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1.
Mol Med Rep ; 23(1)2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33236127

RESUMO

MicroRNAs (miRs) carried in exosomes serve an important role in the pre­metastatic microenvironment and in intercellular interactions. However, the function of exosomal­miR­10a derived from primary colorectal cancer (CRC) cells on fibroblasts in the lung metastatic microenvironment of patients with CRC remains unclear. Reverse transcription­quantitative PCR was performed using samples from patients with CRC, and demonstrated that the expression levels of miR­10a were significantly lower in serum and cancer tissue samples from patients with CRC compared with in serum from healthy individuals and paired non­cancerous tissues, respectively. In addition, the expression levels of miR­10a were inversely associated with the invasion depth of CRC. Exosomal­miR­10a derived from CRC cells reduced the proliferative and migratory activities of primary normal human lung fibroblasts (NHLFs), and the expression levels of IL­6, IL­8 and IL­1ß in NHLFs. The present study provided insight into the phenotypic alterations of NHLFs induced by exosomal­miR­10a derived from CRC cells, which may aid understanding of the mechanism underlying the process of CRC lung metastasis.


Assuntos
Movimento Celular , Neoplasias Colorretais/metabolismo , Exossomos/metabolismo , Fibroblastos/metabolismo , Regulação Neoplásica da Expressão Gênica , Interleucina-1beta/biossíntese , Interleucina-6/biossíntese , Interleucina-8/biossíntese , Pulmão/metabolismo , MicroRNAs/metabolismo , Proteínas de Neoplasias/biossíntese , RNA Neoplásico/metabolismo , Linhagem Celular Tumoral , Técnicas de Cocultura , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Exossomos/genética , Fibroblastos/patologia , Humanos , Interleucina-1beta/genética , Interleucina-6/genética , Interleucina-8/genética , Pulmão/patologia , MicroRNAs/genética , Proteínas de Neoplasias/genética , RNA Neoplásico/genética
2.
Toxicol Appl Pharmacol ; 401: 115092, 2020 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-32512068

RESUMO

Inflammatory breast cancer (IBC) is a highly metastatic and lethal breast cancer. As many as 25-30% of IBCs are triple negative (TN) and associated with low survival rates and poor prognosis. We found that the microenvironment of IBC is characterized by high infiltration of tumor associated macrophages (TAMs) and by over-expression of the cysteine protease cathepsin B (CTSB). TAMs in IBC secrete high levels of the cytokines interleukin-8 (IL-8) and monocyte chemoattractant protein-1 (MCP-1/CCL2) compared to non-IBC patients. Herein, we tested the roles of IL-8 and MCP-1/CCL2 in modulating proteolytic activity and invasiveness of TN-non-IBC as compared to TN-IBC and addressed the underlying molecular mechanism(s) for both cytokines. Quantitative real time PCR results showed that IL-8 and MCP-1/CCL2 were significantly overexpressed in tissues of TN-IBCs. IL-8 and MCP-1/CCL2 induced CTSB expression and activity of the p-Src and p-Erk1/2 signaling pathways relevant for invasion and metastasis in TN-non-IBC, HCC70 cells and TN-IBC, SUM149 cells. Dasatinib, an inhibitor of p-Src, and U0126, an inhibitor of p-Erk1/2, down-regulated invasion and expression of CTSB by HCC70 and SUM149 cells, a mechanism that is reversed by IL-8 and MCP-1/CCL2. Our study shows that targeting the cytokines IL-8 and MCP-1/CCL2 and associated signaling molecules may represent a promising therapeutic strategy in TN-IBC patients.


Assuntos
Quimiocina CCL2/biossíntese , Genes src/fisiologia , Neoplasias Inflamatórias Mamárias/metabolismo , Interleucina-8/biossíntese , Sistema de Sinalização das MAP Quinases/fisiologia , Neoplasias de Mama Triplo Negativas/metabolismo , Adulto , Idoso , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Dasatinibe/farmacologia , Feminino , Genes src/efeitos dos fármacos , Humanos , Neoplasias Inflamatórias Mamárias/patologia , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Pessoa de Meia-Idade , Proteólise/efeitos dos fármacos , Neoplasias de Mama Triplo Negativas/patologia , Microambiente Tumoral/efeitos dos fármacos , Microambiente Tumoral/fisiologia
3.
Prostate ; 80(12): 938-949, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32542667

