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1.
Anticancer Res ; 40(2): 1161-1166, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-32014969

RESUMO

BACKGROUND: Glioblastoma (GBM) is the most common malignant brain tumor in adults and still carries a dismal prognosis. As several studies detected a connection between inflammation and GBM prognosis, we sought to explore possible associations between routinely investigated inflammatory parameters and GBM outcome. PATIENTS AND METHODS: Patients treated for GBM at our Institution between 2004 and 2014 were included. White blood cell count (WBC), C-reactive protein (CRP) and the ratio of platelets and WBC (Plt/WBC) were evaluated preoperatively. Medical records were reviewed for clinical parameters (age, sex, preoperative clinical condition, genetic alterations). Study endpoints were overall (OS) and 1- and 2-year survival. RESULTS: In the final cohort consisting of 565 individuals with GBM, univariate analysis showed significant associations for WBC, CRP and Plt/WBC ratio with OS. Kaplan-Meier survival plot confirmed significantly poorer OS in patients with WBC>12/nl and with CRP≥2.9 mg/dl. In multivariate analysis, a WBC of >12/nl was an independent prognostic factor for all three outcome parameters and CRP≥2.9 mg/dl for OS and 1-year survival. CONCLUSION: Preoperative WBC and CRP values were confirmed as independent predictors of GBM outcome. This emphasizes the need for further evaluation of the role of inflammation in the prognosis of GBM.


Assuntos
Biomarcadores , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/mortalidade , Glioblastoma/metabolismo , Glioblastoma/mortalidade , Adulto , Idoso , Neoplasias Encefálicas/etiologia , Neoplasias Encefálicas/cirurgia , Proteína C-Reativa , Feminino , Glioblastoma/etiologia , Glioblastoma/cirurgia , Humanos , Mediadores da Inflamação , Estimativa de Kaplan-Meier , Contagem de Leucócitos , Masculino , Pessoa de Meia-Idade , Período Pré-Operatório , Prognóstico , Estudos Retrospectivos
2.
Medicine (Baltimore) ; 99(8): e19207, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-32080108

RESUMO

Cigarette smoking is associated with thicker carotid intima-media thickness (IMT), probably partly through inflammatory pathways. However, to what extent does inflammation mediate the smoking-carotid atherosclerosis association is unclear. We investigated the mediating effect of inflammation on the association between cigarette smoking and carotid IMT, and quantified the respective contributions of inflammatory markers to this association.A total of 1752 participants from Guangzhou Biobank Cohort Study-Cardiovascular Disease Sub-cohort (GBCS-CVD) were included. Using causal mediation analysis under the counterfactual framework, we decomposed total effects of cigarette smoking on IMT into indirect effects (through inflammatory response) and direct effects (not through inflammatory response).After adjusting for traditional risk factors, the indirect effects of per 10/L increment in leukocyte and granulocyte, per mg/L increment in high-sensitivity C-reactive protein (hs-CRP), and per mg/dL increment in fibrinogen on carotid IMT was 0.0028 mm (95% confidence interval [CI], 0.0011-0.0047), 0.0019 mm (95% CI, 0.0006-0.0034), 0.0017 mm (95% CI, 0.0006-0.003), and 0.001 mm (95% CI, 0.0001-0.0021), respectively. No evidence for a mediating role of lymphocyte was found. The proportion of the smoking-IMT association mediated by leukocyte, granulocyte, hs-CRP, and fibrinogen was 12.57% (95% CI, 8.50%-22.11%), 8.50% (95% CI, 5.76%-15.09%), 7.64% (95% CI, 5.20%-13.79%), and 4.48% (95% CI, 3.04%-8.03%), respectively. Restricting data analysis to men showed similar results.The effects of cigarette smoking on IMT were partly mediated by leukocyte, hs-CRP, and fibrinogen. The mediating role of leukocyte was likely mainly driven by higher granulocyte.


Assuntos
Espessura Intima-Media Carotídea , Fumar Cigarros/fisiopatologia , Mediadores da Inflamação/metabolismo , Inflamação/fisiopatologia , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Reprodutibilidade dos Testes , Fatores Socioeconômicos
3.
Medicine (Baltimore) ; 99(8): e19214, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-32080113

RESUMO

Langerhans cells (LCs) and plasmacytoid dendritic cells (pDCs) play an important role in the cutaneous immune response to viral infection. Verruca vulgaris (VV) is a chronic benign disease caused by human papillomavirus (HPV) infection.To investigate the possible roles of LCs, pDCs and toll-like receptor (TLR)7/9 signaling pathways in the pathogenesis of VV, we detected the expression of CD1a, CD2AP, CD123, TLR7/9, IFN regulatory factor 7 (IRF7), and interleukin-1 receptor-associated kinase 1 (IRAK1) in VV lesions.The expression of CD1a, CD2AP, CD123, TLR7/9, IRF7, and IRAK1 in 20 VV lesions was tested by immunohistochemistry. The density and number of stained cells were compared between VV lesions and the perilesional normal skin.The density and number of CD1a-, CD2AP-, CD123-, TLR9-, and IRAK1-positive cells in the papillary layer of VV lesions were significantly higher than those in the perilesional normal skin (P < .05). There were no significant differences in the density and positive rate of CD1a+ cells in the epidermis and of TLR7 and IRF7 cells in the dermis between VV lesions and the perilesional normal skin at the edge (P > .05).In VV, the number of LCs increases only in the dermis, indicating that LC's antigen-presenting function might not be inhibited. The increased number of pDCs in VV lesions suggests that HPV infection may recruit the pDCs to the virus-infected epithelium. We speculate that the TLR7/9 downstream signaling pathway is not fully activated in VV, leading to difficulty of HPV removal and the relapse of HPV-infected lesions.


