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1.
Platelets ; 31(8): 1085-1089, 2020 Nov 16.
Artigo em Inglês | MEDLINE | ID: mdl-32857624

RESUMO

Coronavirus disease 2019 (COVID-19) is a global public health emergency with many clinical facets, and new knowledge about its pathogenetic mechanisms is deemed necessary; among these, there are certainly coagulation disorders. In the history of medicine, autopsies and tissue sampling have played a fundamental role in order to understand the pathogenesis of emerging diseases, including infectious ones; compared to the past, histopathology can be now expanded by innovative techniques and modern technologies. For the first time in worldwide literature, we provide a detailed postmortem and biopsy report on the marked increase, up to 1 order of magnitude, of naked megakaryocyte nuclei in the bone marrow and lungs from serious COVID-19 patients. Most likely related to high interleukin-6 serum levels stimulating megakaryocytopoiesis, this phenomenon concurs to explain well the pulmonary abnormal immunothrombosis in these critically ill patients, all without molecular or electron microscopy signs of megakaryocyte infection.


Assuntos
Betacoronavirus/patogenicidade , Medula Óssea/patologia , Infecções por Coronavirus/patologia , Síndrome da Liberação de Citocina/patologia , Coagulação Intravascular Disseminada/patologia , Pulmão/patologia , Pneumonia Viral/patologia , Trombose/patologia , Adulto , Idoso , Autopsia , Betacoronavirus/imunologia , Medula Óssea/imunologia , Medula Óssea/virologia , Núcleo Celular/imunologia , Núcleo Celular/patologia , Núcleo Celular/virologia , Infecções por Coronavirus/complicações , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/virologia , Estado Terminal , Síndrome da Liberação de Citocina/complicações , Síndrome da Liberação de Citocina/imunologia , Síndrome da Liberação de Citocina/virologia , Coagulação Intravascular Disseminada/complicações , Coagulação Intravascular Disseminada/imunologia , Coagulação Intravascular Disseminada/virologia , Evolução Fatal , Interações Hospedeiro-Patógeno/imunologia , Humanos , Interleucina-6/biossíntese , Interleucina-6/imunologia , Pulmão/imunologia , Pulmão/virologia , Masculino , Megacariócitos/imunologia , Megacariócitos/patologia , Megacariócitos/virologia , Pessoa de Meia-Idade , Pandemias , Pneumonia Viral/complicações , Pneumonia Viral/imunologia , Pneumonia Viral/virologia , Índice de Gravidade de Doença , Trombopoese/imunologia , Trombose/complicações , Trombose/imunologia , Trombose/virologia
2.
Mol Immunol ; 125: 172-177, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32707536

RESUMO

Recent studies suggest that microbiome derived 3(3,4-dihydroxy-phenyl) propionic acid (DHCA) attenuates IL-6 cytokine production through downregulation of the epigenetic modifier DNA Methyltransferase 1 (DNMT1) expression and inhibition of DNA methylation at the 5'-C-phosphate-G-3' (CpG)-rich IL6 sequence introns 1 and 3 in a mouse model of depression. In this study, we extended the investigation of DHCA epigenetic mechanisms in IL-6 expression in human peripheral blood mononuclear cells (PBMC). Using Lucia Luciferase reporter gene system we identified CpG-rich sequences in which of methylation is influenced by DHCA similar to what observed in response to treatment with the DNA methylation inhibitor 5-aza-2'-deoxycytidine. Correlation study showed that DNA methylation at select CpG motifs in the IL-6 promoter correlates with IL-6 gene expression. Our study suggests that DHCA is effective in reducing IL-6 expression in human PBMCs, in part, by regulation of methylation in the IL-6 promoter region.


Assuntos
Regulação da Expressão Gênica/efeitos dos fármacos , Monócitos/efeitos dos fármacos , Propionatos/farmacologia , Células Cultivadas , Metilação de DNA/efeitos dos fármacos , Metilação de DNA/genética , Regulação para Baixo , Regulação da Expressão Gênica/genética , Humanos , Interleucina-6/biossíntese , Microbiota , Neuroimunomodulação/efeitos dos fármacos , Neuroimunomodulação/genética
3.
J Immunol ; 205(5): 1198-1206, 2020 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-32680957

RESUMO

Fever in infections correlates with inflammation, macrophage infiltration into the affected organ, macrophage activation, and release of cytokines involved in immune response, hematopoiesis, and homeostatic processes. Angiotensin-converting enzyme 2 (ACE2) is the canonical cell surface receptor for SARS-CoV-2. ACE2 together with angiotensin receptor types 1 and 2 and ACE2 are components of the renin-angiotensin system (RAS). Exacerbated production of cytokines, mainly IL-6, points to macrophages as key to understand differential COVID-19 severity. SARS-CoV-2 may modulate macrophage-mediated inflammation events by altering the balance between angiotensin II, which activates angiotensin receptor types 1 and 2, and angiotensin 1-7 and alamandine, which activate MAS proto-oncogene and MAS-related D receptors, respectively. In addition to macrophages, lung cells express RAS components; also, some lung cells are able to produce IL-6. Addressing how SARS-CoV-2 unbalances RAS functionality via ACE2 will help design therapies to attenuate a COVID-19-related cytokine storm.


