diagnóstico , Fator de Necrose Tumoral alfa/uso terapêutico , Idoso , Antirreumáticos/efeitos adversos , Encéfalo/fisiopatologia , Diagnóstico Diferencial , Quimioterapia Combinada , Feminino , Humanos , Imunossupressores/efeitos adversos , Imagem por Ressonância Magnética/métodos , Metotrexato/efeitos adversos , Prednisolona/efeitos adversos , Toxoplasmose Cerebral/diagnóstico por imagem , Toxoplasmose Cerebral/imunologia , Toxoplasmose Cerebral/patologia , Resultado do Tratamento , Fator de Necrose Tumoral alfa/efeitos adversos
4.
Support Care Cancer ; 28(2): 531-540, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31076897

RESUMO

PURPOSE: Radiotherapy (RTH) usually combined with chemotherapy (C-RTH) is the main method of treatment in head and neck cancer (HNC). The most common complication of RTH is oral mucositis (OM). At a certain stage of RTH, it occurs in almost all patients, often lead to discontinuation of treatment. Tumour necrosis factor alpha (TNF-α) is a cytokine secreted during inflammatory process accompanying RTH and the development of cancer itself. Single nucleotide polymorphism (SNP) of the TNF-α promoter region can potentially affect the function or expression of this cytokine, and thus modulate the risk of occurrence and intensity of OM and shortening of overall survival (OS). METHODS: The study group consisted of 62 patients with HNC in whom intensity-modulated radiation therapy (IMRT) technique was applied. The plasma TNF-α level was assessed using the ELISA Kit. Genotyping was performed using a real-time PCR method. RESULTS: HNC patients with the CC genotype of TNF-α (- 1211 T > C) have higher TNF-α plasma concentrations than those with T allele (10.70 vs 9.62 ng/ml). Patients with the 3rd degree of OM have significantly higher TNF-α levels after 5th (10.40 vs 9.45 ng/ml) and 7th (10.32 vs 9.60 ng/ml) week of RTH. CC genotype was related to a higher risk of 3rd degree OM development in the last weeks of RTH (5th, OR = 7.33; 7th, OR = 23.15). CONCLUSIONS: High TNF-α plasma concentration and CC genotype of TNF-α are related to the higher risk of more severe OM in patients irradiated due to HNC. High TNF-α plasma concentration and CC genotype of TNF-α are independent prognostic factors for patients subjected to RTH due to HNC.


Assuntos
Neoplasias de Cabeça e Pescoço/complicações , Neoplasias de Cabeça e Pescoço/diagnóstico por imagem , Neoplasias de Cabeça e Pescoço/genética , Polimorfismo de Nucleotídeo Único/genética , Regiões Promotoras Genéticas/genética , Radioterapia de Intensidade Modulada/métodos , Estomatite/etiologia , Fator de Necrose Tumoral alfa/efeitos adversos , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Análise de Sobrevida
5.
Phytother Res ; 34(2): 409-417, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31667906

RESUMO

Type 1 diabetes mellitus (T1DM) is a systemic disease and one classical type of total DM. Bilobalide (BB) is constituted of EGb 761. Our purpose was identifying the role of BB in TIDM in the current study. MIN6 cells were treated by TNF-α; then, viability, apoptosis, and insulin secretion were assessed by performing Cell Counting Kit-8 assay, flow cytometry, glucose-stimulated insulin secretion assay, and western blot. The effects of BB were assessed to identify its function. Further, the above mentioned parameters were reassessed when silencing miR-153. TNF-α declined viability and insulin secretion as well as raised apoptosis and inducible nitric oxide synthase (iNOS) expression in MIN6 cells. BB alleviated the apoptosis and dysfunction induced by TNF-α. MiR-153 expression was elevated by BB when induced by TNF-α. Increase of viability and insulin secretion as well as decline of apoptosis and iNOS induced by BB treatment was alleviated by silencing miR-153. The rates of p/t-p70S6K, p/t-mammalian target of rapamycin (mTOR) and p/t-adenosine monophosphate-activated protein kinase (AMPK) were raised by BB and suppressed by silencing miR-153 under TNF-α induced condition. BB raised viability and insulin secretion, declined apoptosis and iNOS expression by up-regulating miR-153. Furthermore, BB activated AMPK/mTOR pathway by up-regulating miR-153.


