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1.
J Oral Sci ; 62(4): 423-426, 2020 Sep 26.
Artigo em Inglês | MEDLINE | ID: mdl-32863319

RESUMO

PURPOSE: Diabetes causes hyperglycemic disorders due to insufficient activity of insulin, and it also increases blood glucose level. Recent studies have reported the relationship between diabetes and periodontal disease. Periodontitis is advanced by inflammatory cytokines stimulated with LPS. The purpose of this study was to investigate the effects of hyperglycemia on the expression of inflammatory cytokines induced by LPS in osteoblasts. METHODS: Cells were cultured for 7 and 14 days in the presence or absence of LPS and glucose. The expression mRNA level of IL-6, RANKL and OCN was determined using real-time PCR. The protein expression of IL-6 and RANKL was also measured using ELISA. RESULTS: LPS and glucose increased the mRNA expression of IL-6, coupled with a decrease in the mRNA expression of OCN, which is associated with IL-6 and glucose. It also increased the protein expression of IL-6 compared to LPS. However, LPS+Glucose did not affect the mRNA and protein expression of RANKL. Furthermore, GLUT4 inhibitor, WZB117, blocked the stimulatory effect of glucose on LPS-induced IL-6 mRNA expression. WZB117 did not affect LPS-reduced OCN mRNA expression. CONCLUSION: These results suggest that high glucose levels increase LPS-induced IL-6 expression mediated by GLUT4.


Assuntos
Transportador de Glucose Tipo 4/fisiologia , Interleucina-6 , Lipopolissacarídeos , Glucose , Proteínas Facilitadoras de Transporte de Glucose , Interleucina-6/metabolismo , Osteoblastos/metabolismo
2.
Front Immunol ; 11: 1708, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32754163

RESUMO

Severe acute respiratory syndrome coronavirus 2 (SARS-Cov-2) is the pathogen that causes coronavirus disease 2019 (COVID-19). As of 25 May 2020, the outbreak of COVID-19 has caused 347,192 deaths around the world. The current evidence showed that severely ill patients tend to have a high concentration of pro-inflammatory cytokines, such as interleukin (IL)-6, compared to those who are moderately ill. The high level of cytokines also indicates a poor prognosis in COVID-19. Besides, excessive infiltration of pro-inflammatory cells, mainly involving macrophages and T-helper 17 cells, has been found in lung tissues of patients with COVID-19 by postmortem examination. Recently, increasing studies indicate that the "cytokine storm" may contribute to the mortality of COVID-19. Here, we summarize the clinical and pathologic features of the cytokine storm in COVID-19. Our review shows that SARS-Cov-2 selectively induces a high level of IL-6 and results in the exhaustion of lymphocytes. The current evidence indicates that tocilizumab, an IL-6 inhibitor, is relatively effective and safe. Besides, corticosteroids, programmed cell death protein (PD)-1/PD-L1 checkpoint inhibition, cytokine-adsorption devices, intravenous immunoglobulin, and antimalarial agents could be potentially useful and reliable approaches to counteract cytokine storm in COVID-19 patients.


Assuntos
Betacoronavirus/imunologia , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/imunologia , Interleucina-6/metabolismo , Pneumonia Viral/tratamento farmacológico , Pneumonia Viral/imunologia , Corticosteroides/uso terapêutico , Animais , Anticorpos Monoclonais Humanizados/farmacologia , Anticorpos Monoclonais Humanizados/uso terapêutico , Antimaláricos/uso terapêutico , Artesunato/uso terapêutico , Infecções por Coronavirus/virologia , Hemoperfusão/métodos , Humanos , Hidroxicloroquina/uso terapêutico , Imunoglobulinas Intravenosas/uso terapêutico , Interleucina-6/antagonistas & inibidores , Camundongos , Pandemias , Pneumonia Viral/virologia , Receptor de Morte Celular Programada 1/antagonistas & inibidores
3.
Stem Cell Res Ther ; 11(1): 361, 2020 08 18.
Artigo em Inglês | MEDLINE | ID: mdl-32811531

RESUMO

BACKGROUND: COVID-19 is a highly infectious respiratory disease. No therapeutics have yet been proven effective for treating severe COVID-19. OBJECTIVES: To determine whether human umbilical cord mesenchymal stem cell infusion may be effective and safe for the treatment of severe COVID-19. METHODS: Patients with severe COVID-19 were randomly divided into 2 groups: the standard treatment group and the standard treatment plus hUC-MSC infusion group. The incidence of progression from severe to critical illness, 28-day mortality, clinical symptom improvement, time to clinical symptom improvement, hematologic indicators including C-reactive protein, lymphocyte number, and interleukin 6, and imaging changes were observed and compared between the two groups. MEASUREMENTS AND MAIN RESULTS: The incidence of progression from severe to critical illness and the 28-day mortality rate were 0 in the hUC-MSC treatment group, while 4 patients in the control group deteriorated to critical condition and received invasive ventilation; 3 of them died, and the 28-day mortality rate was 10.34%. In the hUC-MSC treatment group, the time to clinical improvement was shorter than that in the control group. Clinical symptoms of weakness and fatigue, shortness of breath, and low oxygen saturation obviously improved beginning on the third day of stem cell infusion and reached a significant difference on day 7. CRP and IL-6 levels were significantly lower from day 3 of infusion, the time for the lymphocyte count to return to the normal range was significantly faster, and lung inflammation absorption was significantly shorter on CT imaging in the hUC-MSC group than in the control group. CONCLUSIONS: Intravenous transplantation of hUC-MSCs is a safe and effective method that can be considered a salvage and priority treatment option for severe COVID-19. TRIAL REGISTRATION: Chinese Clinical Trial Registration; ChiCTR2000031494; Registered on 2 April 2020; http:// www.medresman.org.