Assuntos
Betacoronavirus/metabolismo , Infecções por Coronavirus/imunologia , Interleucina-6/biossíntese , Peptidil Dipeptidase A/metabolismo , Pneumonia Viral/imunologia , Sistema Renina-Angiotensina , Angiotensina I/metabolismo , Animais , Betacoronavirus/imunologia , Infecções por Coronavirus/virologia , Humanos , Inflamação/imunologia , Macrófagos/imunologia , Pandemias , Fragmentos de Peptídeos/metabolismo , Pneumonia Viral/virologia , Proteínas Proto-Oncogênicas/metabolismo , Receptor Tipo 1 de Angiotensina/metabolismo , Receptor Tipo 2 de Angiotensina/metabolismo , Receptores Acoplados a Proteínas-G/metabolismo , Receptores Virais/metabolismo
4.
Clin Immunol ; 217: 108487, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32479986

RESUMO

Coronavirus Disease 2019 (COVID-19) is an ongoing public health emergency and new knowledge about its immunopathogenic mechanisms is deemed necessary in the attempt to reduce the death burden, globally. For the first time in worldwide literature, we provide scientific evidence that in COVID-19 vasculitis a life-threatening escalation from type 2 T-helper immune response (humoral immunity) to type 3 hypersensitivity (immune complex disease) takes place. The subsequent deposition of immune complexes inside the vascular walls is supposed to induce a severe inflammatory state and a cytokine release syndrome, whose interleukin-6 is the key myokine, from the smooth muscle cells of blood vessels.


Assuntos
Betacoronavirus/patogenicidade , Infecções por Coronavirus/imunologia , Síndrome da Liberação de Citocina/imunologia , Doenças do Complexo Imune/imunologia , Pneumonia Viral/imunologia , Síndrome Respiratória Aguda Grave/imunologia , Células Th2/imunologia , Vasculite/imunologia , Idoso , Anticorpos Antivirais/biossíntese , Complexo Antígeno-Anticorpo/biossíntese , Betacoronavirus/imunologia , Vasos Sanguíneos/imunologia , Vasos Sanguíneos/patologia , Vasos Sanguíneos/virologia , Complemento C3/biossíntese , Infecções por Coronavirus/complicações , Infecções por Coronavirus/virologia , Síndrome da Liberação de Citocina/complicações , Síndrome da Liberação de Citocina/virologia , Progressão da Doença , Células Endoteliais/imunologia , Células Endoteliais/patologia , Células Endoteliais/virologia , Humanos , Doenças do Complexo Imune/complicações , Doenças do Complexo Imune/virologia , Imunidade Humoral , Imunoglobulina G/biossíntese , Imunoglobulina M/biossíntese , Interleucina-6/biossíntese , Masculino , Pandemias , Pneumonia Viral/complicações , Pneumonia Viral/virologia , Síndrome Respiratória Aguda Grave/complicações , Síndrome Respiratória Aguda Grave/virologia , Células Th2/patologia , Células Th2/virologia , Vasculite/complicações , Vasculite/virologia
5.
Clin Immunol ; 217: 108493, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32526273

Assuntos
Complexo Antígeno-Anticorpo/biossíntese , Betacoronavirus/patogenicidade , Infecções por Coronavirus/imunologia , Síndrome da Liberação de Citocina/imunologia , Doenças do Complexo Imune/imunologia , Pneumonia Viral/imunologia , Síndrome Respiratória Aguda Grave/imunologia , Vasculite/imunologia , Anticorpos Antivirais/biossíntese , Complexo Antígeno-Anticorpo/efeitos dos fármacos , Betacoronavirus/imunologia , Vasos Sanguíneos/efeitos dos fármacos , Vasos Sanguíneos/imunologia , Vasos Sanguíneos/patologia , Vasos Sanguíneos/virologia , Complemento C3/antagonistas & inibidores , Complemento C3/biossíntese , Inativadores do Complemento/uso terapêutico , Infecções por Coronavirus/complicações , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/virologia , Síndrome da Liberação de Citocina/complicações , Síndrome da Liberação de Citocina/tratamento farmacológico , Síndrome da Liberação de Citocina/virologia , Humanos , Doenças do Complexo Imune/complicações , Doenças do Complexo Imune/tratamento farmacológico , Doenças do Complexo Imune/virologia , Imunidade Humoral/efeitos dos fármacos , Proteína Antagonista do Receptor de Interleucina 1/uso terapêutico , Interleucina-6/antagonistas & inibidores , Interleucina-6/biossíntese , Pandemias , Pneumonia Viral/complicações , Pneumonia Viral/tratamento farmacológico , Pneumonia Viral/virologia , Receptores de Interleucina-1/antagonistas & inibidores , Receptores de Interleucina-1/biossíntese , Síndrome Respiratória Aguda Grave/complicações , Síndrome Respiratória Aguda Grave/tratamento farmacológico , Síndrome Respiratória Aguda Grave/virologia , Índice de Gravidade de Doença , Vasculite/complicações , Vasculite/tratamento farmacológico , Vasculite/virologia
6.
Anticancer Res ; 40(6): 3255-3264, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32487620