Assuntos
Apoptose/efeitos dos fármacos , Ciclopentanos/farmacologia , Furanos/farmacologia , Ginkgolídeos/farmacologia , Insulina/análise , MicroRNAs/metabolismo , Animais , Linhagem Celular Tumoral , Camundongos , Óxido Nítrico Sintase Tipo II/metabolismo , Proteínas Quinases S6 Ribossômicas 70-kDa/metabolismo , Transdução de Sinais/efeitos dos fármacos , Serina-Treonina Quinases TOR/metabolismo , Ativação Transcricional , Fator de Necrose Tumoral alfa/efeitos adversos , Regulação para Cima
6.
Arch Oral Biol ; 109: 104584, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31630006

RESUMO

OBJECTIVES: To investigate whether rutin could protect human periodontal ligament stem cells (hPDLSCs) from TNF-α induced damage to osteogenic differentiation in inflammatory environment and detect the underlying mechanism. MATERIALS AND METHODS: hPDLSCs were identified by flow cytometery. TNF-α was used to stimulate hPDLSCs to establish an inflammation model in vitro. Alkaline phosphatase (ALP) staining, ALP activity test, and Alizarin Red staining were used to detect the changes of osteogenic differentiation ability. The mRNA and protein levels of osteogenic genes were evaluated by RT-PCR and Western Blot. The expression of mTOR was also detected by Western Blot. RESULTS: hPDLSCs were positive to MSCs specific surface markers. The inflammatory environment in vitro could be established by stimulating hPDLSCs with TNF-α (20 ng/mL). TNF-α (20 ng/mL) could decrease the ALP activity and mineralization ability of hPDLSCs and down-regulate the expression of osteogenic genes in inflammatory environment. Moreover, rutin could affect TNF-α (20 ng/mL) induced damage to osteogenic differentiation of hPDLSCs in a dose-dependent manner, 10 µmol/L rutin could significantly reverse the damage caused by TNF-α. In addition, rutin inhibited TNF-α-activated mTOR signal transduction by inhibiting the phosphorylation of mTOR, similar to the effects of rapamycin(a specific mTOR inhibitor). CONCLUSIONS: Rutin could protect hPDLSCs from TNF-α induced damage to osteogenic differentiation in inflammatory environment, and rutin is expected to become a new candidate drug for the treatment of bone defect of periodontitis.


Assuntos
Osteogênese , Ligamento Periodontal/citologia , Rutina/farmacologia , Transdução de Sinais , Células-Tronco/efeitos dos fármacos , Serina-Treonina Quinases TOR/metabolismo , Fator de Necrose Tumoral alfa/efeitos adversos , Fosfatase Alcalina/metabolismo , Diferenciação Celular , Células Cultivadas , Humanos , Inflamação , Células-Tronco/citologia
8.
Mayo Clin Proc ; 94(7): 1287-1295, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31272570

RESUMO

OBJECTIVE: To investigate an association between tumor necrosis factors-alpha (TNFα) inhibitors or other immunosuppressants and the development of uveal and cutaneous melanoma. PATIENTS AND METHODS: We performed a retrospective incidence and case-control analysis of patients in Olmsted County, MN, who were diagnosed with uveal or cutaneous melanoma from January 1, 2000, to December 31, 2014. Incidence was adjusted by age and gender to the 2010 US white population. Controls were matched by sex and age to cases at time of diagnosis of melanoma. RESULTS: There were 1221 cases of melanoma (33 uveal, 1188 cutaneous). Combined incidence of uveal and cutaneous melanoma per 100,000 person-years varied by gender (male > female), age (older > younger), and time period: 2010 to 2014 (77.9, 95% confidence interval [CI], 71.1-84.7) ≈ 2005 to 2009 (78.0, 95% CI, 70.9-85.0) > 2000 to 2004 (42.5, 95% CI, 36.9-48.1, P<.001). TNFa inhibitor prescription was not associated with significantly increased risk of melanoma vs controls (1.06% vs 0.41%, P=.06). Immunosuppressive agents, high-dose corticosteroids, and topical immunosuppressants were associated with melanoma (odds ratio [OR] 1.42 CI, 1.03-1.95, 3.30 CI, 2.44-4.48, and 1.87 CI, 1.06-3.28, respectively). An increased number of patients with uveal melanoma received immune modulating agents vs controls, but this was not statistically significant (P=.36). Autoimmune disease itself was not correlated with melanoma (P=.73). CONCLUSION: Exposure to immunosuppressive agents is associated with melanoma. TNFa inhibition and autoimmune disease alone do not significantly increase risk of melanoma. In patients receiving immunosuppressive treatments, physicians should consider monitoring with dilated ophthalmic and full-body skin examinations. Further studies are needed to assess the impact of TNFa inhibitors on development of melanoma, particularly in uveal melanoma.