Assuntos
Células Dendríticas/metabolismo , Células de Langerhans/metabolismo , Receptor 7 Toll-Like/metabolismo , Receptores Toll-Like/metabolismo , Verrugas/fisiopatologia , Adolescente , Adulto , Células Dendríticas/imunologia , Feminino , Humanos , Mediadores da Inflamação/metabolismo , Células de Langerhans/imunologia , Masculino , Transdução de Sinais , Receptor Toll-Like 9/metabolismo , Verrugas/imunologia , Adulto Jovem
4.
Adv Exp Med Biol ; 1240: 1-23, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32060884

RESUMO

Interleukin 1 (IL-1) has long been known for its pleiotropic effects on inflammation that plays a complex, and sometimes contrasting, role in different stages of cancer development. As a major proinflammatory cytokine, IL-1ß is mainly expressed by innate immune cells. IL-1α, however, is expressed by various cell types under physiological and pathological conditions. IL-1R1 is the main receptor for both ligands and is expressed by various cell types, including innate and adaptive immune cell types, epithelial cells, endothelial cells, adipocytes, chondrocytes, fibroblasts, etc. IL-1 and IL-1R1 receptor interaction leads to a set of common signaling pathways, mainly the NF-kB and MAP kinase pathways, as a result of complex positive and negative regulations. The variety of cell types with IL-1R1 expression dictates the role of IL-1 signaling at different stages of cancer, which under certain circumstances leads to contrasting roles in tumor development. Recent availability of IL-1R1 conditional knockout mouse model has made it possible to dissect the role of IL-1/IL-1R1 signaling transduction in different cell types within the tumor microenvironment. This chapter will focus on the role of IL-1/IL-1R1 in different cell types within the tumor microenvironment and discuss the potential of targeting this pathway in cancer therapy.


Assuntos
Interleucina-1/imunologia , Interleucina-1/metabolismo , Transdução de Sinais , Microambiente Tumoral , Animais , Humanos , Mediadores da Inflamação/imunologia , Mediadores da Inflamação/metabolismo , Interleucina-1/antagonistas & inibidores , Camundongos Knockout , Neoplasias/tratamento farmacológico , Neoplasias/imunologia , Neoplasias/metabolismo , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/imunologia , Microambiente Tumoral/efeitos dos fármacos , Microambiente Tumoral/imunologia
5.
Crit Rev Oncol Hematol ; 146: 102840, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31918344

RESUMO

Neuroendocrine neoplasms (NENs) are a group of tumors originating from the neuroendocrine system. They mainly occur in the digestive system and the respiratory tract. It is well-know a strict interaction between neuroendocrine system and inflammation, which can play an important role in NEN carcinogenesis. Inflammatory mediators, which are produced by the tumor microenvironment, can favor cancer induction and progression, and can promote immune editing. On the other hand, a balanced immune system represents a relevant step in cancer prevention through the elimination of dysplastic and cancer cells. Therefore, an inflammatory response may be both pro- and anti-tumorigenic. In this review, we provide an overview concerning the complex interplay between inflammation and gastroenteropancreatic NENs, focusing on the tumorigenesis and clinical implications in these tumors.


Assuntos
Neoplasias Gastrointestinais/imunologia , Mediadores da Inflamação/imunologia , Inflamação/imunologia , Neoplasias Intestinais/imunologia , Tumores Neuroendócrinos/imunologia , Neoplasias Pancreáticas/imunologia , Neoplasias Gástricas/imunologia , Citocinas/metabolismo , Neoplasias Gastrointestinais/patologia , Humanos , Inflamação/metabolismo , Mediadores da Inflamação/metabolismo , Neoplasias Intestinais/patologia , Tumores Neuroendócrinos/patologia , Neoplasias Pancreáticas/patologia , Neoplasias Gástricas/patologia , Microambiente Tumoral
6.
High Blood Press Cardiovasc Prev ; 27(1): 1-8, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31925708

RESUMO

Lipids and endothelium are pivotal players on the scene of atherosclerosis and their interaction is crucial for the establishment of the pathological processes. The endothelium is not only the border of the arterial wall: it plays a key role in regulating circulating fatty acids and lipoproteins and vice versa it is regulated by these lipidic molecules thereby promoting atherosclerosis. Inflammation is another important element in the relationship between lipids and endothelium. Recently, proprotein convertase subtilisin/kexin type 9 (PCSK9) has been recognized as a fundamental regulator of LDL-C and anti-PCSK9 monoclonal antibodies have been approved for therapeutic use in hypercholesterolemia, with the promise to subvert the natural history of the disease. Moreover, growing experimental and clinical evidence is enlarging our understanding of the mechanisms through which this protein may facilitate the genesis of atherosclerosis, independently of its impact on lipid metabolism. In addition, environmental stimuli may affect the post-transcriptional regulation of genes through micro-RNAs, which in turn play a key role in orchestrating the crosstalk between endothelium and cholesterol. Advances in experimental research, with development of high throughput techniques, have led, over the last century, to a tremendous progress in the understanding and fine tuning of the molecular mechanisms leading to atherosclerosis. Identification of pivotal keystone molecules bridging lipid metabolism, endothelial dysfunction and atherogenesis will provide the mechanistic substrate to test valuable targets for prediction, prevention and treatment of atherosclerosis-related disease.