RESUMO

BACKGROUND: The clinical manifestation of benign prostatic hyperplasia (BPH) is causally linked to the inflammatory microenvironment and proliferation of epithelial and stromal cells in the prostate transitional zone. The CXC-chemokine interleukin-8 (IL-8) contributes to inflammation. We evaluated the expression of inflammatory cytokines in clinical specimens, primary cultures, and prostatic lineage cell lines. We investigated whether IL-8 via its receptor system (IL-8 axis) promotes BPH. METHODS: The messenger RNA and protein expression of chemokines, including components of the IL-8 axis, were measured in normal prostate (NP; n = 7) and BPH (n = 21), urine (n = 24) specimens, primary cultures, prostatic lineage epithelial cell lines (NHPrE1, BHPrE1, BPH-1), and normal prostate cells (RWPE-1). The functional role of the IL-8 axis in prostate epithelial cell growth was evaluated by CRISPR/Cas9 gene editing. The effect of a combination with two natural compounds, oleanolic acid (OA) and ursolic acid (UA), was evaluated on the expression of the IL-8 axis and epithelial cell growth. RESULTS: Among the 19 inflammatory chemokines and chemokine receptors we analyzed, levels of IL-8 and its receptors (CXCR1, CXCR2), as well as, of CXCR7, a receptor for CXCL12, were 5- to 25-fold elevated in BPH tissues when compared to NP tissues (P ≤ .001). Urinary IL-8 levels were threefold to sixfold elevated in BPH patients, but not in asymptomatic males and females with lower urinary tract symptoms (P ≤ .004). The expression of the IL-8 axis components was confined to the prostate luminal epithelial cells in both normal and BPH tissues. However, these components were elevated in BPH-1 and primary explant cultures as compared to RWPE-1, NHPrE1, and BHPrE1 cells. Knockout of CXCR7 reduced IL-8, and CXCR1 expression by 4- to 10-fold and caused greater than or equal to 50% growth inhibition in BPH-1 cells. Low-dose OA + UA combination synergistically inhibited the growth of BPH-1 and BPH primary cultures. In the combination, the drug reduction indices for UA and OA were 16.4 and 7852, respectively, demonstrating that the combination was effective in inhibiting BPH-1 growth at significantly reduced doses of UA or OA alone. CONCLUSION: The IL-8 axis is a promotor of BPH pathogenesis. Low-dose OA + UA combination inhibits BPH cell growth by inducing autophagy and reducing IL-8 axis expression in BPH-epithelial cells.


Assuntos
Interleucina-8/metabolismo , Próstata/metabolismo , Próstata/patologia , Hiperplasia Prostática/metabolismo , Hiperplasia Prostática/patologia , Receptores CXCR/metabolismo , Processos de Crescimento Celular/efeitos dos fármacos , Linhagem Celular , Células Cultivadas , Epitélio/efeitos dos fármacos , Epitélio/metabolismo , Epitélio/patologia , Humanos , Interleucina-8/biossíntese , Interleucina-8/genética , Masculino , Ácido Oleanólico/farmacologia , Próstata/efeitos dos fármacos , Hiperplasia Prostática/tratamento farmacológico , Hiperplasia Prostática/genética , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Receptores CXCR/biossíntese , Receptores CXCR/genética , Transdução de Sinais/efeitos dos fármacos , Triterpenos/farmacologia
4.
Mol Cancer Res ; 18(1): 153-165, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31604846

RESUMO

Chronic inflammation and African ancestry are implicated in prostate cancer aggressiveness, and inflammation-related genes are more highly expressed in prostate cancer in African American men. IL8 secretion is also implicated in prostate cancer progression and castration resistance. We used RNA in situ hybridization to localize IL1ß, IL6, IL8, and IL10 mRNA in low- and high-grade prostate cancer from African American and European American men. IL8 was the most abundantly expressed and the only interleukin detected in tumor cells. We further interrogated IL8 expression in primary and metastatic prostate cancer tissue microarrays and both androgen-dependent and castration-resistant patient-derived xenografts (PDX). IL8 was significantly increased in both tumor and benign regions of higher grade cases (ISUP Grade Group 4-5), but there was no difference between races. We determined that IL8 expression in prostate cancer cell lines, distant metastases, and PDX lines was associated with androgen receptor (AR) loss, but not castration resistance. Reciprocal IL8 and AR expression was also observed in high IL8-expressing atrophy lesions with simultaneous AR downregulation. Finally, we show that IL8 is likely repressed by AR binding to the IL8 promoter and is inducible in prostate cancer cells stimulated with lipopolysaccharide only in cells with AR loss. Likewise, AR knockdown in androgen-dependent cells induced IL8 expression, further demonstrating that AR represses IL8 expression. In conclusion, IL8 expression in the tumor microenvironment is associated with aggressive prostate cancer and with AR loss in metastatic disease. IMPLICATIONS: IL8 expression is repressed by AR and is associated with prostate cancer aggressiveness and AR loss in metastatic disease.


Assuntos
Interleucina-8/biossíntese , Neoplasias da Próstata/metabolismo , Receptores Androgênicos/deficiência , Linhagem Celular Tumoral , Células HEK293 , Humanos , Interleucina-8/metabolismo , Células MCF-7 , Masculino , Metástase Neoplásica , Células PC-3 , Neoplasias da Próstata/genética , Neoplasias da Próstata/patologia , Receptores Androgênicos/metabolismo
5.
Toxicol Lett ; 319: 256-263, 2020 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-31639410

RESUMO

Transcription factor activator protein (AP)-1 can be activated in nitrogen-mustard-injured mouse skin, and is thought to participate in the inflammatory response. AP-1 consists of homo- or heterodimers of Fos [c-Fos, Fos-B, fos-related antigen (Fra)-1 and Fra-2] and Jun (c-Jun, JunB and JunD) family members, and information about their expression, location and function are still unclear. In nitrogen-mustard-exposed mouse skin, we found p-ERK activation increased Fra-1 and FosB. Unlike the nucleus location of c-Fos and FosB, Fra-1 and Fra-2 were mainly expressed in the cytoplasm. In nitrogen-mustard-exposed cultured immortalized human keratinocytes (HaCaT cells), Fra-1 in the nucleus functioned as an inhibitor of inflammatory cytokine interleukin (IL)-8. Co-immunoprecipitation showed that Fra-1 formed dimers with IL-8 transcription factors c-Jun, JunB and JunD. Fra-1 depletion increased c-Fos and FosB in the nucleus, accompanied by increased heterodimers of c-Fos/c-Jun, c-Fos/JunB, c-Fos/JunD, and FosB/JunB. In conclusion, Fra-1 trapped in the cytoplasm after nitrogen mustard exposure might be a driving force for IL-8 over-expression in injured skin.