Assuntos
Imunossupressores/efeitos adversos , Melanoma/induzido quimicamente , Neoplasias Cutâneas/induzido quimicamente , Fator de Necrose Tumoral alfa/efeitos adversos , Neoplasias Uveais/induzido quimicamente , Idoso , Idoso de 80 Anos ou mais , Estudos de Casos e Controles , Feminino , Humanos , Incidência , Masculino , Melanoma/epidemiologia , Melanoma/patologia , Pessoa de Meia-Idade , Minnesota/epidemiologia , Estudos Retrospectivos , Fatores de Risco , Neoplasias Cutâneas/epidemiologia , Neoplasias Cutâneas/patologia , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Fator de Necrose Tumoral alfa/uso terapêutico , Neoplasias Uveais/epidemiologia , Neoplasias Uveais/patologia
9.
Phytother Res ; 33(6): 1717-1725, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31016813

RESUMO

Inflammation is considered to be one of the initial critical factors in the occurrence of calcific heart valve disease. This study was to prove Nobiletin (NBT) inhibits inflammation-caused calcification of human valve interstitial cells (hVICs) and to elucidate the involved molecular mechanisms. Tumor necrosis factor-alpha (TNF-α)-induced hVICs were treated with or without NBT. Cell growth and calcification of hVICs were assessed. RNA sequencing was utilized to investigate the gene expression changes. Molecular target prediction and docking assay were further performed. NBT interfered with hVIC growth under TNF-α condition in a dose-dependent manner also presented a gradual decrease of positive Alizarin Red S staining, down-regulation of BMP2, and RUNX2 gene expression. Based on the global gene expression cluster, control and TNF-α plus NBT group showed a high similarity versus TNF-α only group. After Venn interaction of differential expression genes (DEGs), 2,236 common DEGs were identified to display different biological functions and signaling pathways. ABCG2 and AKR1B1 were further selected as prediction targets of NBT involved in RELA, TNF, BMP2, RUNX2, etc. interactions in mediating hVIC calcification. The results show that NBT is a natural product to prevent the occurrence of heart valve calcification.


Assuntos
Estenose da Valva Aórtica/prevenção & controle , Valva Aórtica/efeitos dos fármacos , Valva Aórtica/patologia , Calcinose/prevenção & controle , Flavonas/farmacologia , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/genética , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/metabolismo , Adulto , Aldeído Redutase/genética , Aldeído Redutase/metabolismo , Valva Aórtica/metabolismo , Estenose da Valva Aórtica/genética , Estenose da Valva Aórtica/metabolismo , Estenose da Valva Aórtica/patologia , Calcinose/genética , Calcinose/metabolismo , Calcinose/patologia , Células Cultivadas , Regulação para Baixo/efeitos dos fármacos , Regulação para Baixo/genética , Feminino , Flavonas/química , Regulação da Expressão Gênica/efeitos dos fármacos , Doenças das Valvas Cardíacas/genética , Doenças das Valvas Cardíacas/metabolismo , Doenças das Valvas Cardíacas/patologia , Doenças das Valvas Cardíacas/prevenção & controle , Humanos , Simulação de Acoplamento Molecular , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética , Fator de Necrose Tumoral alfa/efeitos adversos
10.
Actual. osteol ; 15(1): 34-43, ene. abr. 2019. ilus.
Artigo em Espanhol | LILACS | ID: biblio-1049002

RESUMO

La brucelosis es una de las enfermedades zoonóticas más importantes a nivel mundial capaz de producir enfermedad crónica en los seres humanos. La localización osteoarticular es la presentación más común de la enfermedad activa en el hombre. Sin embargo, algunos de los mecanismos moleculares implicados en la enfermedad osteoarticular han comenzado a dilucidarse recientemente. Brucella abortus induce daño óseo a través de diversos mecanismos en los cuales están implicados TNF-α y RANKL. En estos procesos participan células inflamatorias que incluyen monocitos/macrófagos, neutrófilos, linfocitos T del tipo Th17 y linfocitos B. Además, B. abortus puede afectar directamente las células osteoarticulares. La bacteria inhibe la deposición de la matriz ósea por los osteoblastos y modifica el fenotipo de estas células para producir metaloproteinasas de matriz (MMPs) y la secreción de citoquinas que contribuyen a la degradación del hueso. Por otro lado, la infección por B. abortus induce un aumento en la osteoclastogénesis, lo que aumenta la resorción de la matriz ósea orgánica y mineral y contribuye al daño óseo. Dado que la patología inducida por Brucella afecta el tejido articular, se estudió el efecto de la infección sobre los sinoviocitos. Estos estudios revelaron que, además de inducir la activación de estas células para secretar quemoquinas, citoquinas proinflamatorias y MMPs, la infección inhibe la muerte por apoptosis de los sinoviocitos. Brucella es una bacteria intracelular que se replica en el retículo endoplásmico de los macrófagos. El análisis de los sinoviocitos infectados con B. abortus indicó que las bacterias también se multiplican en el retículo endoplasmático, lo que sugiere que la bacteria podría usar este tipo celular para la multiplicación intracelular durante la localización osteoarticular de la enfermedad. Los hallazgos presentados en esta revisión intentan responder a preguntas sobre los mediadores inflamatorios implicados en el daño osteoarticular causado por Brucella. (AU)