Assuntos
Aterosclerose/metabolismo , Colesterol/metabolismo , Dislipidemias/metabolismo , Endotélio Vascular/metabolismo , MicroRNAs/metabolismo , Pró-Proteína Convertase 9/metabolismo , Animais , Aterosclerose/enzimologia , Aterosclerose/genética , Biomarcadores/metabolismo , Dislipidemias/enzimologia , Dislipidemias/genética , Endotélio Vascular/enzimologia , Endotélio Vascular/patologia , Regulação da Expressão Gênica , Humanos , Mediadores da Inflamação/metabolismo , MicroRNAs/genética , Placa Aterosclerótica , Transdução de Sinais
7.
Oncology ; 98(3): 131-137, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31958792

RESUMO

Interleukin-6 (IL-6) is a member of the pro-inflammatory cytokine family, induces the expression of a variety of proteins responsible for acute inflammation, and plays an important role in the proliferation and differentiation of cells in humans. IL-6 signaling is mediated by building a complex of IL-6, the transmembrane IL-6 receptor (mIL-6R) or with soluble forms of IL-6R (sIL-6R), and the signal-transducing subunit molecule gp130. Therefore, three modes for IL-6 signaling may occur in which IL-6 is binding to mIL-6R (classic), to sIL-6R (trans-signaling), or is joined through IL-6R to gp130 on nearby located cells (trans-presentation). These pathways, and the fact that gp130 is ubiquitously expressed, lead to the pleiotropic functions of IL-6. The control of IL-6 signaling is regulated through the induction of suppressor molecules after activation of the IL-6 pathways as well as through the presence of sIL-6R and gp130 forms in the blood. Vice versa, an overproduction of IL-6 and dysregulation of the IL-6 signaling pathways can result in inflammatory and autoimmune disorders as well as cancer development suggesting that IL-6 plays a significant role in the human cytokine network. Several therapeutic agents have been evaluated for inhibiting the cytokine itself, the signaling via the IL-6 receptor, or target kinases (e.g., JAK/STAT) associated with the signaling pathways. Amongst others, tocilizumab (anti-IL-6R humanized antibody) has been approved for the treatment of rheumatoid arthritis, cytokine release syndrome, and idiopathic multicentric Castleman's disease (iMCD), whereas siltuximab (an IL-6 antagonist) received approval for iMCD only. Although not all IL-6-associated diseases respond to IL-6 blockade, a better understanding of the underlying mechanisms of the IL-6 pathways may, therefore, help to find the best treatment for IL-6-associated diseases in the near future.


Assuntos
Mediadores da Inflamação/metabolismo , Inflamação/metabolismo , Interleucina-6/metabolismo , Transdução de Sinais , Anti-Inflamatórios/uso terapêutico , Humanos , Inflamação/tratamento farmacológico , Inflamação/enzimologia , Mediadores da Inflamação/antagonistas & inibidores , Interleucina-6/antagonistas & inibidores , Inibidores de Janus Quinases/uso terapêutico , Janus Quinases/antagonistas & inibidores , Janus Quinases/metabolismo , Terapia de Alvo Molecular , Receptores de Interleucina-6/antagonistas & inibidores , Receptores de Interleucina-6/metabolismo , Fatores de Transcrição STAT/antagonistas & inibidores , Fatores de Transcrição STAT/metabolismo
8.
J Biochem Mol Toxicol ; 34(2): e22433, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31916655

RESUMO

Colorectal cancer (CRC) is the third most common fatal cancer. Indomethacin, a nonsteroidal anti-inflammatory drug, is known to reduce the occurrence of CRC. This study evaluated the potential anticolon cancer effects of juglone (5-hydroxy-1,4-naphthoquinone) in combination with indomethacin. Human colon adenocarcinoma cells (HT29) were subjected to treatment with indomethacin, juglone, and a combination of both. Morphological analysis, cell cycle regulation, and dual staining using acridine orange and ethidium bromide in control and treated cells revealed the apoptotic potential of these compounds. Bcl2 and inflammatory molecules (tumor necrosis factor-α, nuclear factor kappa B, and Cox-2) were found to be decreased with a concomitant increase in the expression of proapoptotic molecules (Bad, Bax, cytochrome c, and PUMA) as a result of the molecular regulation of Wnt, Notch, and peroxisome proliferator-activated receptor-γ signaling. Treatment with juglone was not as effective as with indomethacin; however, a combination of both was shown to be more effective, suggesting that juglone may be considered for therapeutic intervention of colon cancer.


Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Neoplasias do Colo/metabolismo , Indometacina/farmacologia , Mediadores da Inflamação/metabolismo , Naftoquinonas/farmacologia , Anti-Inflamatórios não Esteroides/uso terapêutico , Antineoplásicos/uso terapêutico , Proteínas Reguladoras de Apoptose/metabolismo , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Neoplasias do Colo/tratamento farmacológico , Neoplasias do Colo/patologia , Sinergismo Farmacológico , Células HT29 , Humanos , Indometacina/uso terapêutico , Concentração Inibidora 50 , Naftoquinonas/uso terapêutico , PPAR gama/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Receptores Notch/metabolismo , Transdução de Sinais/efeitos dos fármacos , Via de Sinalização Wnt
9.
Clin Sci (Lond) ; 134(2): 273-287, 2020 Jan 31.
Artigo em Inglês | MEDLINE | ID: mdl-31957803

RESUMO

The current main treatment for coronary artery disease (CAD) is to reduce low-density lipoprotein cholesterol (LDL-C) by statins, which could decrease the incidence of major adverse cardiovascular events (MACEs) by 30%. However, many residual risks still remain. To clarify the mechanism involved, we studied patients with acute myocardial infarction (AMI) with low LDL-C levels. Lymphocytes were isolated, and it was found that despite no difference in plasma LDL-C level, the lymphocyte cholesterol content was higher in AMI patient than those in non-CAD patients; thus, the decrease in intracellular cholesterol content was inconsistent with that in the plasma. Additionally, [3H]-cholesterol efflux rates were lower and mRNA levels of the inflammatory factors tumour necrosis factor-α (TNF-α) and interferon-γ (IFN-γ) higher in AMI lymphocytes. It was found that sulphotransferase 2B1b (SULT2B1b) expression was higher in AMI lymphocytes. Further research using Jurkat T lymphocytes confirmed that SULT2B1b knockdown increased cholesterol efflux capacity and decreased mRNA levels of TNF-α and IFN-γ by increasing liver X receptor (LXR)-ß levels. Furthermore, the degree of CpG island methylation in the SULT2B1b promoter was reduced in cells from AMI patients. In conclusion, SULT2B1b up-regulation due to hypomethylation of its promoter promotes cholesterol accumulation and inflammation by inhibiting LXR-ß in lymphocytes of AMI patients with low LDL-C levels. Therefore, reducing intracellular cholesterol is also important as plasma cholesterol levels. Therapeutic approaches to decrease SULT2B1b expression might be potentially beneficial for CAD prevention by decreasing intracellular cholesterol.


Assuntos
Colesterol/metabolismo , Interferon gama/metabolismo , Linfócitos/metabolismo , Sulfotransferases/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Transporte Biológico , Colesterol/sangue , LDL-Colesterol/metabolismo , Doença da Artéria Coronariana/genética , Doença da Artéria Coronariana/metabolismo , Doença da Artéria Coronariana/prevenção & controle , Metilação de DNA , Humanos , Mediadores da Inflamação/metabolismo , Interferon gama/genética , Células Jurkat , Receptores X do Fígado/genética , Receptores X do Fígado/metabolismo , Infarto do Miocárdio/genética , Infarto do Miocárdio/metabolismo , Infarto do Miocárdio/prevenção & controle , Regiões Promotoras Genéticas/genética , Sulfotransferases/genética , Fator de Necrose Tumoral alfa/genética
10.
Toxicol Lett ; 322: 58-65, 2020 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-31962155

RESUMO

High-level concentrations of chlorine (Cl2) can cause life-threatening lung injuries and the objective in this study was to understand the pathogenesis of short-term sequelae of Cl2-induced lung injury and to evaluate whether pre-treatment with the antioxidant N-acetyl cysteine (NAC) could counteract these injuries using Cl2-exposed precision-cut lung slices (PCLS). The lungs of Sprague-Dawley rats were filled with agarose solution and cut into 250 µm-thick slices that were exposed to Cl2 (20-600 ppm) and incubated for 30 min. The tissue slices were pre-treated with NAC (5-25 mM) before exposure to Cl2. Toxicological responses were analyzed after 5 h by measurement of LDH, WST-1 and inflammatory mediators (IL-1ß, IL-6 and CINC-1) in medium or lung tissue homogenate. Exposure to Cl2 induced a concentration-dependent cytotoxicity (LDH/WST-1) and IL-1ß release in medium. Similar cytokine response was detected in tissue homogenate. Contraction of larger airways was measured using electric-field-stimulation method, 200 ppm and control slices had similar contraction level (39 ± 5%) but in the 400 ppm Cl2 group, the evoked contraction was smaller (7 ± 3%) possibly due to tissue damage. NAC-treatment improved cell viability and reduced tissue damage and the contraction was similar to control levels (50 ± 11%) in the NAC treated Cl2-exposed slices. In conclusion, Cl2 induced a concentration-dependent lung tissue damage that was effectively prevented with pre-treatment with NAC. There is a great need to improve the medical treatment of acute lung injury and this PCLS method offers a way to identify and to test new concepts of treatment of Cl2-induced lung injuries.