Assuntos
Substâncias para a Guerra Química/toxicidade , Epiderme/lesões , Epiderme/metabolismo , Interleucina-8/biossíntese , Mecloretamina/toxicidade , Proteínas Proto-Oncogênicas c-fos/metabolismo , Animais , Linhagem Celular , Núcleo Celular/efeitos dos fármacos , Núcleo Celular/metabolismo , Citoplasma/efeitos dos fármacos , Citoplasma/metabolismo , Humanos , Queratinócitos/metabolismo , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Masculino , Camundongos , Camundongos Pelados , RNA Interferente Pequeno/farmacologia
6.
Med Microbiol Immunol ; 209(1): 59-67, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31673845

RESUMO

Fungi that belong to the genus Paracoccidioides are the etiologic agents of paracoccidioidomycosis, a human systemic mycosis, which occurs in Latin America. Epithelial cell is one of the first cells that interact with these fungi and responds by secreting inflammatory mediators such as cytokines. In the present study, we demonstrate that yeasts of different isolates of Paracoccidioides brasiliensis (Pb18 and Pb03) and Paracoccidioides lutzii (Pb01) distinctly promoted interleukin (IL)-8 secretion by the lung epithelial cell line A549. Depending on the isolate, this cytokine release may rely on the epithelial cell interaction with fungal secreted components or direct contact with the pathogen. In addition, adhesion of yeasts to the pulmonary epithelial cells was also different among Paracoccidioides isolates, and the highest percentage of A549 cells with adhered fungi was observed with P. lutzii. All Paracoccidioides isolates induced an expression increase of α3 and α5 integrins in A549 cells and, using small interfering RNA, we observed that the integrin silencing promoted a reduction of P. lutzii adhesion, which suggests the involvement of integrins in this event. Together, these results indicate that host epithelial cell response may depend on the isolate of Paracoccidioides.


Assuntos
Células Epiteliais Alveolares/metabolismo , Células Epiteliais Alveolares/microbiologia , Interleucina-8/biossíntese , Paracoccidioides/fisiologia , Paracoccidioidomicose/metabolismo , Paracoccidioidomicose/microbiologia , Células A549 , Adesão Celular , Sobrevivência Celular , Células Cultivadas , Citocinas/metabolismo , Inativação Gênica , Humanos , Integrinas/genética
7.
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
8.
Sci Rep ; 9(1): 19173, 2019 12 16.
Artigo em Inglês | MEDLINE | ID: mdl-31844123

RESUMO

Extensive research has revealed the association of continued oxidative stress with chronic inflammation, which could subsequently affect many different chronic diseases. The mycotoxin deoxynivalenol (DON) frequently contaminates cereals crops worldwide, and are a public health concern since DON ingestion may result in persistent intestinal inflammation. There has also been considerable attention over the potential of DON to provoke oxidative stress. In this study, the cytoprotective effect of Schisandrin A (Sch A), one of the most abundant active dibenzocyclooctadiene lignans in the fruit of Schisandra chinensis (Turcz.) Baill (also known as Chinese magnolia-vine), was investigated in HT-29 cells against DON-induced cytotoxicity, oxidative stress and inflammation. Sch A appeared to protect against DON-induced cytotoxicity in HT-29 cells, and significantly lessened the DON-stimulated intracellular reactive oxygen species and nitrogen oxidative species production. Furthermore, Sch A lowered DON-induced catalase, superoxide dismutase and glutathione peroxidase antioxidant enzyme activities but maintains glutathione S transferase activity and glutathione levels. Mechanistic studies suggest that Sch A reduced DON-induced oxidative stress by down-regulating heme oxygenase-1 expression via nuclear factor (erythroid-derived 2)-like 2 signalling pathway. In addition, Sch A decreased the DON-induced cyclooxygenase-2 expression and prostaglandin E2 production and pro-inflammatory cytokine interleukin 8 expression and secretion. This may be mediated by preventing DON-induced translocation of nuclear factor-κB, as well as activation of mitogen-activated protein kinases pathways. In the light of these findings, we concluded that Sch A exerted a cytoprotective role in DON-induced toxicity in vitro, and it would be valuable to examine in vivo effects.