RESUMO

BACKGROUND/AIM: Rta, a transactivator of Epstein-Barr virus, is associated with progression of nasopharyngel carcinoma (NPC); however, its mechanism of contribution to the pathogenesis of NPC remains unclear. Interleukin-6 (IL-6), a tumor promoter, is detected in NPC. This in vitro study examined whether and how Rta promotes NPC progression by up-regulating IL-6. MATERIALS AND METHODS: Semiquantitative reverse transcription-polymerase chain reaction (RT-PCR), quantitative real-time PCR, ELISA, immunoblotting assays, reporter gene assays, and transwell migration assays were performed. RESULTS: In NPC cells, Rta up-regulated IL-6 expression at the mRNA and protein levels, and the Rta's C-terminus was essential for promoter activation and expression of IL-6. The induction of IL-6 by Rta also required activation of extracellular signal-regulated kinase 1/2 and activator protein-1. Furthermore, IL-6 secreted from Rta-expressing NPC cells promoted migration of Rta-negative NPC cells by activating IL-6 receptor/Janus kinase/signal transducer and activator of transcription 3 pathway. CONCLUSION: Rta contributes to progression of NPC cells through induction of IL-6 in vitro.


Assuntos
Proteínas Imediatamente Precoces/metabolismo , Interleucina-6/metabolismo , Janus Quinases/metabolismo , Neoplasias/metabolismo , Receptores de Interleucina-6/metabolismo , Fator de Transcrição STAT3/metabolismo , Transativadores/metabolismo , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Neoplasias da Mama/virologia , Linhagem Celular Tumoral , Movimento Celular/fisiologia , Humanos , Proteínas Imediatamente Precoces/genética , Interleucina-6/biossíntese , Interleucina-6/genética , Sistema de Sinalização das MAP Quinases , Células MCF-7 , Carcinoma Nasofaríngeo/genética , Carcinoma Nasofaríngeo/metabolismo , Carcinoma Nasofaríngeo/patologia , Carcinoma Nasofaríngeo/virologia , Neoplasias Nasofaríngeas/genética , Neoplasias Nasofaríngeas/metabolismo , Neoplasias Nasofaríngeas/patologia , Neoplasias Nasofaríngeas/virologia , Neoplasias/genética , Neoplasias/patologia , Neoplasias/virologia , Transdução de Sinais , Neoplasias Gástricas/genética , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/patologia , Neoplasias Gástricas/virologia , Transativadores/genética , Fator de Transcrição AP-1/metabolismo , Transfecção , Regulação para Cima
7.
Prostate ; 80(10): 731-741, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32356572

RESUMO

BACKGROUND: Male lower urinary tract symptoms (LUTS) occur in more than half of men above 50 years of age. LUTS were traditionally attributed to benign prostatic hyperplasia (BPH) and therefore the clinical terminology often uses LUTS and BPH interchangeably. More recently, LUTS were also linked to fibrogenic and inflammatory processes. We tested whether osteopontin (OPN), a proinflammatory and profibrotic molecule, is increased in symptomatic BPH. We also tested whether prostate epithelial and stromal cells secrete OPN in response to proinflammatory stimuli and identified downstream targets of OPN in prostate stromal cells. METHODS: Immunohistochemistry was performed on prostate sections obtained from the transition zone of patients who underwent surgery (Holmium laser enucleation of the prostate) to relieve LUTS (surgical BPH, S-BPH) or patients who underwent radical prostatectomy to remove low-grade prostate cancer (incidental BPH, I-BPH). Images of stained tissue sections were captured with a Nuance Multispectral Imaging System and histoscore, as a measure of OPN staining intensity, was determined with inForm software. OPN protein abundance was determined by Western blot analysis. The ability of prostate cells to secrete osteopontin in response to IL-1ß and TGF-ß1 was determined in stromal (BHPrS-1) and epithelial (NHPrE-1 and BHPrE-1) cells by enzyme-linked immunosorbent assay. Quantitative polymerase chain reaction was used to measure gene expression changes in these cells in response to OPN. RESULTS: OPN immunostaining and protein levels were more abundant in S-BPH than I-BPH. Staining was distributed across all cell types with the highest levels in epithelial cells. Multiple OPN protein variants were identified in immortalized prostate stromal and epithelial cells. TGF-ß1 stimulated OPN secretion by NHPrE-1 cells and both IL-1ß and TGF-ß1 stimulated OPN secretion by BHPrS-1 cells. Interestingly, recombinant OPN increased the mRNA expression of CXCL1, CXCL2, CXCL8, PTGS2, and IL6 in BHPrS-1, but not in epithelial cell lines. CONCLUSIONS: OPN is more abundant in prostates of men with S-BPH compared to men with I-BPH. OPN secretion is stimulated by proinflammatory cytokines, and OPN acts directly on stromal cells to drive the synthesis of proinflammatory mRNAs. Pharmacological manipulation of prostatic OPN may have the potential to reduce LUTS by inhibiting both inflammatory and fibrotic pathways.