Assuntos
Infecções por Coronavirus/terapia , Transplante de Células-Tronco Mesenquimais , Pneumonia Viral/terapia , Cordão Umbilical/citologia , Adulto , Idoso , Betacoronavirus/isolamento & purificação , Betacoronavirus/patogenicidade , Proteína C-Reativa/metabolismo , China , Infecções por Coronavirus/mortalidade , Infecções por Coronavirus/virologia , Feminino , Humanos , Interleucina-6/metabolismo , Contagem de Linfócitos , Masculino , Células-Tronco Mesenquimais/citologia , Células-Tronco Mesenquimais/metabolismo , Pessoa de Meia-Idade , Pandemias , Pneumonia Viral/mortalidade , Pneumonia Viral/virologia , Taxa de Sobrevida , Tórax/diagnóstico por imagem , Tomografia Computadorizada por Raios X , Transplante Homólogo , Resultado do Tratamento
4.
Int J Biol Sci ; 16(13): 2382-2391, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32760206

RESUMO

COVID-19 is a public health emergency that has rapidly spread to over 200 countries and regions, and no effective treatment has been established to date. Severe and critical cases have been associated with higher mortality due to acute respiratory distress syndrome (ARDS) and cytokine storm. Based on the novelty and recent emergence of COVID-19, no effective treatment regimen has been identified, thus prompting clinicians to engage in drug repurposing to address the immediate therapeutic need. This study focused on the molecular target angiotensin-converting enzyme 2 (ACE2) of SARS-CoV-2 and screened a group of ACE2 agonists by bioinformatics. Glucocorticoids are a type of ACE2 activator. We verified the efficacy of nine chemicals on regulating ACE2 expression in human GES-1, an upper digestive tract epithelial cell line, and THP-1, a human monocyte cell line, and found that several glucocorticoids imparted activating effects on ACE2 in both cell lines. The drugs triciribine and kinetin riboside activate ACE2 expression or inhibit IL-6 production in macrophages to some extent. In addition, we compared the efficacies of several glucocorticoids. Hydrocortisone showed the strongest effect on ACE2 activation, followed by prednisolone, dexamethasone, and methylprednisolone. We retrospectively analyzed the therapeutic efficacy of nine severe or critical patients from a cohort of 90 COVID-19 cases, who received medium to small doses of glucocorticoids from our integrated medical team in Wuhan. Seven out of nine patients revealed significant improvement in clinical parameters and chest CT images. This study provides experimental and clinical evidence that medium-to-low-dose glucocorticoids may play a protective role in the respiratory and digestive systems by activating ACE2 and suppressing cytokine storm.


Assuntos
Infecções por Coronavirus/tratamento farmacológico , Glucocorticoides/uso terapêutico , Interleucina-6/metabolismo , Peptidil Dipeptidase A/metabolismo , Pneumonia Viral/tratamento farmacológico , Adenosina/uso terapêutico , Adulto , Idoso , Antivirais/uso terapêutico , Betacoronavirus , Linhagem Celular , Linhagem Celular Tumoral , Infecções por Coronavirus/metabolismo , Citocinas/metabolismo , Células Epiteliais/virologia , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Hidrocortisona/uso terapêutico , Cinetina/uso terapêutico , Macrófagos/efeitos dos fármacos , Masculino , Pessoa de Meia-Idade , Monócitos/virologia , Pandemias , Pneumonia Viral/metabolismo , Estudos Retrospectivos , Ribonucleosídeos/uso terapêutico , Transcriptoma
5.
Proc Natl Acad Sci U S A ; 117(36): 22351-22356, 2020 09 08.
Artigo em Inglês | MEDLINE | ID: mdl-32826331

RESUMO

Cytokine release syndrome (CRS) is a life-threatening complication induced by systemic inflammatory responses to infections, including bacteria and chimeric antigen receptor T cell therapy. There are currently no immunotherapies with proven clinical efficacy and understanding of the molecular mechanisms of CRS pathogenesis is limited. Here, we found that patients diagnosed with CRS from sepsis, acute respiratory distress syndrome (ARDS), or burns showed common manifestations: strikingly elevated levels of the four proinflammatory cytokines interleukin (IL)-6, IL-8, monocyte chemotactic protein-1 (MCP-1), and IL-10 and the coagulation cascade activator plasminogen activator inhibitor-1 (PAI-1). Our in vitro data indicate that endothelial IL-6 trans-signaling formed an inflammation circuit for robust IL-6, IL-8, and MCP-1 production and promoted PAI-1 production; additionally, an IL-6 signaling blockade by the human monoclonal antibody tocilizumab blunted endothelial cell activation. Plasma from severe COVID-19 patients similarly exhibited increased IL-6, IL-10, and MCP-1 levels, but these levels were not as high as those in patients with CRS from other causes. In contrast, the PAI-1 levels in COVID-19 patients were as highly elevated as those in patients with bacterial sepsis or ARDS. Tocilizumab treatment decreased the PAI-1 levels and alleviated critical illness in severe COVID-19 patients. Our findings suggest that distinct levels of cytokine production are associated with CRS induced by bacterial infection and COVID-19, but both CRS types are accompanied by endotheliopathy through IL-6 trans-signaling. Thus, the present study highlights the crucial role of IL-6 signaling in endothelial dysfunction during bacterial infection and COVID-19.