Assuntos
Ciclo-Octanos/farmacologia , Citoproteção , Enterócitos/patologia , Inflamação/patologia , Lignanas/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Compostos Policíclicos/farmacologia , Tricotecenos/toxicidade , Catalase/metabolismo , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Pontos de Checagem do Ciclo Celular/genética , Morte Celular/efeitos dos fármacos , Núcleo Celular/efeitos dos fármacos , Núcleo Celular/metabolismo , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/genética , Ciclo-Oxigenase 2/genética , Ciclo-Oxigenase 2/metabolismo , Citoproteção/efeitos dos fármacos , Dinoprostona/biossíntese , Enterócitos/efeitos dos fármacos , Enterócitos/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Glutationa Peroxidase/metabolismo , Células HT29 , Heme Oxigenase-1/genética , Heme Oxigenase-1/metabolismo , Humanos , Inflamação/genética , Mediadores da Inflamação/metabolismo , Interleucina-8/biossíntese , Peroxidação de Lipídeos/efeitos dos fármacos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Modelos Biológicos , Fator 2 Relacionado a NF-E2/metabolismo , NF-kappa B/metabolismo , Nitritos/metabolismo , Estresse Oxidativo/genética , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Superóxido Dismutase/metabolismo
9.
Front Immunol ; 10: 2643, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31803183

RESUMO

Cystic fibrosis (CF) results from deficient CF transmembrane conductance regulator (CFTR) protein activity leading to defective epithelial ion transport. Pulmonary degradation due to excessive inflammation is the main cause of morbidity and mortality in CF patients. By analysing miRNAs (small RNAseq) in human primary air-liquid interface cell cultures, we measured the overexpression of miR-636 in CF patients compared to non-CF controls. We validated these results in explant biopsies and determined that the mechanism underlying miR-636 overexpression is linked to inflammation. To identify specific targets, we used bioinformatics analysis to predict whether miR-636 targets the 3'-UTR mRNA regions of IL1R1 and RANK (two pro-inflammatory cytokine receptors), IKBKB (a major protein in the NF-κB pathway), and FAM13A (a modifier gene of CF lung phenotype implicated in epithelial remodelling). Using bronchial epithelial cells from CF patients to conduct a functional analysis, we showed a direct interaction between miR-636 and IL1R1, RANK, and IKBKB, but not with FAM13A. These interactions led to a decrease in IL1R1 and IKKß protein expression levels, while we observed an increase in RANK protein expression levels following the overexpression of miR-636. Moreover, NF-κB activity and IL-8 and IL-6 secretions decreased following the transfection of miR-636 mimics in CF cells. Similar but opposite effects were found after transfection with an antagomiR-636 in the same cells. Furthermore, we demonstrated that miR-636 was not regulated by Pseudomonas aeruginosa in our model. We went on to show that miR-636 is raised in the blood neutrophils, but not in the plasma, of CF patients and may have potential as a novel biomarker. Collectively, our findings reveal a novel actor for the regulation of inflammation in CF, miR-636, which is able to reduce constitutive NF-κB pathway activation when it is overexpressed.


Assuntos
Fibrose Cística/complicações , MicroRNAs/fisiologia , Pneumonia/etiologia , Células Cultivadas , Humanos , Quinase I-kappa B/genética , Interleucina-6/biossíntese , Interleucina-8/biossíntese , MicroRNAs/análise , NF-kappa B/fisiologia , Receptor Ativador de Fator Nuclear kappa-B/genética , Receptores Tipo I de Interleucina-1/genética , Transdução de Sinais
10.
J Med Microbiol ; 68(12): 1813-1822, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31674896

RESUMO

Introduction. Chronic pulmonary infection is associated with colonization with multiple micro-organisms but host-microbe and microbe-microbe interactions are poorly understood.Aim. This study aims to investigate the differences in host responses to mono- and co-infection with S. aureus and B. cenocepacia in human airway epithelial cells.Methodology. We assessed the effect of co-infection with B. cenocepacia and S. aureus on host signalling and inflammatory responses in the human airway epithelial cell line 16HBE, using ELISA and western blot analysis.Results. The results show that B. cenocepacia activates MAPK and NF-κB signalling pathways, subsequently eliciting robust interleukin (IL)-8 production. However, when airway epithelial cells were co-treated with live B. cenocepacia bacteria and S. aureus supernatants (conditioned medium), the pro-inflammatory response was attenuated. This anti-inflammatory effect was widely exhibited in the S. aureus isolates tested and was mediated via reduced MAPK and NF-κB signalling, but not via IL-1 receptor or tumour necrosis factor receptor modulation. The staphylococcal effectors were characterized as small, heat-stable, non-proteinaceous and not cell wall-related factors.Conclusion. This study demonstrates for the first time the host response in a S. aureus/B. cenocepacia co-infection model and provides insight into a staphylococcal immune evasion mechanism, as well as a therapeutic intervention for excessive inflammation.


Assuntos
Brônquios/imunologia , Infecções por Burkholderia/imunologia , Burkholderia cenocepacia/imunologia , Coinfecção/imunologia , Inflamação/etiologia , Infecções Estafilocócicas/imunologia , Células Cultivadas , Células Epiteliais/imunologia , Humanos , Evasão da Resposta Imune , Interleucina-8/biossíntese , Sistema de Sinalização das MAP Quinases/fisiologia , NF-kappa B/fisiologia
11.
Proc Natl Acad Sci U S A ; 116(43): 21659-21665, 2019 10 22.
Artigo em Inglês | MEDLINE | ID: mdl-31591201