Assuntos
Acetilcisteína/farmacologia , Anti-Inflamatórios/farmacologia , Antioxidantes/farmacologia , Cloro/toxicidade , Mediadores da Inflamação/metabolismo , Lesão Pulmonar/prevenção & controle , Pulmão/efeitos dos fármacos , Animais , Sobrevivência Celular/efeitos dos fármacos , Quimiocina CXCL1/metabolismo , Citoproteção , Relação Dose-Resposta a Droga , Feminino , Técnicas In Vitro , Interleucina-1beta/metabolismo , Interleucina-6/metabolismo , Pulmão/metabolismo , Pulmão/patologia , Pulmão/fisiopatologia , Lesão Pulmonar/induzido quimicamente , Lesão Pulmonar/metabolismo , Lesão Pulmonar/patologia , Ratos Sprague-Dawley
11.
Adv Exp Med Biol ; 1232: 277-282, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31893421

RESUMO

Acidification of the cellular microenvironment is found in different pathological states such as inflammation, ischemia and in solid tumors. It can affect cell function and phenotype, and by this aggravate the pathological process. Epithelial cells are a relevant functional part in several normal organs as well as in tumors and will thus be challenged by the acidic extracellular pH (acidosis). Therefore, the impact of acidosis on the expression of different inflammatory mediators (MCP-1, IL-6, osteopontin, iNOS, TNF-α, and COX-2), as well as the role of different signaling pathways regulating the expression, was studied in epithelial normal rat kidney cells (NRK-52E). Acidosis led to an increase in TNF-α expression but a down-regulation of MCP-1, iNOS and COX-2. Expression of IL-6 was only slightly modulated, while osteopontin was not regulated at all. Since acidosis activates ERK1/2 and p38 signaling in NRK-52E cells, the impact of MAP kinase signaling pathways on the expression of the inflammatory markers was analyzed. At normal pH, blocking ERK1/2 or p38 decreased the level of MCP-1, iNOS and partly TNF-α. However, the effect of acidosis on the expression of inflammatory mediators was not affected by inhibition of the MAP kinase pathways. In conclusion, our results show that an acidic microenvironment affects the transcriptional program of epithelial cells. Low pH mostly reduced the expression of pathological relevant genes and might thus repress inflammatory processes induced by epithelial cells.


Assuntos
Acidose , Células Epiteliais , Regulação da Expressão Gênica , Mediadores da Inflamação , Proteínas Quinases p38 Ativadas por Mitógeno , Acidose/metabolismo , Animais , Linhagem Celular , Quimiocina CCL2/genética , Ciclo-Oxigenase 2/genética , Células Epiteliais/metabolismo , Mediadores da Inflamação/metabolismo , Sistema de Sinalização das MAP Quinases/fisiologia , Óxido Nítrico Sintase Tipo II/genética , Ratos , Fator de Necrose Tumoral alfa/genética
12.
J Stroke Cerebrovasc Dis ; 29(1): 104485, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31706751

RESUMO

OBJECTIVES: Tenascin-C (TNC) is upregulated in serum and cerebrospinal fluid after subarachnoid hemorrhage (SAH) and the deficiency of TNC could alleviate neuronal apoptosis and neuroinflammation after SAH. However, the specific mechanism of TNC regulating neuronal apoptosis and neuroinflammation after SAH is not well recognized. The aim of this study was to investigate whether PI3K/Akt/ NF-κB signaling pathway is involved in the regulation of TNC on early brain injury after SAH. METHODS: Oxygen hemoglobin (OxyHb) was used to induce SAH models in PC12 cells, and classified into control, SAH, LY294002, SAH+TNC-siRNA and SAH+TNC-siRNA+LY groups. Western blotting was applied to examine the protein expression of TNC, Caspase-3, Bax, Bcl-2, PI3K, p-Akt, and p-NF-κB. Reverse transcription quantitative polymerase chain reaction was applied to examine the TNC mRNA expression. Cholecystokinin (CCK)-8 and flow cytometry were used to examine cell proliferation and apoptosis, respectively. ELISA was applied to examine the content of interleukin 6, interleukin 1ß, and tumor necrosis factor α. We showed that the TNC protein was highly expressed in SAH cell model. RESULTS: OxyHb inhibited cell proliferation, promoted cell apoptosis and the expression of proapoptotic protein, and promoted proinflammatory cytokine secretion in PC12 cells, which were restored following TNC gene silencing. Moreover, OxyHb decreased the expression of PI3K and p-Akt and increased the expression of p-NF-κB p65 in PC12 cells, which were activated following TNC gene silencing. The LY294002 weakened the effect of TNC gene silencing. CONCLUSIONS: The TNC gene silencing relieved neuronal apoptosis and neuroinflammation by activating the PI3K/Akt/ NF-κB signaling pathway. TNC-induced neuroinflammation would be a new target to improve outcome after SAH.


Assuntos
Apoptose , Mediadores da Inflamação/metabolismo , Neurônios/metabolismo , Fosfatidilinositol 3-Quinase/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Hemorragia Subaracnóidea/metabolismo , Tenascina/metabolismo , Fator de Transcrição RelA/metabolismo , Animais , Proteínas Reguladoras de Apoptose/metabolismo , Proliferação de Células , Neurônios/patologia , Células PC12 , Fosforilação , Interferência de RNA , Ratos , Transdução de Sinais , Hemorragia Subaracnóidea/genética , Hemorragia Subaracnóidea/patologia , Tenascina/genética
13.
Histochem Cell Biol ; 153(1): 49-62, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31637472