Assuntos
Síndrome da Liberação de Citocina/metabolismo , Células Endoteliais/metabolismo , Interleucina-6/metabolismo , Inibidor 1 de Ativador de Plasminogênio/metabolismo , Transdução de Sinais , Adulto , Idoso , Anticorpos Monoclonais Humanizados/uso terapêutico , Betacoronavirus , Queimaduras/metabolismo , Queimaduras/patologia , Células Cultivadas , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/metabolismo , Infecções por Coronavirus/patologia , Síndrome da Liberação de Citocina/tratamento farmacológico , Síndrome da Liberação de Citocina/patologia , Citocinas/sangue , Citocinas/metabolismo , Células Endoteliais/efeitos dos fármacos , Feminino , Humanos , Inflamação , Interleucina-6/sangue , Masculino , Pessoa de Meia-Idade , Pandemias , Inibidor 1 de Ativador de Plasminogênio/sangue , Pneumonia Viral/tratamento farmacológico , Pneumonia Viral/metabolismo , Pneumonia Viral/patologia , Receptores de Interleucina-6/antagonistas & inibidores , Receptores de Interleucina-6/metabolismo , Síndrome do Desconforto Respiratório do Adulto/metabolismo , Síndrome do Desconforto Respiratório do Adulto/patologia , Sepse/metabolismo , Sepse/patologia
6.
Life Sci ; 258: 118217, 2020 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-32768575

RESUMO

AIMS: Astrocytes expressing the aquaporin-4 (AQP4) water channel are pathogenic, disease specific immunoglobulins (IgG) found in neuromyelitis optica spectrum disorder (NMOSD), referred to as NMO-IgG, which targets astrocytic AQP4. The interleukin-6 (IL-6) signaling when astrocytes were exposed to NMO-IgG present in the serum of NMOSD patients was evaluated. MAIN METHODS: Serum or human-IgG from NMOSD or healthy controls were exposed to astrocytes. The selectivity and immuno-pathological consequences of Ig binding to surface epitopes were measured by confocal microscopy. Astrocytes were exposed to medium, IL-6, soluble IL-6 receptor (sIL-6R), IL-6 + sIL-6R (IL-6/R), NMO-IgG or control-IgG, NMO-IgG + IL-6/R. The expression of key proteins in IL-6 signaling pathway, IL-6 cytokine and mRNA levels were evaluated by western blotting, enzyme-linked immunosorbent assay and quantitative polymerase chain reaction, respectively. KEY FINDINGS: Serum or NMO-IgG from NMOSD patients both induced the rapid downregulation of AQP4 expression on the surface of astrocytes. Stimulation of astrocytes with NMO-IgG, IL-6/R, and NMO-IgG + IL-6/R resulted in the enhancement of IL-6 mRNA expression. Meanwhile, the exogenous addition of NMO-IgG elicited an inflammatory transcriptional response that involved signaling through the Janus kinase/signal transducer and activator of transcription 3 (JAK/STAT3) pathway. Inhibition of the IL-6/JAK/STAT3 pathway with the JAK1/2 specific inhibitor, AZD1480, reversed the associated increase of IL-6. SIGNIFICANCE: Our findings suggest that NMO-IgG can stimulate the astrocytic JAK1/2/STAT3-dependent inflammatory response, which represents one of the important events in NMO pathogenesis. Inhibition of the JAK1/2 signaling pathway may be a novel promising therapy for NMOSD.


Assuntos
Astrócitos/metabolismo , Imunoglobulina G/sangue , Interleucina-6/metabolismo , Janus Quinases/metabolismo , Neuromielite Óptica/sangue , Fator de Transcrição STAT3/metabolismo , Adulto , Idoso , Animais , Astrócitos/efeitos dos fármacos , Autoanticorpos/sangue , Autoanticorpos/farmacologia , Células Cultivadas , Feminino , Humanos , Imunoglobulina G/farmacologia , Interleucina-6/agonistas , Masculino , Pessoa de Meia-Idade , Ratos , Ratos Wistar , Fator de Transcrição STAT3/agonistas , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/fisiologia , Adulto Jovem
7.
Nat Commun ; 11(1): 4075, 2020 08 14.
Artigo em Inglês | MEDLINE | ID: mdl-32796847