RESUMO

Autism spectrum disorder (ASD) does not have a distinct pathogenesis or effective treatment. Increasing evidence supports the presence of immune dysfunction and inflammation in the brains of children with ASD. In this report, we present data that gene expression of the antiinflammatory cytokine IL-37, as well as of the proinflammatory cytokines IL-18 and TNF, is increased in the amygdala and dorsolateral prefrontal cortex of children with ASD as compared to non-ASD controls. Gene expression of IL-18R, which is a receptor for both IL-18 and IL-37, is also increased in the same brain areas of children with ASD. Interestingly, gene expression of the NTR3/sortilin receptor is reduced in the amygdala and dorsolateral prefrontal cortex. Pretreatment of cultured human microglia from normal adult brains with human recombinant IL-37 (1 to 100 ng/mL) inhibits neurotensin (NT)-stimulated secretion and gene expression of IL-1ß and CXCL8. Another key finding is that NT, as well as the proinflammatory cytokines IL-1ß and TNF increase IL-37 gene expression in cultured human microglia. The data presented here highlight the connection between inflammation and ASD, supporting the development of IL-37 as a potential therapeutic agent of ASD.


Assuntos
Tonsila do Cerebelo/metabolismo , Transtorno do Espectro Autista/metabolismo , Interleucina-1/metabolismo , Microglia/metabolismo , Neurotensina/metabolismo , Córtex Pré-Frontal/metabolismo , Proteínas Adaptadoras de Transporte Vesicular/metabolismo , Células Cultivadas , Criança , Humanos , Interleucina-18/metabolismo , Subunidade alfa de Receptor de Interleucina-18/metabolismo , Interleucina-1beta/biossíntese , Interleucina-8/biossíntese , Fator de Necrose Tumoral alfa/metabolismo
12.
Mol Med Rep ; 20(4): 2990-3002, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31432147

RESUMO

Gene expression and DNA methylation levels affect the outcomes of patients with cancer. The present study aimed to establish a multigene risk model for predicting the outcomes of patients with cervical cancer (CerC) treated with or without radiotherapy. RNA sequencing training data with matched DNA methylation profiles were downloaded from The Cancer Genome Atlas database. Patients were divided into radiotherapy and non­radiotherapy groups according to the treatment strategy. Differently expressed and methylated genes between the two groups were identified, and 8 prognostic genes were identified using Cox regression analysis. The optimized risk model based on the 8­gene signature was defined using the Cox's proportional hazards model. Kaplan­Meier survival analysis indicated that patients with higher risk scores exhibited poorer survival compared with patients with lower risk scores (log­rank test, P=3.22x10­7). Validation using the GSE44001 gene set demonstrated that patients in the high­risk group exhibited a shorter survival time comprared with the low­risk group (log­rank test, P=3.01x10­3). The area under the receiver operating characteristic curve values for the training and validation sets were 0.951 and 0.929, respectively. Cox regression analyses indicated that recurrence and risk status were risk factors for poor outcomes in patients with CerC treated with or without radiotherapy. The present study defined that the 8­gene signature was an independent risk factor for the prognosis of patients with CerC. The 8­gene prognostic model had predictive power for CerC prognosis.


Assuntos
Regulação Neoplásica da Expressão Gênica , Interleucina-8/biossíntese , Modelos Biológicos , Proteínas de Neoplasias/biossíntese , Neoplasias do Colo do Útero , Adulto , Intervalo Livre de Doença , Feminino , Humanos , Interleucina-8/genética , Pessoa de Meia-Idade , Proteínas de Neoplasias/genética , Valor Preditivo dos Testes , Taxa de Sobrevida , Neoplasias do Colo do Útero/genética , Neoplasias do Colo do Útero/metabolismo , Neoplasias do Colo do Útero/mortalidade , Neoplasias do Colo do Útero/radioterapia
13.
Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi ; 35(6): 498-504, 2019 Jun.
Artigo em Chinês | MEDLINE | ID: mdl-31292053

RESUMO

Objective To observe the effect of selectively inhibiting STAT3 on the production of IL-8 and cell apoptosis of THP-1 cells by Stattic, and explore the underlying mechanism. Methods THP-1 cells were treated with different concentrations of Stattic ( 0, 1, 5, 10, 15, 20 µmol/L) for 0, 1, 3, 6, 12, 24 hours. Reverse transcription PCR or real-time PCR was performed to detect the mRNA expression of IL-8, IL-6, IL-1ß and tumor necrosis factor-α (TNF-α); ELISA was used to detect the protein expression of IL-8; flow cytometry was applied to evaluate the apoptosis of THP-1 cells; and Western blot analysis was performed to detect the phosphorylation of STAT3 and extracellular signal-regulated kinase (ERK). Reverse transcription PCR was used to test the effect of U0126 at different concentrations (0, 1, 5, 10 µmol/L) on the mRNA expression of IL-8 induced by Stattic in THP-1 cells. Results Stattic significantly up-regulated the mRNA and protein expression of IL-8 in THP-1 cells in a concentration range of 10~20 µmol/L, and induced cell apoptosis only at high concentration (15, 20 µmol/L). Treated with Stattic for 0, 1, 3, 6, 12, 24 hours, IL-8 mRNA was significantly up-regulated, and after 6 hours, the expression of IL-8 protein and apoptosis of THP-1 cells were up-regulated in a time-dependent manner. STAT3 phosphorylation was inhibited in a time- and dose-dependent manner by Stattic. ERK phosphorylation was induced by different concentrations of Stattic in a time-dependent manner. In addition, U0126, a selective inhibitor of ERK pathway, inhibited Stattic-induced IL-8 expression in a concentration-dependent manner. Conclusion Stattic, a selective STAT3 inhibitor, can induce the apoptosis and IL-8 production by activating ERK signaling pathway in THP-1 cells.