Assuntos
Osteopontina/biossíntese , Hiperplasia Prostática/metabolismo , Quimiocinas CXC/biossíntese , Quimiocinas CXC/genética , Ciclo-Oxigenase 2/biossíntese , Ciclo-Oxigenase 2/genética , Humanos , Imuno-Histoquímica , Interleucina-6/biossíntese , Interleucina-6/genética , Masculino , Osteopontina/genética , Hiperplasia Prostática/genética , Hiperplasia Prostática/patologia , RNA Mensageiro/biossíntese , RNA Mensageiro/genética , Células Estromais/metabolismo , Células Estromais/patologia
9.
Toxicol Appl Pharmacol ; 393: 114931, 2020 04 15.
Artigo em Inglês | MEDLINE | ID: mdl-32109511

RESUMO

BACKGROUND: Concanavalin A (ConA) is a well-established model to induce autoimmune hepatitis (AIH) in mice which mimics pathological alterations that occur in human. The pathogenesis of ConA-induced AIH involves many signaling pathways. Montelukast is a leukotriene receptor antagonist that is mainly used in the management of asthma. The antioxidant, anti-inflammatory and anti-apoptotic effects of montelukast have been reported in previous studies. Lately, montelukast has been documented to confer protection against various inflammatory diseases. Up to date, no study has explored the effect of montelukast on AIH induced by ConA. AIM AND METHOD: This study aims to detect the protective effects of montelukast (10 mg/kg) on ConA (20 mg/kg)- induced AIH in mice and to demonstrate its hepatoprotective mechanisms. Hepatic function, histological changes, oxidative stress, inflammation, autophagy, and apoptotic markers were investigated. RESULTS: Hepatic function and histological data revealed that treatment with montelukast significantly attenuated ConA-induced hepatic damage. Montelukast significantly reduced JNK level and NFκB p65 expression, and inhibited proinflammatory cytokines (TNF-α and IL-6) as well as oxidative stress (MDA, NO, and GSH). Moreover, inflammatory cells (CD4+ infiltration and the levels of apoptotic markers (Bax and caspase-3) besides autophagy biomarkers (Beclin1 and LC3) were reduced. CONCLUSION: Our results suggest that montelukast could be a potential therapeutic drug against the ConA-induced AIH through its anti-oxidant, anti-inflammatory, anti- autophagy as well as anti-apoptotic properties.


Assuntos
Acetatos/uso terapêutico , Hepatite Autoimune/tratamento farmacológico , Antagonistas de Leucotrienos/uso terapêutico , MAP Quinase Quinase 4 , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Quinolinas/uso terapêutico , Fator de Necrose Tumoral alfa , Animais , Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Concanavalina A , Hepatite Autoimune/patologia , Interleucina-6/biossíntese , Fígado/metabolismo , Fígado/patologia , Testes de Função Hepática , Camundongos , Camundongos Endogâmicos BALB C , Estresse Oxidativo/efeitos dos fármacos , Fator de Transcrição RelA/biossíntese
10.
Nat Immunol ; 21(3): 321-330, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-32066949

RESUMO

Differentiation of CD4+ T cells into either follicular helper T (TFH) or type 1 helper T (TH1) cells influences the balance between humoral and cellular adaptive immunity, but the mechanisms whereby pathogens elicit distinct effector cells are incompletely understood. Here we analyzed the spatiotemporal dynamics of CD4+ T cells during infection with recombinant vesicular stomatitis virus (VSV), which induces early, potent neutralizing antibodies, or recombinant lymphocytic choriomeningitis virus (LCMV), which induces a vigorous cellular response but inefficient neutralizing antibodies, expressing the same T cell epitope. Early exposure of dendritic cells to type I interferon (IFN), which occurred during infection with VSV, induced production of the cytokine IL-6 and drove TFH cell polarization, whereas late exposure to type I IFN, which occurred during infection with LCMV, did not induce IL-6 and allowed differentiation into TH1 cells. Thus, tight spatiotemporal regulation of type I IFN shapes antiviral CD4+ T cell differentiation and might instruct vaccine design strategies.


Assuntos
Linfócitos T CD4-Positivos/imunologia , Interferon Tipo I/metabolismo , Imunidade Adaptativa , Transferência Adotiva , Animais , Linfócitos T CD4-Positivos/classificação , Diferenciação Celular/imunologia , Feminino , Interleucina-6/biossíntese , Vírus da Coriomeningite Linfocítica/imunologia , Vírus da Coriomeningite Linfocítica/patogenicidade , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Análise Espaço-Temporal , Linfócitos T Auxiliares-Indutores/imunologia , Células Th1/imunologia , Vírus da Estomatite Vesicular Indiana/imunologia , Vírus da Estomatite Vesicular Indiana/patogenicidade , Vírus da Estomatite Vesicular New Jersey/imunologia , Vírus da Estomatite Vesicular New Jersey/patogenicidade
11.
Cancer Immunol Res ; 8(3): 321-333, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31964625