RESUMO

Hematopoietic ageing involves declining erythropoiesis and lymphopoiesis, leading to frequent anaemia and decreased adaptive immunity. How intrinsic changes to the hematopoietic stem cells (HSCs), an altered microenvironment and systemic factors contribute to this process is not fully understood. Here we use bone marrow stromal cells as sensors of age-associated changes to the bone marrow microenvironment, and observe up-regulation of IL-6 and TGFß signalling-induced gene expression in aged bone marrow stroma. Inhibition of TGFß signalling leads to reversal of age-associated HSC platelet lineage bias, increased generation of lymphoid progenitors and rebalanced HSC lineage output in transplantation assays. In contrast, decreased erythropoiesis is not an intrinsic property of aged HSCs, but associated with decreased levels and functionality of erythroid progenitor populations, defects ameliorated by TGFß-receptor and IL-6 inhibition, respectively. These results show that both HSC-intrinsic and -extrinsic mechanisms are involved in age-associated hematopoietic decline, and identify therapeutic targets that promote their reversal.


Assuntos
Envelhecimento/metabolismo , Células-Tronco Hematopoéticas/metabolismo , Interleucina-6/metabolismo , Células-Tronco Mesenquimais/metabolismo , Fator de Crescimento Transformador beta1/metabolismo , Envelhecimento/genética , Animais , Medula Óssea , Ciclo Celular/fisiologia , Células Cultivadas , Modelos Animais de Doenças , Células Precursoras Eritroides , Eritropoese/genética , Eritropoese/fisiologia , Feminino , Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Hematopoese , Interleucina-6/genética , Linfopoese/genética , Linfopoese/fisiologia , Proteínas de Membrana , Camundongos , Camundongos Endogâmicos C57BL , Células Mieloides , Transdução de Sinais , Nicho de Células-Tronco , Fator de Crescimento Transformador beta1/genética
8.
Life Sci ; 258: 118177, 2020 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-32738364

RESUMO

AIM: Omapatrilat is an antagonist of angiotensin-converting (ACE) and neprilysin-neuropeptidase (NEP) enzymes. The aim of our study is to show that omapatrilat may have beneficial effects as a treatment for polymicrobial sepsis. MAIN METHODS: A cecal ligation and puncture (CLP) sepsis model was used to evaluate 10 and 20 mg/kg doses of omapatrilat in mice (n = 30) fasted for 12 h. The lungs were removed 12 h after CLP, and lung levels of cytokines (tumor necrosis factor-alpha [TNF-α], interleukin-6 [IL-6], NF-κB), iNOS and eNOS mRNA expression, GSH and MDA levels, and ACE and NEP activities were determined. Histopathological examinations were also performed. KEY FINDINGS: Omapatrilat treatment provided a dose-dependent reduction in oxidative stress and inflammatory parameters in lung tissues. Omapatrilat administration decreased lung iNOS and eNOS mRNA levels at 20 mg/kg dose. Histopathological analysis revealed a decline in the thickening and edema areas in the alveolar septa in the Sepsis+OMA20 group. SIGNIFICANCE: Omapatrilat, a dual ACE and NEP inhibitor, protected lung tissue from sepsis damage by reducing ACE and NEP activities, by decreasing the mRNA expression levels of pro-inflammatory cytokines (TNF-α, IL-6, and NF-κB), by suppressing leukocyte infiltration and edema, by restoring iNOS and eNOS levels, and by restoring SOD activity and GSH and MDA levels, thereby reducing oxidative stress.


Assuntos
Neprilisina/metabolismo , Peptidil Dipeptidase A/metabolismo , Sepse/enzimologia , Transdução de Sinais , Animais , Biomarcadores/metabolismo , Interleucina-6/genética , Interleucina-6/metabolismo , Pulmão/enzimologia , Pulmão/patologia , Masculino , Camundongos Endogâmicos BALB C , NF-kappa B/metabolismo , Óxido Nítrico Sintase Tipo II/metabolismo , Óxido Nítrico Sintase Tipo III/metabolismo , Estresse Oxidativo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Sepse/patologia , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/metabolismo
9.
Biomed Pharmacother ; 129: 110436, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32768938

RESUMO

The present study investigates the differences in inflammatory agents alterations, immune function, and leukocyte differential count evaluation in severe pneumonia of SARS-COV-2 patients with Yidu-toxicity blocking lung syndrome after the recommended Chinese medicine prescription of Yidu-toxicity blocking lung decoction. A total of 40 patients with yidu-toxicity blocking lung syndrome, diagnosed as severe pneumonia of SARS-COV-2 following the latest Chinese national recommendations for the diagnosis and treatment of pneumonia caused by SARS-COV-2 (the 5th edition), were recruited. They were randomly divided into the pure western medicine therapy group (PWM) and integrated into Chinese and Western medicine therapy group (ICW). The general strategies were given to both groups according to the national recommendations, and the ICW group was given Yidu-toxicity blocking lung decoction extraorally. A radioimmunoassay method was adopted to detect the content of IL-6, IL-8,IL-2R,TNF-α, procalcitonin (PCT) and high-sensitivity C-reactive protein (hs-CRP) in sera. Flow cytometry was used to determine the peripheral blood lymphocyte subsets (the levels of CD3+, CD4+, CD8+, and the ratios of CD4+/CD8+). The white blood cell counts (WBC#), neutrophils count(N#), and lymphocyte counts (L#) were measured using a fully automatic blood rheological instrument. The t-test or Rank Sum Test and Spearman analysis were conducted to evaluate the differences. The results showed that IL-6 (P = 0.013) and TNF-α (P = 0.035) levels in the PWM group were significantly higher than those in the ICW group after treatment. Infection related indicators such as WBC#, N#, L#, hs-CRP showed no differences. The analysis showed that there was no statistical difference in the values of CD4 and CD8 between the two groups. By the end of Day 29, all patients were discharged and the final cure rate for both group were 100 %. Taken together, we conclude that Yidu-toxicity blocking lung decoction could relieve inflammation of SARS-COV-2 patients with yidu-toxicity blocking lung syndrome by eliminating inflammatory agents. CM can serve as a complementary medication to western medicine, which should be highlighted in clinical settings.