Assuntos
Apoptose , Óxidos S-Cíclicos/farmacologia , MAP Quinases Reguladas por Sinal Extracelular , Interleucina-8/biossíntese , Fator de Transcrição STAT3/antagonistas & inibidores , Humanos , Sistema de Sinalização das MAP Quinases , Fosforilação , Células THP-1
14.
Nanotoxicology ; 13(7): 861-878, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31349755

RESUMO

Effects of two kinds of multiwall carbon nanotubes (MWCNTs) on cells were examined. The effects of MWNT-7, which has been reported to be carcinogenic, and MWCNT-B, whose toxicity is unclear, were examined in both epithelial cells and macrophages. Human lung carcinoma A549 cells were used as representative epithelial cells and differentiated human monocyte THP-1 cells, as well as rat pulmonary macrophages NR8383, were employed to examine possible harmful effects of the MWCNTs. The MWCNTs induced the production of chemokines such as interleukin-8 (IL-8). MWCNTs were found to more strongly affect macrophages than epithelial cells. In addition, the toxicity was more pronounced in the MWNT-7 exposed cells than in those exposed to MWCNT-B. Cytochalasin D and amiloride treatment of differentiated THP-1 cells reduced cell-associated MWCNTs and IL-8 induction. To confirm these cellular influences in vivo, intratracheal administration of each type of MWCNT was performed by pharyngeal aspiration in the mouse lung. Analysis of bronchoalveolar lavage fluid (BALF) showed increase of inflammatory monocyte in MWNT-7 exposed animals at 1week after. In addition, neutrophils in the BALF were also significantly increased MWNT-7 exposed animals at 1 week and 1 month after. Aspiration of MWNT-7 caused formation of granulomas in the lung. Formation of the granulomas was not observed in the case of MWCNT-B. These results suggest that cellular uptake of the MWCNTs by phagocytosis and chemokine induction is important aspects of their toxicity.


Assuntos
Células Epiteliais/efeitos dos fármacos , Macrófagos/efeitos dos fármacos , Nanotubos de Carbono/toxicidade , Animais , Células Cultivadas , Humanos , Interleucina-8/biossíntese , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Fagocitose/efeitos dos fármacos
15.
Sci Rep ; 9(1): 10513, 2019 07 19.
Artigo em Inglês | MEDLINE | ID: mdl-31324844

RESUMO

Several epidemiological studies have pointed at serum uric acid (SUA) as an independent risk factor for mortality, diabetes, hypertension, cardiovascular and kidney disease; however, no clear pathogenic pathway is established. Uric acid (UA) crystals show pro-inflammatory properties and can thus create or contribute to the state of chronic low-grade inflammation, a widely accepted pathogenic mechanism in several of the above-mentioned pathologies. On the other hand, soluble uric acid possesses antioxidant properties that might attenuate inflammatory responses. We aimed to explore the net effects of experimentally rising SUA in human whole blood cultures on several mediators of inflammation. Production of TNF-α, IL-1ß, IL-1RA, MCP-1 and IL-8 was assessed upon addition of 200 µM UA, 500 µM UA or monosodium urate (MSU) crystals in the presence or absence of 5 ng/ml lipopolysaccharide (LPS). RT-qPCR and multiplex bead based immunoassay were used to measure mRNA expression and cytokine release at 2 and 4 h of culture, respectively. 14C labeled UA was used to assess intracellular uptake of UA. We show that crystallized, but not soluble, UA induces production of pro-inflammatory mediators in human whole blood. Soluble UA is internalized in blood cells but does not potentiate or reduce LPS-induced release of cytokines.


Assuntos
Células Sanguíneas/efeitos dos fármacos , Inflamação/sangue , Ácido Úrico/farmacologia , Células Sanguíneas/metabolismo , Hemocultura , Quimiocina CCL2/biossíntese , Quimiocina CCL2/genética , Cristalização , Feminino , Humanos , Proteína Antagonista do Receptor de Interleucina 1/biossíntese , Proteína Antagonista do Receptor de Interleucina 1/genética , Interleucina-1beta/biossíntese , Interleucina-1beta/genética , Interleucina-8/biossíntese , Interleucina-8/genética , Lipopolissacarídeos/farmacologia , Masculino , RNA Mensageiro/biossíntese , Solubilidade , Fator de Necrose Tumoral alfa/biossíntese , Fator de Necrose Tumoral alfa/genética , Ácido Úrico/química
16.
Osteoarthritis Cartilage ; 27(11): 1680-1691, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31325494