RESUMO

Endoplasmic reticulum (ER) stress could participate in high-fat diet (HFD)-induced hepatic steatosis. The current study aims to investigate the role of ER stress as well as inflammation as possible pathophysiologic mechanisms of HFD-induced hepatic steatosis at ultrastructure and molecular levels. Fifteen control rats on ordinary diet and 30 HFD-fed rats were enrolled in the study. Histological and EM examinations of rats' liver were carried out. Molecular study of TNF-α, CRP, and HNF4α by RT qPCR as well as biochemical investigation of liver function and lipids profile were done. Hepatic steatosis was induced with lipid droplets accumulation at histological level and mega-mitochondria with reduced ER-mitochondrial distance at EM level. Increased gene expression of TNF-α and CRP was significantly correlated with the reduced HNF4α expression and with other ER stress markers. In conclusion, endoplasmic reticulum stress, confirmed at ultrastructure level, plays an important role in pathogenesis of HFD-induced hepatic steatosis. HNF4α downregulation as well as increased expression of hs-CRP and TNF-α enforce the concept of interplay between ER stress, hepatic subclinical inflammation, and disturbed gene expression regulation in the pathogenesis of HFD-induced hepatic steatosis.


Assuntos
Estresse do Retículo Endoplasmático , Fígado Gorduroso/metabolismo , Fator 4 Nuclear de Hepatócito/metabolismo , Mediadores da Inflamação/metabolismo , Animais , Dieta Hiperlipídica/efeitos adversos , Modelos Animais de Doenças , Inflamação/metabolismo , Inflamação/fisiopatologia , Masculino , Ratos , Ratos Sprague-Dawley
14.
Scand J Immunol ; 91(3): e12856, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31794090

RESUMO

Atopic dermatitis (AD) is a chronic inflammatory skin disease. A hallmark of AD is dry itchy skin that results from defects in the epidermal barrier function. Aloe vera is used widely to promote general health and is administered topically to treat skin conditions such as eczema, burns and wounds. However, effects of A vera on AD were not fully elucidated. In this study, we investigated the oral administration of processed A vera gel (PAG) containing low molecular weight Aloe polysaccharides to treat ovalbumin (OVA)-induced AD in mice. Oral administration of PAG suppressed total and OVA-specific IgE production in sera and decreased the epidermal thickness of skin. Numbers of Ki-67-positive cells were reduced by PAG treatment. Expression levels of tight junction genes, including those that encode ZO-1, Claudin-1 and Claudin-8, were decreased in AD skin lesions, whereas oral administration of PAG partially restored the expression levels of tight junction genes. In addition, IL-4 and IL-17A mRNA transcript levels were reduced in skin lesions after PAG treatment. Taken together, our findings suggest that oral administration of PAG ameliorated AD, normalized tight junction gene expression and suppressed inflammatory cytokines in AD skin.


Assuntos
Aloe/química , Antialérgicos/farmacologia , Dermatite Atópica/etiologia , Exsudatos de Plantas/farmacologia , Polissacarídeos/farmacologia , Junções Íntimas/efeitos dos fármacos , Junções Íntimas/imunologia , Animais , Antialérgicos/química , Biomarcadores , Citocinas/metabolismo , Dermatite Atópica/tratamento farmacológico , Dermatite Atópica/patologia , Modelos Animais de Doenças , Progressão da Doença , Feminino , Mediadores da Inflamação/metabolismo , Queratinócitos/efeitos dos fármacos , Queratinócitos/imunologia , Queratinócitos/metabolismo , Camundongos , Ovalbumina/efeitos adversos , Exsudatos de Plantas/química , Polissacarídeos/química , Pele/efeitos dos fármacos , Pele/imunologia , Pele/metabolismo , Pele/patologia
15.
Food Chem Toxicol ; 135: 110873, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31600566

RESUMO

In this study, the protective effects of Croton hookeri (CH) extract on renal injury were investigated in streptozotocin (STZ)-induced diabetic rats. Diabetes was induced by a single injection of STZ (45 mg/kg) to Sprague-Dawley rats. After 5 days, CH extract (200 mg/kg) was administered daily by oral gavage for 2 weeks. Administration of CH extracts significantly reduced blood glucose levels in STZ-induced diabetic rats. STZ-induced changes in total cholesterol, LDL, HDL, ALT, AST, BUN, and serum creatinine levels were significantly restored by treatment with CH extract. Abnormal levels of SOD, catalase, glutathione, and oxidized GSH (GSSG) in STZ-treated rats were also significantly recovered by CH extract treatment. CH extract markedly reduced the expression of collagen-1, fibronectin, and α-SMA in the kidney of STZ-induced diabetic rats. In particular, oxidative DNA damages, MDA, TGF-ß, IL-1ß, and IL-6 levels were significantly reduced in STZ-treated rats following treatment with CH extract, whereas IL-10 showed opposite trend. STZ-induced SIRT1, SIRT3 downregulation and cloudin-1 upregulation in the kidney were dramatically recovered by CH extract treatment. Our data suggest that CH extract protects against diabetic-induced nephropathy by inhibiting oxidative stress and inflammation. Therefore, it has potential as a food supplement to alleviate renal dysfunction caused by diabetes-induced nephropathy.