Assuntos
Infecções por Coronavirus/tratamento farmacológico , Medicamentos de Ervas Chinesas/farmacologia , Inflamação/tratamento farmacológico , Pneumonia Viral/tratamento farmacológico , Betacoronavirus/efeitos dos fármacos , Betacoronavirus/isolamento & purificação , Infecções por Coronavirus/virologia , Medicamentos de Ervas Chinesas/administração & dosagem , Feminino , Humanos , Inflamação/virologia , Interleucina-6/metabolismo , Contagem de Leucócitos , Contagem de Linfócitos , Subpopulações de Linfócitos , Masculino , Pessoa de Meia-Idade , Pandemias , Pneumonia Viral/virologia , Índice de Gravidade de Doença , Fator de Necrose Tumoral alfa/metabolismo
11.
Anticancer Res ; 40(8): 4711-4717, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32727797

RESUMO

BACKGROUND: Continuous oral administration of lipopolysaccharide (LPS) enhances the phagocytic ability of macrophages, which is useful for preventing various diseases. Here, we attempted to create an in vitro model of continuous administration of LPS. MATERIALS AND METHODS: RAW264.7 cells were stimulated with LPS three times every 24 h (repeated stimulation), and phagocytic ability and inflammatory cytokine [interleukin-6 (IL6) and tumor necrosis factor-α (TNFα)] production were measured. RESULTS: The phagocytic ability was increased by a single stimulation with LPS and was maintained by repeated stimulation. IL6 production increased with a single stimulation with LPS; however, IL6 production by repeated stimulation with LPS was comparable to that of non-stimulation with LPS. On the other hand, the amount of TNFα was significantly increased by single and repeated stimulation with LPS. CONCLUSION: Repeated stimulation with LPS in RAW264.7 cells triggered a phenotype that was similar to that of macrophages after continuous oral administration of LPS. This suggests that this study model may reproduce the enhancement of macrophage phagocytosis, an effect afforded by continuous oral administration of LPS.


Assuntos
Lipopolissacarídeos/farmacologia , Macrófagos/efeitos dos fármacos , Fagocitose/efeitos dos fármacos , Animais , Linhagem Celular , Citocinas/metabolismo , Interleucina-6/metabolismo , Macrófagos/metabolismo , Camundongos , Células RAW 264.7 , Fator de Necrose Tumoral alfa/metabolismo
12.
PLoS One ; 15(7): e0234614, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32649728

RESUMO

Exosomes appear to be effective inter-cellular communicators delivering several types of molecules, such as proteins and RNAs, suggesting that they could influence neural stem cell (NSC) differentiation. Our RNA sequencing studies demonstrated that the RNAs related to cell proliferation and astrocyte differentiation were upregulated in human mesenchymal stem cells (hMSC) when co-cultured with exosomes obtained from the culture medium of human glioma cells (U87). Metallothionein 3 and elastin genes, which are related to cell proliferation, increased 10 and 7.2 fold, respectively. Expression of genes for astrocyte differentiation, such as tumor growth factor alpha, induced protein 3 of the NOTCH1 family, colony stimulating factor and interleukin 6 of the STAT3 family and Hes family bHLH transcription factor 1 also increased by 2.3, 10, 4.7 and 2.9 fold, respectively. We further examined the effects of these exosomes on rat fetal neural stem cell (rNSC) differentiation using the secreted exosomes from U87 glioma cells or exosomes from U87 cells that were stimulated with interleukin 1ß (IL-1ß). The rNSCs, extracted from rat brains at embryonic day 14 (E14), underwent a culture protocol that normally leads to predominant (~90%) differentiation to ODCs. However, in the presence of the exosomes from untreated or IL-1ß-treated U87 cells, significantly more cells differentiated into astrocytes, especially in the presence of exosomes obtained from the IL-1ß-challenged glioma cells. Moreover, glioma-derived exosomes appeared to inhibit rNSC differentiation into ODCs or astrocytes as indicated by a significantly increased population of unlabeled cells. A portion of the resulting astrocytes co-expressed both CD133 and glial fibrillary acidic protein (GFAP) suggesting that exosomes from U87 cells could promote astrocytic differentiation of NSCs with features expected from a transformed cell. Our data clearly demonstrated that exosomes secreted by human glioma cells provide a strong driving force for rat neural stem cells to differentiate into astrocytes, uncovering potential pathways and therapeutic targets that might control this aggressive tumor type.