Brucellosis is one of the most important zoonotic diseases that can produce chronic disease in humans worldwide. Osteoarticular involvement is the most common presentation of human active disease. The molecular mechanisms implicated in bone damage have started to be elucidated. B. abortus induces bone damage through diverse mechanisms in which TNF-α and RANKL are implicated. These processes are driven by inflammatory cells, including monocytes/macrophages, neutrophils, Th17 lymphocytes and B cells. Also, Brucella abortus (B. abortus) can directly affect osteoarticular cells. The bacterium inhibits bone matrix deposition by osteoblast and modifies the phenotype of these cells to produce matrix methalloproteinases (MMPs) and cytokine secretion that contribute to bone matrix degradation. B. abortus also affects osteoclast increasing mineral and organic bone matrix resorption and contributing to bone damage. Since the pathology induced by Brucella species involves joint tissue, experiments conducted in sinoviocytes revealed that besides inducing the activation of these cells to secrete chemokines, proinflammatory cytokines and MMPS, the infection also inhibits sinoviocyte apoptosis. Brucella is an intracellular bacterium that replicate in the endoplasmic reticulum of macrophages. The analysis of B. abortus infected sinoviocytes indicated that bacteria also replicate in their reticulum suggesting that the bacterium could use this cell type for intracellular replication during the osteoarticular localization of the disease. The findings presented in this review try to answer key questions about the inflammatory mediators involved in osteoarticular damage caused by Brucella. (AU)


Assuntos
Humanos , Animais , Osteoartrite/patologia , Brucella abortus/patogenicidade , Brucelose/patologia , Osteoartrite/imunologia , Osteoblastos/patologia , Osteócitos/microbiologia , Osteogênese/imunologia , Brucella abortus/imunologia , Brucelose/etiologia , Brucelose/imunologia , Linfócitos B/patologia , Citocinas/efeitos adversos , Fator de Necrose Tumoral alfa/efeitos adversos , Metaloproteinases da Matriz/síntese química , Ligante RANK/efeitos adversos , Células Th17/patologia , Sinoviócitos/imunologia , Macrófagos/patologia , Neutrófilos/patologia
11.
J Clin Pharm Ther ; 44(4): 553-560, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30763469

RESUMO

WHAT IS KNOWN AND OBJECTIVE: Anti-tumour necrosis factor-alpha (anti-TNF-α) therapy is known to raise the risk of granulomatous infections, leading to development of risk management strategies at national or global level. This study aimed to determine the relative risk (RR) of tuberculosis (TB) due to anti-TNF-α usage in patients with rheumatologic diseases (RDs) in a nationwide basis. METHOD: This retrospective cohort study included patients with rheumatoid arthritis (RA), ankylosing spondylitis, juvenile idiopathic arthritis or psoriatic arthritis (PsA) that treated with or without anti-TNF-α agents, as registered in the national prescription information system between years 2013 and 2015. Two-year RR of TB after anti-TNF-α therapy initiation was calculated in this RD population, including main subgroups. RESULTS AND DISCUSSION: The study cohort included 413 500 RD patients, where anti-TNF-α(+) arm (n = 2117) had mean age of 41.9 ± 13.4 years and male distribution of 54.3%. Four patients among anti-TNF-α users developed TB compared to 128 patients in anti-TNF-α-naïve group (189 vs 31 cases per 100 000 patients, respectively), yielding a 2-year RR of 6.07 (95% CI, 2.25-16.42) with an attributable risk of 0.16%. These RRs (95% CI), which were particularly pronounced, were 5.39 (1.69-7.17) in men, 6.12 (2.26-16.55) in adults, and 5.70 (1.41-23.08) in RA and 13.46 (1.58-114.40) in PsA patients. There was no difference between the anti-TNF-α users who developed and undeveloped TB regarding drug utilization characteristics, except significantly less immunosuppressive drug exposure in TB patients. WHAT IS NEW AND CONCLUSION: This study is the first prescription-based nationwide study to suggest an elevated RR of TB in a comparably younger population with a broad spectrum of RDs managed with any approved anti-TNF-α drug in Turkey.