Assuntos
Croton/química , Nefropatias Diabéticas/prevenção & controle , Extratos Vegetais/farmacologia , Animais , Biomarcadores/urina , Glicemia/metabolismo , Peso Corporal/efeitos dos fármacos , Citocinas/metabolismo , Nefropatias Diabéticas/metabolismo , Nefropatias Diabéticas/urina , Alimento Funcional , Produtos Finais de Glicação Avançada/metabolismo , Mediadores da Inflamação/metabolismo , Rim/efeitos dos fármacos , Rim/metabolismo , Rim/fisiopatologia , Masculino , Tamanho do Órgão/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Estreptozocina
16.
J Surg Res ; 246: 170-181, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31590030

RESUMO

BACKGROUND: Electroacupuncture has been reported to protect the body from organ damages, but its mechanisms remain to be explored. This research was designed to investigate the function of electroacupuncture in lung injury resulted from hind limb ischemia-reperfusion (LIR) and whether p38 mitogen-activated protein kinase (p38 MAPK)-mediated nuclear factor erythroid-2-related factor-2 (Nrf2)/heme oxygenase (HO)-1 pathway contributes to the protective effect of electroacupuncture on LIR-originated lung damage. MATERIALS AND METHODS: Rabbits were subjected to occluding femoral artery for 2 h. Then they received reperfusion for 4 h to establish lung injury model. Electroacupuncture stimulation was performed bilaterally at Feishu and Zusanli acupoints for 15 min once a day for 5 d before the experiment and throughout the hind LIR model performing in the experimental day. Blood samples and lung tissues were collected to examine the role of electroacupuncture treatment in inflammatory response, oxidative stress, and lung injury. Both the protein expression and the messenger RNA level of Nrf2 and HO-1 were detected. RESULTS: The results showed that electroacupuncture treatment remarkably alleviated lung injury, decreased inflammatory cytokines secretion, attenuated lung oxidative stress, increased the amount of Nrf2 and HO-1, and increased the ratio of phospho-p38 MAPK to p38 MAPK after LIR. However, the protective effects exerted by electroacupuncture were reversed to some extent by the preconditioning with SB203580, a p38 MAPK-specific inhibitor. CONCLUSIONS: These results suggested that electroacupuncture could attenuate lung injury in rabbits subjected to LIR by inhibition of proinflammatory cytokine response and oxidative stress through activating p38 MAPK-mediated Nrf2/HO-1 pathway.


Assuntos
Lesão Pulmonar Aguda/prevenção & controle , Eletroacupuntura , Extremidades/irrigação sanguínea , Sistema de Sinalização das MAP Quinases/imunologia , Traumatismo por Reperfusão/complicações , Lesão Pulmonar Aguda/imunologia , Lesão Pulmonar Aguda/patologia , Animais , Modelos Animais de Doenças , Artéria Femoral/cirurgia , Heme Oxigenase-1/metabolismo , Humanos , Imidazóis/farmacologia , Mediadores da Inflamação/imunologia , Mediadores da Inflamação/metabolismo , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Masculino , Fator 2 Relacionado a NF-E2/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Estresse Oxidativo/imunologia , Piridinas/farmacologia , Coelhos , Traumatismo por Reperfusão/imunologia , Traumatismo por Reperfusão/terapia , Resultado do Tratamento , Proteínas Quinases p38 Ativadas por Mitógeno/antagonistas & inibidores , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
17.
Br J Radiol ; 93(1107): 20190224, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31317768

RESUMO

The combination of radiotherapy and immunotherapy is one of the most promising strategies for cancer treatment. Recent clinical results support the pre-clinical experiments pointing to a benefit for the combined treatment in metastatic patients. Charged particle therapy (using protons or heavier ions) is considered one of the most advanced radiotherapy techniques, but its cost remains higher than conventional X-ray therapy. The most important question to be addressed to justify a more widespread use of particle therapy is whether they can be more effective than X-rays in combination with immunotherapy. Protons and heavy ions have physical advantages compared to X-rays that lead to a reduced damage to the immune cells, that are required for an effective immune response. Moreover, densely ionizing radiation may have biological advantages, due to different cell death pathways and release of cytokine mediators of inflammation. We will discuss results in esophageal cancer patients showing that charged particles can reduce the damage to blood lymphocytes compared to X-rays, and preliminary in vitro studies pointing to an increased release of immune-stimulating cytokines after heavy ion exposure. Pre-clinical and clinical studies are ongoing to test these hypotheses.


Assuntos
Neoplasias Esofágicas/radioterapia , Radioterapia com Íons Pesados/métodos , Terapia com Prótons/métodos , Radioimunoterapia/métodos , Morte Celular , Citocinas/metabolismo , DNA/efeitos da radiação , Dano ao DNA , Neoplasias Esofágicas/imunologia , Humanos , Imunoterapia/economia , Mediadores da Inflamação/metabolismo , Linfócitos/efeitos da radiação , Linfopenia/etiologia , Raios X/efeitos adversos
18.
Oncology ; 98(1): 42-47, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31437849

RESUMO

INTRODUCTION: Smoking induces inflammation and an immune response. A cancer-related inflammatory response has been seen in smoking and nonsmoking head and neck squamous cell carcinoma (HNSCC) patients. OBJECTIVES: The aim of this study was to analyze the possible separated effects of smoking or HNSCC on 18 inflammatory or immune regulatory biomarkers. METHODS: Fifty-one nonsmoking and 36 smoking pretreated HNSCC patients and 101 nonsmoking and 39 smoking controls were included in this study. The levels of 18 inflammatory or immune regulatory biomarkers were analyzed. A multivariable linear regression model was used to predict the impact of smoking and HNSCC on the levels of the biomarkers. RESULTS: Smoking had the highest impact on total WBC, IFN-γ, and MCP-1 levels. The highest impact of HNSCC was found on neutrophils, neutrophil-to-lymphocyte ratio, HsCRP, MIP-1b, and TNF-α levels. CONCLUSION: IdentifyingHNSCC or smoking-related inflammatory biomarkers might contribute to the understanding of the immune response in HNSCC patients. This study could provide information of inflammatory biomarkers in HNSCC patients.