RESUMO

OBJECTIVE: We evaluated the ability of Coll2-1, a type II collagen peptide, to activate pro-inflammatory pathways in synovial cells and to induce arthritis in Lewis rats. METHOD: Human synoviocytes and chondrocytes from knee OA patients were cultured for 24 h with/without Coll2-1 and/or purified immunoglobulin G (AS0619) binding specifically this peptide, and/or CLI-095, a TLR-4 signaling inhibitor and/or apocynin and diphenyleneiodonium, Reactive oxygen species (ROS) production inhibitors. The Interleukin (IL)-8 and Vascular Endothelium Growth Factor (VEGF) expression, the IL-8 production, the IκB-α and p65 phosphorylation and ROS were evaluated. Coll2-1 peptide, bovine type II collagen (CIA), streptococcal cell wall (SCW) or saline solution were injected into Lewis rats. The Coll2-1 peptide was injected subcutaneously (SC; 20-200µg/100µl/animal) or intra-articularly (IA; 0.5-5µg/50µl/animal) and compared to CIA injected in SC (200µg/100µl/animal) and SCW in IA (5µg/50µl/animal). The animals were injected on day 0 and monitored for 28 days. Histological lesions assessment was performed using an arthritis score. RESULTS: Coll2-1 peptide significantly increased IL-8 gene expression and production by synoviocytes. AS0619 and CLI-095 significantly decreased IL-8 expression. Coll2-1 induced p65 and IκBα phosphorylation and oxidative stress inhibitors decreased it. In human chondrocytes culture, Coll2-1 significantly increased MMP-3 and VEGF gene expression. In Lewis rats, CIA, SCW or Coll2-1 injection triggered arthritis. Like CIA or SCW, Coll2-1 induced synovitis, loss of cartilage proteoglycans, cartilage structure lesion and subchondral bone remodeling. CONCLUSIONS: Coll2-1 activates synoviocytes to produce IL-8 and induces arthritis in rat. These findings suggest that neutralizing Coll2-1 could be a therapeutic approach of arthritis.


Assuntos
Colágeno Tipo II/genética , Regulação da Expressão Gênica , Estresse Oxidativo , Fragmentos de Peptídeos/genética , RNA/genética , Sinoviócitos/metabolismo , Sinovite/genética , Idoso , Animais , Células Cultivadas , Colágeno Tipo II/biossíntese , Modelos Animais de Doenças , Feminino , Humanos , Interleucina-8/biossíntese , Interleucina-8/genética , Masculino , Pessoa de Meia-Idade , Fragmentos de Peptídeos/biossíntese , Ratos , Ratos Endogâmicos Lew , Sinoviócitos/patologia , Sinovite/metabolismo , Sinovite/patologia
17.
Am J Physiol Gastrointest Liver Physiol ; 317(4): G398-G407, 2019 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-31314571

RESUMO

Initial colonizing bacteria play a critical role in completing the development of the immune system in the gastrointestinal tract of infants. Yet, the interaction of colonizing bacterial organisms with the developing human intestine favors inflammation over immune homeostasis. This characteristic of bacterial-intestinal interaction partially contributes to the pathogenesis of necrotizing enterocolitis (NEC), a devastating premature infant intestinal inflammatory disease. However, paradoxically some unique pioneer bacteria (initial colonizing species) have been shown to have a beneficial effect on the homeostasis of the immature intestine and the prevention of inflammation. We have reported that one such pioneer bacterium, Bacteroides fragilis (B. fragilis), and its surface component polysaccharide A (PSA) inhibit IL-1ß-induced inflammation in a human primary fetal small intestinal cell line (H4 cells). In this study, using transcription profiling of H4 cellular RNA after pretreatment with or without PSA before an inflammatory stimulation of IL-1ß, we have begun to further determine the cellular mechanism for anti-inflammation. We show that a developmentally regulated gene, zona pellucida protein 4 (ZP4), is uniquely elevated after IL-1ß stimulation and reduced with PSA exposure. ZP4 was known as a sperm receptor-mediating species-specific binding protein in the initial life of mammals. However, its intestinal epithelial function is unclear. We found that ZP4 is a developmentally regulated gene involved with immune function and regulated by both Toll-like receptor 2 and 4. Knockdown of ZP4-affected PSA inhibited IL-8 mRNA expression in response to IL-1ß. This represents an initial study of ZP4 innate immune function in immature enterocytes. This study may lead to new opportunity for efficient treatment of NEC.NEW & NOTEWORTHY This study extends previous observations to define the cellular mechanisms of polysaccharide A-induced anti-inflammation in immature enterocytes using transcription profiling of enterocyte genes after preexposure to polysaccharide A before an inflammatory stimulus with IL-1ß.


Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Bacteroides fragilis/química , Enterócitos/metabolismo , Polissacarídeos/farmacologia , Glicoproteínas da Zona Pelúcida/genética , Glicoproteínas da Zona Pelúcida/metabolismo , Anti-Inflamatórios não Esteroides/química , Linhagem Celular , Quimiocina CXCL5/biossíntese , Quimiocina CXCL5/genética , Enterócitos/efeitos dos fármacos , Feto/metabolismo , Regulação da Expressão Gênica no Desenvolvimento/efeitos dos fármacos , Técnicas de Silenciamento de Genes , Humanos , Interleucina-1beta/biossíntese , Interleucina-8/biossíntese , Interleucina-8/genética , Polissacarídeos/química , Receptor 2 Toll-Like/metabolismo , Receptor 4 Toll-Like/metabolismo
18.
Int J Mol Med ; 44(3): 949-959, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31257455