RESUMO

CD8+ T cells can be polarized into several different subsets as defined by the cytokines they produce and the transcription factors that govern their differentiation. Here, we identified the polarizing conditions to induce an IL22-producing CD8+ Tc22 subset, which is dependent on IL6 and the aryl hydrocarbon receptor transcription factor. Further characterization showed that this subset was highly cytolytic and expressed a distinct cytokine profile and transcriptome relative to other subsets. In addition, polarized Tc22 were able to control tumor growth as well as, if not better than, the traditional IFNγ-producing Tc1 subset. Tc22s were also found to infiltrate the tumors of human patients with ovarian cancer, comprising up to approximately 30% of expanded CD8+ tumor-infiltrating lymphocytes (TIL). Importantly, IL22 production in these CD8+ TILs correlated with improved recurrence-free survival. Given the antitumor properties of Tc22 cells, it may be prudent to polarize T cells to the Tc22 lineage when using chimeric antigen receptor (CAR)-T or T-cell receptor (TCR) transduction-based immunotherapies.


Assuntos
Imunoterapia Adotiva/métodos , Interleucina-6/farmacologia , Interleucinas/imunologia , Linfócitos do Interstício Tumoral/imunologia , Neoplasias Ovarianas/terapia , Subpopulações de Linfócitos T/imunologia , Linfócitos T Citotóxicos/imunologia , Animais , Fatores de Transcrição Hélice-Alça-Hélice Básicos/imunologia , Polaridade Celular/imunologia , Feminino , Humanos , Interleucina-6/biossíntese , Interleucina-6/genética , Interleucina-6/imunologia , Linfócitos do Interstício Tumoral/efeitos dos fármacos , Melanoma Experimental/genética , Melanoma Experimental/imunologia , Melanoma Experimental/patologia , Melanoma Experimental/terapia , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/imunologia , Neoplasias Ovarianas/patologia , Receptores de Antígenos de Linfócitos T/imunologia , Receptores de Antígenos de Linfócitos T/metabolismo , Receptores de Hidrocarboneto Arílico/imunologia , Proteínas com Domínio T/imunologia , Subpopulações de Linfócitos T/efeitos dos fármacos , Linfócitos T Citotóxicos/efeitos dos fármacos , Linfócitos T Auxiliares-Indutores/efeitos dos fármacos , Linfócitos T Auxiliares-Indutores/imunologia , Transcriptoma , Células Tumorais Cultivadas
12.
Carbohydr Polym ; 230: 115629, 2020 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-31887898

RESUMO

The research described here focused on the effect of sulfated red algal polysaccharides (κ-, κ/ß-, ι/κ-carrageenan) individually and in combination with lipopolysaccharide (LPS) on the synthesis of prostaglandin E2 (PGE2) and cytokines (interleukin [IL]-1ß and IL-6) in whole blood model in vitro. The results demonstrated that, at high concentrations, carrageenans have substantial ability to modulate PGE2 synthesis and stimulate IL-1ß and IL-6 synthesis. A low degree of sulfate and high molecular weight were a prerequisite for the ability of carrageenans to modulate PGE2 synthesis. Further, we investigated the ability of the carrageenans alone and in combination with casein to affect bile salt permeability through an artificial membrane imitating the gastrointestinal barrier. The least sulfated κ/ß-carrageenan could retain bile salt permeation the most but less efficiently than cholestyramine. The polysaccharides did not affect pancreatic lipase activity. Our data confirm a possible mechanism of the cholesterol-reducing properties of carrageenan.


Assuntos
Carragenina/farmacologia , Dinoprostona/biossíntese , Lipase/metabolismo , Ácidos e Sais Biliares/metabolismo , Células Sanguíneas/efeitos dos fármacos , Células Sanguíneas/metabolismo , Carragenina/química , Permeabilidade da Membrana Celular , Células Cultivadas , Humanos , Interleucina-1beta/biossíntese , Interleucina-6/biossíntese , Metabolismo dos Lipídeos
13.
J Cancer Res Clin Oncol ; 146(4): 1101-1102, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31807866

RESUMO

Fever may represent a risk factor for NSCLC by increasing IL-6 expression. In this light, an accurate and rapid control of fever among lung cancer patients should be carefully added to the treatment plan. On this regard, concerns increase when doubts arise regarding the applicability of hyperthermia on NSCLC given the potential interaction of IL-6 with NSCLC. Thus, I suggest that randomized, controlled double-arm clinical studies are warranted for an evidence-based evaluation of feasibility of the hyperthermia application in the management of NSCLC.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/fisiopatologia , Febre/fisiopatologia , Interleucina-6/biossíntese , Neoplasias Pulmonares/fisiopatologia , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Carcinoma Pulmonar de Células não Pequenas/terapia , Retroalimentação Fisiológica , Febre/metabolismo , Humanos , Hipertermia Induzida/efeitos adversos , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/terapia , Ensaios Clínicos Controlados Aleatórios como Assunto
14.
Nat Prod Res ; 34(3): 351-358, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30580601

RESUMO

A new sesquiterpene (1) and a new monoterpene (2), together with thirteen known compounds (3-15) were isolated from an ethanol extract of the roots of Aristolochia debilis Sieb. et Zucc. The structures of compounds 1 and 2 were elucidated using HR-ESI-MS, 1D and 2D NMR spectroscopy. Anti-inflammatory effects of the isolated compounds were evaluated in terms of inhibition of nitric oxide, tumour-necrosis factor-α and interleukin-6 production in lipopolysaccharide-stimulated RAW264.7 cells. Compounds 1-9 and 12-15 significantly inhibited the levels of NO, TNF-α and IL-6 in LPS-induced RAW264.7 cells from concentrations of 3 µM to 30 µM.