Assuntos
Antirreumáticos/efeitos adversos , Antirreumáticos/uso terapêutico , Doenças Reumáticas/tratamento farmacológico , Tuberculose/induzido quimicamente , Fator de Necrose Tumoral alfa/efeitos adversos , Fator de Necrose Tumoral alfa/uso terapêutico , Adulto , Artrite Psoriásica/tratamento farmacológico , Artrite Reumatoide/tratamento farmacológico , Feminino , Humanos , Imunossupressores/uso terapêutico , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Fatores de Risco , Turquia
12.
Clin Exp Rheumatol ; 37(4): 649-655, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30767865

RESUMO

OBJECTIVES: To determine the incidence of serious infections (SIs) among the spondyloarthropathy (SpA) patients from the "Gruppo Italiano per lo Studio delle Early Arthritis" (GISEA) registry and treated with tumour necrosis factor (TNF) inhibitors (TNFIs), and to identify the factors associated with the development of the infections. METHODS: This observational study on 3321 GISEA-registered SpA patients collected real-world demographic and clinical data relating to their biological drug treatments. The overall incidence of infections was analysed by type of SpA. RESULTS: A total of 3321 SpA patients (1731 males, 52.2%; mean age 47±13 years; median disease duration 3 years, interquartile range [IQR] 0-8) were eligible for inclusion in the analysis. Two hundred and fifty-nine patients experienced at least one of 391 microbiologically diagnosed SIs, 32% of which were recorded during the first 12 months of treatment. The overall incidence of SIs was 43.9/1000 patient-years of follow-up (95% confidence interval [CI] 39.6-48.4): 29.9/1000 (95% CI 23.1-38.1) among those treated with adalimumab (ADA); 36.1/1000 (95% CI 30.0-43.1) among those treated with etanercept (ETN); and 61.4/1000 (95% CI 53.3-70.5) among those treated with infliximab (INF). The highest incidence was observed among the patients with psoriatic arthritis (PsA), but the difference was statistically significant only in comparison with the patients with undifferentiated SpA (p=0.002), whose incidence of SIs was also lower than in the patients with ankylosing spondylitis (AS) (p=0.034). Multivariate models showed that the number of comorbidities (hazard ratio [HR] 1.29, 95%CI 1.2-1.4; p<0.001), age at the start of TNFi treatment (HR 0.99, 95%CI 0.97-0.99; p=0.030), steroid use (HR 1.40, 95%CI 1.1-1.8; p=0.012) and male sex (HR 0.72, 95%CI 0.5-0.9; p=0.012) were all statistically significant predictors of infection. The factors independently associated with a lower risk of SIs were the use of ETN (HR 0.52, 95%CI 0.4-0.7; p<0.001) or ADA (HR 0.59, 95%CI 0.4-0.8; p=0.002) rather than INF. CONCLUSIONS: The incidence of SIs was higher among patients with PsA or AS than among those with undifferentiated SpA, and among patients treated with INF than among those treated with ADA or ETN. Male sex, steroid use and the number of comorbidities were all factors predictive of SIs.


Assuntos
Antirreumáticos/efeitos adversos , Infecções/etiologia , Espondiloartropatias/complicações , Fator de Necrose Tumoral alfa/efeitos adversos , Adalimumab , Adulto , Antirreumáticos/uso terapêutico , Etanercepte , Feminino , Humanos , Infecções/epidemiologia , Infliximab , Itália , Masculino , Pessoa de Meia-Idade , Sistema de Registros , Espondiloartropatias/tratamento farmacológico , Espondiloartropatias/imunologia , Inquéritos e Questionários , Fator de Necrose Tumoral alfa/uso terapêutico
13.
Stem Cell Res Ther ; 10(1): 5, 2019 01 03.
Artigo em Inglês | MEDLINE | ID: mdl-30606261