Assuntos
Astrócitos/metabolismo , Diferenciação Celular/fisiologia , Exossomos/fisiologia , Células-Tronco Neurais/metabolismo , Animais , Astrócitos/fisiologia , Proliferação de Células , Células Cultivadas , Técnicas de Cocultura , Elastina/metabolismo , Exossomos/metabolismo , Regulação da Expressão Gênica/genética , Glioma/metabolismo , Humanos , Interleucina-6/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Células-Tronco Neurais/fisiologia , Neurônios/metabolismo , Cultura Primária de Células , Ratos , Fator de Transcrição STAT3/metabolismo
13.
Int J Immunogenet ; 47(4): 319-323, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32654378

RESUMO

Susceptibility to viral infection, development of immunity, response to treatment and patient clinical outcomes are all under the control of heritable factors in the host. In the context of the current SARS-Cov-2 pandemic, this review considers existing immunogenetic knowledge of virus-immune system interactions. A major focus is to highlight areas in which work is required in order to improve understanding of antiviral immune responses and to move towards improved patient management.


Assuntos
Infecções por Coronavirus/imunologia , Infecções por Coronavirus/patologia , Síndrome da Liberação de Citocina/imunologia , Imunidade Inata/imunologia , Pneumonia Viral/imunologia , Pneumonia Viral/patologia , Betacoronavirus/imunologia , Infecções por Coronavirus/tratamento farmacológico , Síndrome da Liberação de Citocina/tratamento farmacológico , Síndrome da Liberação de Citocina/patologia , Suscetibilidade a Doenças/imunologia , Humanos , Interleucina-1beta/metabolismo , Interleucina-6/metabolismo , Pandemias , Pneumonia Viral/tratamento farmacológico , Fator de Necrose Tumoral alfa/metabolismo
15.
Gene ; 759: 144969, 2020 Oct 30.
Artigo em Inglês | MEDLINE | ID: mdl-32712064

RESUMO

Sepsis-induced acute lung injury (ALI) remains one of the most common disorders in hospitals. The aim of this research was to explore the underlying characteristics and mechanisms of artesunate (AS) in protecting rat lungs from sepsis. The sepsis-induced ALI model was generated in SD rats by the intratracheal administration of lipopolysaccharide (LPS, 5 mg/kg) for 24 h. The rats were randomly assigned into 4 groups: Sham, LPS, LPS + AS, and LPS + AS + LY294002. Pathological evaluation of the lungs was conducted by HE staining, immunofluorescence, and TUNEL assay, and the MPO activity and the W/D ratio of each group were evaluated. The levels of inflammatory mediators (TNF-α and IL-6) were measured by immunoblotting, immunofluorescence and real-time PCR. Western blotting was used to determine the protein levels of PI3K, cleaved Caspase-3, p-mTOR, mTOR, p-Akt, and Akt in the lungs. The MPO activity, W/D ratio and lung injury score were obviously elevated after induction of ALI by LPS. Nevertheless, these alterations could be inhibited by AS. In addition, sepsis decreased the levels of p-mTOR, p-Akt, and PI3K and elevated the expression of cl-caspase-3, TNF-α, and IL-6 in the lungs. After AS administration, these alterations were obviously decreased, but treatment with the PI3K antagonist LY294002 inhibited the function of AS. AS could partially protect against LPS-induced ALI by inhibiting apoptosis and inflammatory mediator production, and this function is perhaps associated with the regulation of the mTOR/AKT/PI3K axis. These findings suggest that AS may possess certain beneficial characteristics in protecting the lungs from sepsis.


Assuntos
Lesão Pulmonar Aguda/tratamento farmacológico , Anti-Inflamatórios/uso terapêutico , Artesunato/uso terapêutico , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Sepse/complicações , Serina-Treonina Quinases TOR/metabolismo , Lesão Pulmonar Aguda/etiologia , Animais , Anti-Inflamatórios/farmacologia , Apoptose , Artesunato/farmacologia , Interleucina-6/metabolismo , Ratos , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacos , Fator de Necrose Tumoral alfa/metabolismo
16.
Diabetes Res Clin Pract ; 167: 108338, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32712122