RESUMO

Pistacia weinmannifolia (PW) has been used in traditional Chinese medicine to treat headaches, dysentery, enteritis and influenza. However, PW has not been known for treating respiratory inflammatory diseases, including chronic obstructive pulmonary disease (COPD). The present in vitro analysis confirmed that PW root extract (PWRE) exerts anti­inflammatory effects in phorbol myristate acetate­ or tumor necrosis factor α (TNF­α)­stimulated human lung epithelial NCI­H292 cells by attenuating the expression of interleukin (IL)­8, IL­6 and Mucin A5 (MUC5AC), which are closely associated with the pulmonary inflammatory response in the pathogenesis of COPD. Thus, the aim of the present study was to evaluate the protective effect of PWRE on pulmonary inflammation induced by cigarette smoke (CS) and lipopolysaccharide (LPS). Treatment with PWRE significantly reduced the quantity of neutrophils and the levels of inflammatory molecules and toxic molecules, including tumor TNF­α, IL­6, IL­8, monocyte chemoattractant protein­1, neutrophil elastase and reactive oxygen species, in the bronchoalveolar lavage fluid of mice with CS­ and LPS­induced pulmonary inflammation. PWRE also attenuated the influx of inflammatory cells in the lung tissues. Furthermore, PWRE downregulated the activation of nuclear factor­κB and the expression of phosphodiesterase 4 in the lung tissues. Therefore, these findings suggest that PWRE may be a valuable adjuvant treatment for COPD.


Assuntos
Interleucina-8/biossíntese , Lipopolissacarídeos/efeitos adversos , NF-kappa B/metabolismo , Pistacia/química , Extratos Vegetais/farmacologia , Pneumonia Bacteriana/etiologia , Pneumonia Bacteriana/metabolismo , Fumaça/efeitos adversos , Animais , Linhagem Celular , Citocinas/metabolismo , Modelos Animais de Doenças , Mediadores da Inflamação/metabolismo , Lipopolissacarídeos/imunologia , Camundongos , Neutrófilos/imunologia , Neutrófilos/metabolismo , Extratos Vegetais/química , Fator de Necrose Tumoral alfa/metabolismo , Fator de Necrose Tumoral alfa/farmacologia
19.
Oncogene ; 38(28): 5566-5579, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31147602

RESUMO

Cancer-associated fibroblasts (CAFs), one of the major components of a tumour microenvironment, comprise heterogeneous populations involved in tumour progression. However, it remains obscure how CAF heterogeneity is governed by cancer cells. Here, we show that cancer extracellular vesicles (EVs) induce a series of chemokines in activated fibroblasts and contribute to the formation of the heterogeneity. In a xenograft model of diffuse-type gastric cancer, we showed two distinct fibroblast subpopulations with alpha-smooth muscle actin (α-SMA) expression or chemokine expression. MicroRNAs (miRNAs) profiling of the EVs and the transfection experiment suggested that several miRNAs played a role in the induction of chemokines such as CXCL1 and CXCL8 in fibroblasts, but not for the myofibroblastic differentiation. Clinically, aberrant activation of CXCL1 and CXCL8 in CAFs correlated with poorer survival in gastric cancer patients. Thus, this link between chemokine expression in CAFs and tumour progression may provide novel targets for anticancer therapy.


Assuntos
Fibroblastos Associados a Câncer/metabolismo , Quimiocina CXCL1/biossíntese , Vesículas Extracelulares/metabolismo , Interleucina-8/biossíntese , Neoplasias Gástricas/patologia , Células Estromais/patologia , Actinas/metabolismo , Animais , Linhagem Celular Tumoral , Xenoenxertos , Humanos , Camundongos , Neoplasias Gástricas/metabolismo , Microambiente Tumoral
20.
Environ Pollut ; 252(Pt B): 1216-1224, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31252119

RESUMO

The effects of methylamine on human health have been debated for several years, but the exact adverse outcomes and definite signaling cascades have not been elucidated yet. Herein, a NF-κB signal pathway, a positive regulator of inflammation was identified as the main pathway of methylamine exposure induced adverse effects in bronchial airway cells (16HBE) for the first time. The results indicated that methylamine could stimulate the overproduction of reactive oxygen species (ROS) in cytoplasm and mitochondria of 16HBE cells. Moreover, ROS accelerate the translocation and phosphorylation of NF-κB in nucleic and promote the expression of inflammatory, such as IL-8 and IL-6. As a result, methylamine was found to be increased ROS-mediated NF-κB activation in cells, leading to the production of inflammatory cytokine. Furthermore, the results also showed that methylamine could affect the expression of cytokines related genes, p53, STAT3, Bcl2, c-myc, Cyclin D, Hes1, Mcl-1, TGF-ß2. The breakdown of those cell proliferation and apoptosis related genes were leading to a common toxic mechanism of cell death. In summary, our work uncovers a mechanism by which methylamine can induce the formation of inflammation response and demonstrates potential inflammation and carcinogenesis in human airway cell upon the methylamine inhaled.


Assuntos
Poluentes Atmosféricos/toxicidade , Exposição Ambiental/efeitos adversos , Inflamação/patologia , Pneumopatias/induzido quimicamente , Metilaminas/toxicidade , Fator de Transcrição RelA/metabolismo , Apoptose/efeitos dos fármacos , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Citocinas/metabolismo , Regulação da Expressão Gênica , Humanos , Interleucina-6/biossíntese , Interleucina-8/biossíntese , Mitocôndrias/metabolismo , Fosforilação , Transporte Proteico/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais/efeitos dos fármacos
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