RESUMO

BACKGROUND: The etiology and pathology osteonecrosis of the femoral head (ONFH) are not completely clarified. As a cytokine participating in systemic inflammation, tumor necrosis factor alpha (TNFα) has been shown to be involved in the pathogenesis of ONFH. However, the role of TNFα in ONFH is not clearly clarified. In the present study, we investigated the effects of TNFα on proliferation, angiogenesis, and osteogenic differentiation of rat bone mesenchymal stem cells (rMSCs) and the underlying mechanisms. METHODS: All femoral bone tissues were separated in surgeries. After extracting total RNA and protein, we evaluated TNFα content by ELISA and the relative expression levels of genes by quantitative real-time PCR and western blot. Also, immunohistochemistry staining was performed to observe the expression of Runx2 in the bone samples. Chick embryo chorioallantoic membrane (CAM) assay was performed to observe the effect of TNFα on angiogenesis. The genomic DNAs were treated by bisulfite modification, and methylation status of CpG sites in the CpG islands of human and rat Runx2 gene promoter was determined by DNA sequencing. The binding of H3K4me3 and H3K27me3 in Runx2 promoter was checked by ChIP assay. RNA-seq analysis was used to find out the genes and pathways changed by TNFα in rMSCs. RESULTS: The results demonstrate TNFα promotes cell proliferation and angiogenesis whereas inhibits osteogenesis. Epigenetic regulations including DNA methylation and histone modifications play important roles in mediating the effect of TNFα on osteogenic differentiation. We find an increased rate of CpG methylation in rat Runx2 promoter in TNFα-treated rMSCs, as well as significantly increased occupancy of H3K27me3 in Runx2 gene promoter. The content of TNFα in necrotic tissue is much lower than that of normal tissue. And relevantly, human Runx2 promoter is demethylated in necrotic tissue using bone samples from patient with ONFH. In addition, we have observed that Wnt signaling pathway is inhibited by TNFα as multiple Wnts are markedly decreased in TNFα-treated rMSCs by RNA-seq analysis. CONCLUSION: Taken together, our study shows that TNFα plays complicated roles in the pathogenesis of ONFH, including proliferation, angiogenesis, and osteogenesis. Targeting TNFα should not be considered as an applicable strategy to inhibit the progression of ONFH.


Assuntos
Metilação de DNA/genética , Cabeça do Fêmur/anormalidades , Osteonecrose/induzido quimicamente , Esteroides/efeitos adversos , Fator de Necrose Tumoral alfa/efeitos adversos , Animais , Diferenciação Celular , Proliferação de Células , Embrião de Galinha , Humanos , Masculino , Ratos , Ratos Sprague-Dawley
14.
Intern Med ; 58(10): 1473-1477, 2019 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-30626837

RESUMO

Although numerous recent studies have reported the development of sarcoidosis in patients treated with tumor necrosis factor alpha (TNF-α) inhibitors, it is unclear whether the pathogenesis of drug-induced sarcoidosis is identical to that of spontaneous sarcoidosis. We herein present the case of a patient who developed sarcoidosis 6 months after the introduction of etanercept as treatment for rheumatoid arthritis. Typical clinical symptoms with noncaseating epithelioid granulomas detected in a mediastinal lymph node specimen were consistent with the diagnosis of sarcoidosis. Immunohistochemistry revealed Propionibacterium acnes in the noncaseating granulomas. The present findings suggest that Propionibacterium acnes is a cause of sarcoidosis, even when the disease is induced by TNF-α inhibitors.


Assuntos
Antiasmáticos/efeitos adversos , Artrite Reumatoide/complicações , Artrite Reumatoide/tratamento farmacológico , Etanercepte/efeitos adversos , Etanercepte/uso terapêutico , Propionibacterium acnes/patogenicidade , Sarcoidose/induzido quimicamente , Fator de Necrose Tumoral alfa/efeitos adversos , Antiasmáticos/uso terapêutico , Feminino , Granuloma/patologia , Humanos , Linfonodos/patologia , Masculino , Mediastino/patologia , Pessoa de Meia-Idade
15.
Am J Physiol Lung Cell Mol Physiol ; 316(1): L157-L174, 2019 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-30407866

RESUMO

Short-chain fatty acids (SCFAs), produced as by-products of dietary fiber metabolism by gut bacteria, have anti-inflammatory properties and could potentially be used for the treatment of inflammatory diseases, including asthma. The direct effects of SCFAs on inflammatory responses in primary human lung mesenchymal cells have not been assessed. We investigated whether SCFAs can protect against tumor necrosis factor (TNF)α-induced inflammation in primary human lung fibroblasts (HLFs) and airway smooth muscle (ASM) cells in vitro. HLFs and ASM cells were exposed to SCFAs, acetate (C2:0), propionate (C3:0), and butyrate (C4:0) (0.01-25 mM) with or without TNFα, and the release of proinflammatory cytokines, IL-6, and CXCL8 was measured using ELISA. We found that none of the SCFAs suppressed TNFα-induced cytokine release. On the contrary, challenge with supraphysiological concentrations (10-25 mM), as might be used therapeutically, of propionate or butyrate in combination with TNFα resulted in substantially greater IL-6 and CXCL8 release from HLFs and ASM cells than challenge with TNFα alone, demonstrating synergistic effects. In ASM cells, challenge with acetate also enhanced TNFα-induced IL-6, but not CXCL8 release. Synergistic upregulation of IL-6 and CXCL8 was mediated through the activation of free fatty acid receptor (FFAR)3, but not FFAR2. The signaling pathways involved were further examined using specific inhibitors and immunoblotting, and responses were found to be mediated through p38 MAPK signaling. This study demonstrates that proinflammatory, rather than anti-inflammatory effects of SCFAs are evident in lung mesenchymal cells.