RESUMO

AIMS: The objective of this study is to explore the association between documented diabetes, fasting plasma glucose (FPG), and the clinical outcomes of Coronavirus disease 2019 (COVID-19). METHODS: This retrospective study included 255 patients with COVID-19. Of these, 214 were admitted to isolation wards and 41were admitted to intensive care units (ICUs). Demographic, clinical, treatment, and laboratory data were collected and compared between ICU and non-ICU patients. Multivariable logistic regression models were used to explore the risk factors associated with poor clinical outcomes (ICU admission or death). RESULTS: There were significant changes in several clinical parameters in ICU patients (leukopenia, lymphopenia, elevated D-dimer, as well as higher levels of FPG, cardiac troponin, serum ferritin, IL-6, and high-sensitivity C-reactive protein)compared with non-ICU patients. The prevalence of known diabetes was substantially higher in ICU than non-ICU patients (31.7% vs. 17.8%, P = 0.0408). Multivariable regression analysis showed that a history of diabetes [odds ratio (OR), 0.099; 95% confidence interval (CI), 0.016-0.627; P = 0.014], high FPG at admission (OR, 1.587; 95% CI, 1.299-1.939, P < 0.001), high IL-6 (OR, 1.01; 95% CI, 1.002-1.018, P = 0.013), and D-dimer higher than 1 mg/L at admission (OR, 4.341; 95% CI, 1.139-16.547, P = 0.032) were independent predictors of poor outcomes. Cox proportional hazards analysis showed that compared with FPG < 7 mmol/L, FPG levels of 7.0-11.1 mmol/L and ≥ 11.1 mmol/L were associated with an increased hazard ratio (HR) for poor outcome (HR, 5.538 [95% CI, 2.269-13.51] and HR, 11.55 [95% CI, 4.45-29.99], respectively). CONCLUSION: Hyperglycemia and a history of diabetes on admission predicted poor clinical outcomes in COVID-19.


Assuntos
Glicemia/metabolismo , Infecções por Coronavirus/metabolismo , Diabetes Mellitus/metabolismo , Hiperglicemia/metabolismo , Unidades de Terapia Intensiva , Pneumonia Viral/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Betacoronavirus , China/epidemiologia , Infecções por Coronavirus/epidemiologia , Infecções por Coronavirus/mortalidade , Diabetes Mellitus/epidemiologia , Feminino , Produtos de Degradação da Fibrina e do Fibrinogênio/metabolismo , Hospitalização , Humanos , Hiperglicemia/epidemiologia , Interleucina-6/metabolismo , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Mortalidade , Análise Multivariada , Pandemias , Pneumonia Viral/epidemiologia , Pneumonia Viral/mortalidade , Prognóstico , Modelos de Riscos Proporcionais , Estudos Retrospectivos , Fatores de Risco , Índice de Gravidade de Doença , Adulto Jovem
17.
Eur J Clin Invest ; 50(10): e13362, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32726868

RESUMO

BACKGROUND: Identification of reliable outcome predictors in coronavirus disease 2019 (COVID-19) is of paramount importance for improving patient's management. METHODS: A systematic review of literature was conducted until 24 April 2020. From 6843 articles, 49 studies were selected for a pooled assessment; cumulative statistics for age and sex were retrieved in 587 790 and 602 234 cases. Two endpoints were defined: (a) a composite outcome including death, severe presentation, hospitalization in the intensive care unit (ICU) and/or mechanical ventilation; and (b) in-hospital mortality. We extracted numeric data on patients' characteristics and cases with adverse outcomes and employed inverse variance random-effects models to derive pooled estimates. RESULTS: We identified 18 and 12 factors associated with the composite endpoint and death, respectively. Among those, a history of CVD (odds ratio (OR) = 3.15, 95% confidence intervals (CIs) 2.26-4.41), acute cardiac (OR = 10.58, 5.00-22.40) or kidney (OR = 5.13, 1.78-14.83) injury, increased procalcitonin (OR = 4.8, 2.034-11.31) or D-dimer (OR = 3.7, 1.74-7.89), and thrombocytopenia (OR = 6.23, 1.031-37.67) conveyed the highest odds for the adverse composite endpoint. Advanced age, male sex, cardiovascular comorbidities, acute cardiac or kidney injury, lymphocytopenia and D-dimer conferred an increased risk of in-hospital death. With respect to the treatment of the acute phase, therapy with steroids was associated with the adverse composite endpoint (OR = 3.61, 95% CI 1.934-6.73), but not with mortality. CONCLUSIONS: Advanced age, comorbidities, abnormal inflammatory and organ injury circulating biomarkers captured patients with an adverse clinical outcome. Clinical history and laboratory profile may then help identify patients with a higher risk of in-hospital mortality.


Assuntos
Lesão Renal Aguda/epidemiologia , Doenças Cardiovasculares/epidemiologia , Infecções por Coronavirus/terapia , Produtos de Degradação da Fibrina e do Fibrinogênio/metabolismo , Pneumonia Viral/terapia , Pró-Calcitonina/metabolismo , Fumar/epidemiologia , Trombocitopenia/epidemiologia , Doença Aguda , Corticosteroides/uso terapêutico , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Betacoronavirus , Proteína C-Reativa/metabolismo , Transtornos Cerebrovasculares/epidemiologia , Infecções por Coronavirus/epidemiologia , Infecções por Coronavirus/metabolismo , Infecções por Coronavirus/mortalidade , Diabetes Mellitus/epidemiologia , Feminino , Ferritinas/metabolismo , Cardiopatias , Mortalidade Hospitalar , Hospitalização , Humanos , Hipertensão/epidemiologia , Unidades de Terapia Intensiva , Interleucina-6/metabolismo , Hepatopatias/epidemiologia , Linfopenia/epidemiologia , Masculino , Pessoa de Meia-Idade , Neoplasias/epidemiologia , Obesidade/epidemiologia , Pandemias , Pneumonia Viral/epidemiologia , Pneumonia Viral/metabolismo , Pneumonia Viral/mortalidade , Prognóstico , Doença Pulmonar Obstrutiva Crônica/epidemiologia , Respiração Artificial , Índice de Gravidade de Doença , Fatores Sexuais , Adulto Jovem
18.
Science ; 369(6504): 718-724, 2020 08 07.
Artigo em Inglês | MEDLINE | ID: mdl-32661059