Assuntos
Anti-Inflamatórios/isolamento & purificação , Aristolochia/química , Monoterpenos/isolamento & purificação , Raízes de Plantas/química , Sesquiterpenos/isolamento & purificação , Animais , Anti-Inflamatórios/química , Anti-Inflamatórios/farmacologia , Interleucina-6/antagonistas & inibidores , Interleucina-6/biossíntese , Lipopolissacarídeos , Camundongos , Estrutura Molecular , Monoterpenos/química , Monoterpenos/farmacologia , Óxido Nítrico/antagonistas & inibidores , Óxido Nítrico/biossíntese , Células RAW 264.7 , Sesquiterpenos/química , Sesquiterpenos/farmacologia , Análise Espectral/métodos , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Fator de Necrose Tumoral alfa/biossíntese
15.
Nat Prod Res ; 34(2): 225-232, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30580619

RESUMO

One new aryldihydronaphthalene-type lignan (1) together with eight known lignans (2-4, 7-11) as well as two caffeic-acid dimers (5, 6) were isolated from an ethanol extract of the whole plant of Corispermum mongolicum Iljin (Chenopodiaceae). The chemical structures of these compounds were determined from 1D and 2D NMR and HR-ESI-MS spectra, and results were compared with data from the literature. This study is the first demonstration of nine compounds (2 and 4-11) isolated from the Chenopodiaceae family, with one of these (3) from the genus Corispermum. Anti-inflammatory effects of the isolated compounds were evaluated in terms of inhibition of production of nitric oxide, tumour necrosis factor-α, and interleukin-6 in lipopolysaccharide-induced RAW 264.7 cells.


Assuntos
Anti-Inflamatórios/isolamento & purificação , Chenopodiaceae/química , Lignanas/isolamento & purificação , Extratos Vegetais/química , Animais , Anti-Inflamatórios/química , Anti-Inflamatórios/farmacologia , Chenopodiaceae/metabolismo , Interleucina-6/biossíntese , Lignanas/química , Lignanas/farmacologia , Lipopolissacarídeos , Camundongos , Estrutura Molecular , Óxido Nítrico/antagonistas & inibidores , Óxido Nítrico/biossíntese , Células RAW 264.7 , Fator de Necrose Tumoral alfa/biossíntese , Fator de Necrose Tumoral alfa/efeitos dos fármacos
16.
Toxicol Lett ; 319: 119-128, 2020 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-31682869

RESUMO

Long-term exposure to fine particulate matter (PM2.5) may cause or exacerbate many diseases, including respiratory inflammation. However, the full mechanism is not yet fully understood. The newly discovered long chain non-coding RNA, though unable to encode proteins, regulates multiple life activities and participates in the development of inflammation. In this study, we set up a cell inflammation model by using normal bronchial 16HBE cells exposed to PM2.5. High-throughput sequencing, as well as real-time fluorescent quantitative PCR detection and validation, was performed on the inflamed cells to evaluate the expression level of long chain noncoding RNA that helped us to identify the LncRNA LOC101927514. Inhibiting LncRNA LOC101927514 expression by RNAi, reflected in a reduction in inflammation, is driven by PM2.5. In addition, we identify LncRNA LOC101927514 to be located within the nucleus and binds to STAT3, altering the inflammatory state of the cells and IL6 and IL8 release. This study identifies that LncRNA LOC101927514 is a new potential target for future treatment of the inflammatory response activated by PM2.5 in the respiratory system.


Assuntos
Poluentes Atmosféricos/toxicidade , Brônquios/efeitos dos fármacos , Células Epiteliais/efeitos dos fármacos , Inflamação/induzido quimicamente , Inflamação/genética , Material Particulado/toxicidade , RNA Longo não Codificante/genética , Fator de Transcrição STAT3/metabolismo , Contagem de Células , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Humanos , Interleucina-6/biossíntese , Interleucina-6/genética , Interleucina-8/biossíntese , Interleucina-8/genética , Fosforilação , Ligação Proteica , RNA Longo não Codificante/metabolismo
17.
Arterioscler Thromb Vasc Biol ; 40(2): 323-334, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31852218