Assuntos
Ácidos Graxos Voláteis/efeitos adversos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Células-Tronco Mesenquimais/metabolismo , Fator de Necrose Tumoral alfa/efeitos adversos , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo , Adulto , Idoso , Células Cultivadas , Ácidos Graxos Voláteis/farmacologia , Feminino , Fibroblastos/metabolismo , Fibroblastos/patologia , Humanos , Inflamação/induzido quimicamente , Inflamação/metabolismo , Inflamação/patologia , Interleucina-6/metabolismo , Interleucina-8/metabolismo , Pulmão , Masculino , Células-Tronco Mesenquimais/patologia , Pessoa de Meia-Idade , Miócitos de Músculo Liso/metabolismo , Miócitos de Músculo Liso/patologia , Receptores de Superfície Celular/metabolismo , Receptores Acoplados a Proteínas-G/metabolismo , Fator de Necrose Tumoral alfa/farmacologia
16.
Curr Opin Organ Transplant ; 24(1): 12-19, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30507704

RESUMO

PURPOSE OF REVIEW: Regulated cell death (RCD) is likely to play a role in organ rejection but it is unclear how it may be invoked. A well-known trigger of regulated cell death is tumor necrosis factor-alpha (TNF), which activates both caspase-dependent apoptosis and caspase-independent necroptosis. TNF is best known as a pro-inflammatory cytokine because it activates NFκB and MAPK signaling to induce expression of pro-inflammatory genes. RECENT FINDINGS: Emerging data from animal models now suggest that TNF-induced cell death can also be inflammatory. Therefore, the role of cellular demise in regulating immunity should be considered. In transplantation, TNF could have a role in cellular injury or death from ischemia reperfusion (IR) injury and this may dictate organ survival. The default response to TNF in most cells is survival, rather than death, because of the presence of cell death checkpoints. However, cells succumb to TNF-driven death when these checkpoints are disrupted, and sensitivity to death likely reflects a reduction in molecules that fortify these checkpoints. We propose that a cell's propensity to die in response to TNF may underlie allograft rejection. SUMMARY: Genetic, epigenetic, and posttranslational control of death checkpoint regulators in donor tissues may determine graft survival. Therapeutically, drugs that prevent donor cell demise could be useful in preventing organ rejection.


Assuntos
Morte Celular/genética , Fator de Necrose Tumoral alfa/efeitos adversos , Apoptose , Humanos , Doadores de Tecidos
17.
Inflammation ; 42(1): 319-330, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30259241

RESUMO

Growth differentiation factor-11 (GDF11) is a key member of the transforming growth factor ß (TGF-ß) superfamily, which plays a momentous role in both normal physiological processes and pathophysiology processes. Recently, it was reported that GDF11 was closely associated with several inflammatory conditions and protected against development of inflammation. Psoriasis-like skin inflammation is a common skin inflammatory disease, yet much is unknown about the underlying mechanisms. In this study, we investigated the expression pattern of GDF11 in two psoriasis-like skin inflammation mice models and tumor necrosis factor-α (TNF-α)-induced RAW264.7 macrophages. Furthermore, RAW264.7 cell was cultured, and GDF11 antagonized the inflammatory function of TNF-α in vitro. Moreover, imiquimod-induced mice model and IL-23-induced mice model were established to investigate the anti-inflammatory role of GDF11 in vivo. As a result, the administration of GDF11 remarkably attenuated the severity of skin inflammation in both two mice models. Additionally, the activation of nuclear NF-κB (nuclear factor κ-light-chain-enhancer of activated B cells) signaling pathway was repressed by GDF11 treatment. Collectively, GDF11 may represent a promising molecular target for the prevention and treatment of psoriasis-like skin inflammation.