Assuntos
Biomarcadores/sangue , Fumar Cigarros , Mediadores da Inflamação/sangue , Carcinoma de Células Escamosas de Cabeça e Pescoço/sangue , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Casos e Controles , Fumar Cigarros/efeitos adversos , Citocinas/metabolismo , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Carcinoma de Células Escamosas de Cabeça e Pescoço/diagnóstico , Carcinoma de Células Escamosas de Cabeça e Pescoço/etiologia , Carga Tumoral , Adulto Jovem
19.
Int J Cancer ; 146(3): 692-698, 2020 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-30924141

RESUMO

Several studies found that the systemic immune-inflammation index (SII) is a prognostic factor for mortality in patients with solid tumors. It is unknown whether an increased SII in generally healthy individuals reflects a risk for developing cancer. Our objective was to investigate the association between the SII and incident cancers in a prospective cohort study. Data were obtained from the Rotterdam Study; a population-based study of individuals aged ≥45 years, between 2002 and 2013. The SII at baseline was calculated from absolute blood counts. The association between the SII and the risk of any solid incident cancer during follow-up was assessed using Cox proportional hazard models. Individuals with a prior cancer diagnosis were excluded. Data of 8,024 individuals were included in the analyses. The mean age at baseline was 65.6 years (SD 10.5 years) and the majority were women. During a maximum follow-up period of 10.7 years, 733 individuals were diagnosed with cancer. A higher SII at baseline was associated with a 30% higher risk of developing a solid cancer (HR of 1.30 [95% CI; 1.11-1.53]), after adjustment for age, sex, socioeconomic status, smoking, BMI and type 2 diabetes. The absolute cumulative 10-year cancer risk increased from 9.7% in the lowest quartile of SII to 14.7% in the highest quartile (p-value = 0.009). The risk of developing cancer was persistent over time and increased for individuals with the longest follow-up. In conclusion, a high SII is a strong and independent risk indicator for developing a solid cancer.


Assuntos
Mediadores da Inflamação/sangue , Inflamação/diagnóstico , Neoplasias/epidemiologia , Idoso , Feminino , Seguimentos , Humanos , Inflamação/sangue , Inflamação/imunologia , Mediadores da Inflamação/imunologia , Masculino , Pessoa de Meia-Idade , Países Baixos/epidemiologia , Estudos Prospectivos , Fatores de Risco , Índice de Gravidade de Doença , Fatores de Tempo
20.
Phytochem Anal ; 31(1): 57-67, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31286597

RESUMO

INTRODUCTION: In European traditional medicine, common ash leaf infusion is recommended by European Medicines Agency to treat minor articular pain and to increase the amount of urine for flushing minor urinary complaints. However, a comprehensive ultra-high-performance liquid chromatography diode array detector electrospray ionisation tandem mass spectrometry (UHPLC-DAD-ESI-MS/MS) analysis of this pharmacopeial plant material has never been performed. Moreover, the number of biological and pharmacological investigations proving the usefulness of this plant material in recommended traditional uses is surprisingly small. OBJECTIVE: Phytochemical profiling of ash leaf samples from different commercial and natural sources and the determination of the in vitro effects on inflammatory mediators in a model of human neutrophils. METHODS: Ash leaf samples were characterised by total hydroxycinnamic acid content and by high-performance thin layer chromatography (HPTLC), UHPLC-DAD-ESI-MS/MS methods. The effects of leaf infusions on reactive oxygen species (ROS), tumor necrosis factor (TNF-α), interleukin 8 (IL-8), interleukin 1ß (IL-1ß), and monocyte chemoattractant protein 1 (MCP-1) production by neutrophils were measured using luminol-dependent chemiluminescence and enzyme-linked immunosorbent assay (ELISA). RESULTS: In ash leaf samples 64 compounds were identified or partly identified together with four unknown compounds. The major compounds detected belong to different structural groups, including phenolic acid derivatives, phenylethanoids, flavonoids, iridoids, secoiridoids and lignans. The major compounds detected in ash samples were chlorogenic acid, quercetin-3-O-rutinoside, verbascoside, oleuropein and ligstroside. However, one sample contained coumarin derivatives. This finding suggested adulteration with other Fraxinus species and/or plant parts. All infusions were able to inhibit ROS, cytokine and chemokine production. CONCLUSIONS: The performed phytochemical and biological analyses contribute to the knowledge about this pharmacopeial plant material and supports its traditional use to treat minor inflammatory complaints.


Assuntos
Fraxinus , Espectrometria de Massas em Tandem , Cromatografia Líquida de Alta Pressão , Cromatografia em Camada Delgada , Flavonoides , Humanos , Mediadores da Inflamação , Extratos Vegetais , Espectrometria de Massas por Ionização por Electrospray
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