RESUMO

OBJECTIVE: Deep venous thrombosis (DVT), one of the most common venous thromboembolic disorders, is closely linked with pulmonary embolism and post-thrombotic syndrome, both of which have a high mortality. However, the factors that trigger DVT formation are still largely unknown. Elevated expression of IL (interleukin)-6-an important inflammatory cytokine-has been linked with DVT formation. However, the molecular mechanisms leading to the elevated IL-6 in DVT remain unclear. Here, we proposed that epigenetic modification of IL-6 at the post-transcriptional level may be a crucial trigger for IL-6 upregulation in DVT. Approach and Results: To explore the association between microRNAs and IL-6 in DVT, we performed microRNA microarray analysis and experiments both in vitro and in vivo. Microarray and quantitative real-time polymerase chain reaction results showed that IL-6 expression was increased while miR-338-5p level was decreased substantially in peripheral blood mononuclear cells of patients with DVT, and there was significant negative correlation between miR-338-5p and IL-6. Experiments in vitro showed that overexpressed miR-338-5p reduced IL-6 expression, while miR-338-5p knockdown increased IL-6 expression. Moreover, our in vivo study found that mice with anti-IL-6 antibody or agomiR-338-5p delivery resulted in decreased IL-6 expression and alleviated DVT formation, whereas antagomiR-338-5p acted inversely. Most of miR-338-5p was found located in cytoplasm by fluorescence in situ hybridization. Dual-luciferase reporter assay identified direct binding between miR-338-5p and IL-6. CONCLUSIONS: Our results suggest that decreased miR-338-5p promotes DVT formation by increasing IL-6 expression.


Assuntos
Regulação da Expressão Gênica , Interleucina-6/genética , Extremidade Inferior/irrigação sanguínea , MicroRNAs/genética , Trombose Venosa/genética , Angiografia , Animais , Células Cultivadas , Ensaio de Imunoadsorção Enzimática , Feminino , Humanos , Interleucina-6/biossíntese , Masculino , Camundongos , Camundongos Endogâmicos C57BL , MicroRNAs/biossíntese , Pessoa de Meia-Idade , RNA/genética , Estudos Retrospectivos , Ultrassonografia Doppler em Cores , Trombose Venosa/diagnóstico , Trombose Venosa/metabolismo
18.
Drug Discov Ther ; 13(5): 261-267, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31723097

RESUMO

Insulin resistance in obese condition is related to chronic low-grade inflammation which leads to insulin signaling impairment. Centella asiatica (L.) is an herb that exhibits anti-inflammatory and blood sugar-lowering activity (hypoglycemia). The study aims to investigate the molecular mechanism of C. asiatica extract in insulin sensitivity improvement in a coculture of lipopolysaccharide (LPS)-induced 3T3-L1 adipocytes and RAW 264.7 macrophages. A coculture of 3T3-L1 adipocytes and RAW 264.7 macrophages were incubated with LPS to induce insulin resistance in the adipocytes. An extract of C. asiatica was added to coculture cells and after 24 hours, insulin sensitivity and inflammatory response were determined, including glucose consumption, glucose transporter-4 (GLUT-4), insulin receptor substrate-1 (IRS-1), and interleukin-6 (IL-6) mRNA expression. C. asiatica extract at a concentration of 500 µg/mL increased glucose consumption and induced GLUT-4 and IRS-1 mRNA expression significantly in a coculture of LPS-induced 3T3-L1 adipocytes and RAW 264.7 macrophages. The pro-inflammatory cytokines IL-6 mRNA expression was decreased in the coculture cells after treatment with C. asiatica extract at a concentration of 500 µg/mL. This result indicates that C. asiatica has an effect to stimulate glucose consumption in the coculture cells that might be mediated via GLUT-4/IRS-1 pathway as a result of IL-6 inhibition. These findings suggest that the C. asiatica extract inhibits inflammation and improves insulin sensitivity in a coculture of LPS-induced 3T3-L1 adipocytes and RAW 264.7 macrophages.


Assuntos
Adipócitos/efeitos dos fármacos , Inflamação/prevenção & controle , Resistência à Insulina , Macrófagos/efeitos dos fármacos , Triterpenos/farmacologia , Adipócitos/metabolismo , Animais , Anti-Inflamatórios/farmacologia , Técnicas de Cocultura , Glucose/metabolismo , Transportador de Glucose Tipo 4/biossíntese , Inflamação/induzido quimicamente , Proteínas Substratos do Receptor de Insulina/biossíntese , Interleucina-6/biossíntese , Lipopolissacarídeos , Macrófagos/metabolismo , Camundongos
19.
Oxid Med Cell Longev ; 2019: 1709718, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31781324