Assuntos
Proteínas Morfogenéticas Ósseas/farmacologia , Fatores de Diferenciação de Crescimento/farmacologia , Inflamação/tratamento farmacológico , Psoríase , Dermatopatias/tratamento farmacológico , Animais , Modelos Animais de Doenças , Inflamação/induzido quimicamente , Macrófagos/efeitos dos fármacos , Camundongos , NF-kappa B/metabolismo , Células RAW 264.7 , Dermatopatias/patologia , Fator de Necrose Tumoral alfa/efeitos adversos
18.
Biochim Biophys Acta Mol Basis Dis ; 1865(2): 391-402, 2019 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-30476545

RESUMO

Chronic inflammation in the liver provokes fibrosis and, on long-term, carcinogenesis. This sequence is prototypically recapitulated in mice with hepatocyte-specific knock-out of the NF-κB essential modulator (NEMO), termed NEMOLPC-KO mice, in which increased hepatocyte apoptosis and compensatory regeneration cause steatosis, inflammation and fibrosis. Natural killer T (NKT) cells carrying the chemokine receptor CXCR6 participate in liver inflammation and injury responses. Here, we investigated the role of CXCR6 in the NEMOLPC-KO mouse model. Unexpectedly, genetic deletion of CXCR6 enhanced hepatocyte death, inflammation and fibrosis in NEMOLPC-KO mice. Although CXCR6 expression is restricted to immune cells in the liver, the adoptive transfer of CXCR6+ cells did not protect NEMOLPC-KOCxcr6-/- mice from hepatic injury. Gene array analyses revealed up-regulated stress response and metabolism pathways in hepatocytes from NEMOLPC-KOCxcr6-/- mice, functionally corresponding to an increased susceptibility of these hepatocytes to TNFα-induced cell death in vitro. These data revealed a novel CXCR6-dependent mechanism of suppressing inflammatory hepatocytic responses to cellular stress.


Assuntos
Fígado Gorduroso/metabolismo , Fígado Gorduroso/prevenção & controle , Inflamação/metabolismo , Inflamação/prevenção & controle , Peptídeos e Proteínas de Sinalização Intracelular/deficiência , Receptores CXCR6/metabolismo , Transferência Adotiva , Animais , Apoptose , Células Cultivadas , Citocromo P-450 CYP4A/metabolismo , Fígado Gorduroso/patologia , Hepatócitos/metabolismo , Hepatócitos/patologia , Inflamação/patologia , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Fígado/lesões , Fígado/metabolismo , Fígado/patologia , Masculino , Camundongos Knockout , Receptores CXCR6/deficiência , Estresse Fisiológico , Fator de Necrose Tumoral alfa/efeitos adversos , Regulação para Cima
20.
Artigo em Russo | MEDLINE | ID: mdl-30251985

RESUMO

AIM: To investigate the ability of the neuroprotector dimebon to prevent alterations in brain lipid metabolism caused byTNF-α. MATERIAL AND METHODS: The ability of dimebon (2,8-Dimethyl-5-[2-(6-methyl-3-pyridinyl)ethyl]-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole hydrochloride) to prevent alterations in brain lipid metabolism caused byTNF-α was studied in 65 male mice (20+2g weight). TNF-α (10 mkg/mouse), dimebon (0.2 mg/kg) and their combination were injected intraperitoneally. Thirty min, 2, 4 and 24 h after injection, lipid level alterations in total fractions and molecular species of phospholipids (phosphatidylcholine, lysophosphatidylcholine, sphingomyelin and phosphatidylethanolamine) were measured with mass-spectrometry in the hippocampus, cortex and cerebellum. RESULTS AND CONCLUSION: After injection of TNF-α into mice, there are significant changes in the level of all tested phospholipids. Dimebon at a dose of 0.2 mg/kg alone does not cause any changes in the content of all tested phospholipids, but injected together with TNF-α prevents cytokine induced alterations in the lipid content. The selectivity of TNF-α and dimebon influence on certain molecular species of various phospholipids in different parts of mouse brain is found. The presented data suggest protective properties of dimebon preventing the development of proinflammatory syndrome induced by TNF-α in the animal brain.


Assuntos
Indóis , Fármacos Neuroprotetores , Fosfolipídeos , Fator de Necrose Tumoral alfa , Animais , Hipocampo , Indóis/farmacologia , Indóis/uso terapêutico , Masculino , Camundongos , Fármacos Neuroprotetores/farmacologia , Fármacos Neuroprotetores/uso terapêutico , Fosfatidilcolinas , Fosfolipídeos/metabolismo , Fator de Necrose Tumoral alfa/efeitos adversos
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