RESUMO

Coronavirus disease 2019 (COVID-19) is characterized by distinct patterns of disease progression that suggest diverse host immune responses. We performed an integrated immune analysis on a cohort of 50 COVID-19 patients with various disease severity. A distinct phenotype was observed in severe and critical patients, consisting of a highly impaired interferon (IFN) type I response (characterized by no IFN-ß and low IFN-α production and activity), which was associated with a persistent blood viral load and an exacerbated inflammatory response. Inflammation was partially driven by the transcriptional factor nuclear factor-κB and characterized by increased tumor necrosis factor-α and interleukin-6 production and signaling. These data suggest that type I IFN deficiency in the blood could be a hallmark of severe COVID-19 and provide a rationale for combined therapeutic approaches.


Assuntos
Betacoronavirus/imunologia , Infecções por Coronavirus/imunologia , Interferon alfa-2/metabolismo , Interferon-alfa/metabolismo , Interferon beta/metabolismo , Pneumonia Viral/imunologia , Adulto , Idoso , Betacoronavirus/fisiologia , Infecções por Coronavirus/virologia , Estado Terminal , Estudos Transversais , Feminino , Perfilação da Expressão Gênica , Humanos , Imunidade Inata , Inflamação , Interleucina-6/metabolismo , Masculino , Pessoa de Meia-Idade , NF-kappa B/metabolismo , Pandemias , Pneumonia Viral/virologia , Transdução de Sinais , Subpopulações de Linfócitos T/imunologia , Fator de Necrose Tumoral alfa/metabolismo , Carga Viral
19.
PLoS One ; 15(7): e0235743, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32645052

RESUMO

Granulomatosis with polyangiitis (GPA) is an autoimmune disease affecting mainly small blood vessels. B-cells are important in the GPA pathogenesis as precursors of autoantibody-producing cells but likely also contribute (auto)antibody-independently. This has been underlined by the effectiveness of B-cell-depletion (with Rituximab) in inducing and maintaining disease remission. Mycophenolate-mofetil (MMF) and azathioprine (AZA) are immunosuppressive therapies frequently used in GPA-patients. Interestingly, MMF-treated GPA-patients are more prone to relapses than AZA-treated patients, while little is known about the influence of these drugs on B-cells. We investigated whether MMF or AZA treatment (or their active compounds) alters the circulating B-cell subset distribution and has differential effects on in vitro B-cell proliferation and cytokine production in GPA-patients that might underlie the different relapse rate. Circulating B-cell subset frequencies were determined in samples from AZA-treated (n = 13), MMF-treated (n = 12), untreated GPA-patients (n = 19) and matched HCs (n = 41). To determine the ex vivo effects of the active compounds of MMF and AZA, MPA and 6-MP respectively, on B-cell proliferation and cytokine production, PBMCs of untreated GPA-patients (n = 29) and matched HCs (n = 30) were cultured for 3-days in the presence of CpG-oligodeoxynucleotides (CpG) with MPA or 6-MP. After restimulation (with phorbol myristate acetate, calcium-ionophore), cytokine-positive B-cell frequencies were measured. Finally, to assess the effect of MMF or AZA treatment on in vitro B-cell proliferation and cytokine production, PBMCs of MMF-treated (n = 18), and AZA-treated patients (n = 28) and HCs (n = 41) were cultured with CpG. The memory B-cell frequency was increased in AZA- compared to MMF-treated patients, while no other subset was different. The active compounds of MMF and AZA showed in vitro that MPA decreased B-cell proliferation in GPA-patients and HCs. B-cell proliferation in MMF- and AZA-treated patients was not different. Finally, the IL-6+ B-cell frequency was decreased by MPA compared to 6-MP. No differences in IL-10+, IL-6+ or TNFα+ B-cell proportions or proliferation were found in MMF- and AZA-treated patients. Our results indicate that MMF could be superior to AZA in inhibiting B-cell cytokine production in GPA-patients. Future studies should assess the effects of these immunosuppressive drugs on other immune cells to elucidate mechanisms underlying the potential differences in relapse rates.


Assuntos
Linfócitos B/imunologia , Granulomatose com Poliangiite , Imunossupressores/farmacologia , Ácido Micofenólico/farmacologia , Adulto , Idoso , Azatioprina/farmacologia , Subpopulações de Linfócitos B/imunologia , Linfócitos B/efeitos dos fármacos , Linfócitos B/metabolismo , Proliferação de Células/efeitos dos fármacos , Citocinas/metabolismo , Feminino , Citometria de Fluxo , Granulomatose com Poliangiite/tratamento farmacológico , Granulomatose com Poliangiite/imunologia , Humanos , Interleucina-6/metabolismo , Masculino , Mercaptopurina/farmacologia , Pessoa de Meia-Idade
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