RESUMO

Objective: To observe whether metformin (MET) plays a protective role in acute lung injury (ALI) induced by paraquat (PQ) poisoning in rats by activating the AMPK/NF-κB signaling pathway. Methods: PQ exposure was used to construct a rat model of ALI and a model of acute type II alveolar epithelial cell (RLE-6TN) injury, and MET intervention was performed. Rat lung tissue samples were collected to evaluate pathological changes in rat lung tissue, the oxidation index, and inflammatory factors; cell viability was detected by CCK-8 assays, and the protein expression levels of phospho-AMPK and phospho-NF-κBp65 in rat lung tissue and RLE-6TN cells were observed by Western blotting. Results: Compared with the PQ group, the MET treatment group showed significantly (1) reduced lung wet/dry ratio (W/D: 4.67 ± 0.31 vs. 5.45 ± 0.40, P < 0.001), (2) reduced pathological changes in lung tissue, (3) decreased MDA levels (nmol/mg prot: 2.70 ± 0.19 vs. 3.08 ± 0.15, P < 0.001) and increased SOD and GSH-Px activities (U/mg prot: 76.17 ± 5.22 vs. 45.23 ± 6.58, 30.40 ± 2.84 vs. 21.00 ± 3.20; all P < 0.001) in lung tissue homogenate, (4) reduced levels of IL-1ß, IL-6, and TNF-α in lung tissue homogenates (pg/mL: 47.87 ± 5.06 vs. 66.77 ± 6.55; 93.03 ± 7.41 vs. 107.39 ± 9.81; 75.73 ± 6.08 vs. 89.12 ± 8.94; all P < 0.001), (5) increased activity of RLE-6TN cells (%: 0.69 ± 0.09, 0.76 ± 0.06, and 0.58 ± 0.03 vs. 0.50 ± 0.05; all P < 0.05), (6) decreased protein levels of phospho-NF-κBp65 in lung homogenates and RLE-6TN cells (p-NF-κB/NF-κB: 0.47 ± 0.09 vs. 0.81 ± 0.13; 0.26 ± 0.07 vs. 0.79 ± 0.13; all P < 0.01), and (7) upregulated protein expression of phospho-AMPK in lung homogenates and RLE-6TN cells (p-AMPK/AMPK: 0.88 ± 0.05 vs. 0.36 ± 0.12; 0.93 ± 0.03 vs. 0.56 ± 0.15; all P < 0.01). After the addition of the AMPK inhibitor Compound C (Com C), the protein expression levels of phospho-AMPK and phospho-NF-κBp65 returned to baseline. Conclusion: MET can effectively alleviate ALI induced by paraquat poisoning and increase the viability of cells exposed to paraquat. The mechanism may be related to the activation of the AMPK/NF-κB pathway, downregulation of inflammatory mediators such as IL-6 and TNF-α, and upregulation of the SOD and GSH-Px oxidation index, and these effects can be inhibited by the AMPK inhibitor Com C.


Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Lesão Pulmonar Aguda/prevenção & controle , Pulmão/metabolismo , Metformina/farmacologia , Paraquat/envenenamento , Transdução de Sinais/efeitos dos fármacos , Lesão Pulmonar Aguda/induzido quimicamente , Lesão Pulmonar Aguda/metabolismo , Lesão Pulmonar Aguda/patologia , Animais , Regulação para Baixo/efeitos dos fármacos , Interleucina-6/biossíntese , Pulmão/patologia , Masculino , Ratos , Ratos Sprague-Dawley , Fator de Transcrição RelA/metabolismo , Fator de Necrose Tumoral alfa/biossíntese
20.
Int J Mol Sci ; 20(22)2019 Nov 07.
Artigo em Inglês | MEDLINE | ID: mdl-31703282

RESUMO

The Janus kinase-2/ signal transducer and activators of transcription-3 (JAK2/STAT3) pathway and interleukin-6 (IL-6) are pleiotropic signal transduction systems that are responsible for induction of many cytokines and growth factors. It is unknown whether the renin angiotensin aldosterone system (RAAS) peptide, angiotensin (Ang) III induces JAK2/STAT3 and IL-6 in vascular smooth muscle cells (VSMCs). Thus, the purpose of this study was to investigate whether Ang III induces the JAK2/STAT3 pathway leading to IL-6 production in cultured VSMCs isolated from Wistar rats and determine whether differences exist in spontaneously hypertensive rat (SHR) VSMCs. We gauged Ang III's effects on this pathway by measuring its action on STAT3 as well as IL-6 production. Ang III behaved similarly as Ang II in stimulation of STAT3 phosphorylation in Wistar and SHR VSMCs. Moreover, there were no differences in this Ang III effect in SHR versus Wistar VSMCs. In Wistar VSMCs, Ang II and Ang III significantly induced IL-6 protein secretion and mRNA expression. However, IL-6 protein secretions mediated by these peptides were significantly greater in SHR VSMCs. Ang III induced the JAK2/STAT3 pathway, leading to IL-6 protein secretion and IL-6 mRNA expression via actions on AT1Rs. Moreover, the actions of Ang III to induce IL-6 production was dysregulated in SHR VSMCs. These findings suggest that Ang III acts on AT1Rs to induce JAK2/STAT3, leading to an increase in IL-6 in cultured VSMCs. These findings are important in establishing Ang III as an important physiologically relevant peptide in VSMCs.


Assuntos
Angiotensina III/farmacologia , Interleucina-6/biossíntese , Janus Quinase 2/metabolismo , Músculo Liso Vascular/metabolismo , Miócitos de Músculo Liso/metabolismo , Fator de Transcrição STAT3/metabolismo , Animais , Masculino , Músculo Liso Vascular/patologia , Miócitos de Músculo Liso/patologia , Ratos , Ratos Endogâmicos SHR , Ratos Wistar
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