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1.
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
2.
Life Sci ; 242: 117248, 2020 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-31899224

RESUMO

Diabetic nephropathy is the most common long-term complication of diabetes mellitus. The Methylglyoxal (MGO) production is mainly by metabolic pathways, such as lipolysis and glycolysis, its increases in the DM enhances oxidative stress and plays a crucial role in the diabetic nephrotic pathogenesis. Phosphocreatine (PCr) can improve lipopolysaccharide, ox-LDL-induced atherosclerosis, and alleviate vascular endothelial cell injury in diabetes. The aim of our present study is to examine the potential role of phosphocreatine (PCr) as a molecule protects against diabetes-induced Kidney Injury in-vitro and in-vivo through ERK/Nrf2/HO-1 signaling pathway. NRK-52E cells treatment with PCr obviously suppressed MGO-induced change of viability, apoptosis, coupled with decreased Bax/Bcl-2ratio, casapse-9 and caspase-3expressions. We determined the generation of reactive oxygen species (ROS) using membrane permeable fluorescent probe DCFH-DA as well as intracellular calcium by flow cytometry. ERK, Nrf2 and HO-1 expressions were determined by Western blot. PCr pretreatment significantly returned the oxidative stress enzymes to normal condition in-vitro and in-vivo. PCr pretreatment significantly reduced apoptosis, calcium and ROS production, induced by MGO, in NRK-52E cells. Moreover, pretreatment with PCr significantly inhibited cleaved caspase-3, cleaved caspase-9 and p-ERK expressions, while increased Nrf-2 and HO-1 expressions. Furthermore, PCr pretreatment significantly decreased p-ERK expression of MGO-induced injury in NRK-52E cells transfected with p-ERK cDNA. In conclusion, the renal protective effect of PCr in-vitro and in-vivo depends on suppressing apoptosis and ROS generation through ERK mediated Nrf-2/HO-1 pathway, suggesting that PCr may be a novel therapeutic candidate for the diabetic nephropathy treatment.


Assuntos
Nefropatias Diabéticas/prevenção & controle , Heme Oxigenase (Desciclizante)/metabolismo , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Fator 2 Relacionado a NF-E2/metabolismo , Fosfocreatina/uso terapêutico , Animais , Apoptose/efeitos dos fármacos , Western Blotting , Cálcio/metabolismo , Linhagem Celular , Diabetes Mellitus Experimental/complicações , Citometria de Fluxo , Imunofluorescência , Masculino , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Espécies Reativas de Oxigênio/metabolismo
3.
Eur J Histochem ; 64(1)2020 Jan 23.
Artigo em Inglês | MEDLINE | ID: mdl-31988531

RESUMO

Chronic rhinosinusitis with nasal polyps (CRSwNP) is a persistent sinonasal mucosa inflammatory disease with still unclear pathophysiologic mechanisms that imply events of tissue repair and structural remodelling. Several cascades seem to have a considerable role in the onset and progression of mucosa hyperproliferation in nasal polyps including transforming growth factor ß/Small mother against decapentaplegic (TGFß/Smads), mitogenactivated protein kinases (MAPKs), advanced glycosylation end-products (AGEs) together with epithelial-tomesenchymal transition (EMT). Since many inflammatory mediators are reported to play important roles in the development of nasal polyps (NP) disease, this study aimed to analyse the correlation between the AGEs/receptor of advanced glycosylation end-products (RAGE)/extracellular signal-regulated kinase (ERK) signalling pathway and the main markers of EMT to better understand the influence that they exert on the remodelling of nasal mucous membranes in patients affected by CRSwNP vs normal controls. A total of 30 patients were enrolled in this study. Immunohistochemical analysis, using AGE, RAGE, p-ERK, MMP-3, TGF-ß1, Smad2/3, Collagen I-III, α-SMA, E-cadherin, IL-6 and Vimentin antibodies, was performed. AGE, RAGE, ERK, p-ERK and MMP3 were also evaluated using western blot analysis. We observed an overexpression of the AGE/RAGE/p-ERK and the main mesenchymal markers of EMT (Vimentin and IL-6) in CRSwNP vs controls whereas the TGF-ß/Smad3 pathway did not show any significant differences between the two groups of patients. These observations suggest a complex network of processes in the pathogenesis of NP, and the AGE/RAGE/ERK pathway and EMT might work together in promoting tissue remodelling in the formation of CRSwNP.


Assuntos
Transição Epitelial-Mesenquimal/fisiologia , Sistema de Sinalização das MAP Quinases/fisiologia , Pólipos Nasais/etiologia , Sinusite/etiologia , Adulto , Doença Crônica , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Feminino , Produtos Finais de Glicação Avançada/metabolismo , Humanos , Imuno-Histoquímica , Interleucina-6/metabolismo , Masculino , Mucosa Nasal/patologia , Pólipos Nasais/patologia , Pólipos Nasais/fisiopatologia , Receptor para Produtos Finais de Glicação Avançada/metabolismo , Sinusite/patologia , Sinusite/fisiopatologia , Vimentina/metabolismo
4.
Life Sci ; 240: 117110, 2020 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-31786191

RESUMO

AIMS: Thymic carcinoma is a rare epithelial tumor, for which, optimal pharmacotherapeutic methods have not yet been established. To develop new drug treatments for thymic carcinoma, we investigated the effects of fluvastatin-mediated pharmacological inhibition of 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR) on thymic carcinoma. MAIN METHODS: Thymic carcinoma tissue was surgically excised and HMGCR expression was assessed by immunohistochemistry. Ty82 human thymic carcinoma cells were treated with fluvastatin (1-10 µM) and their growth was monitored. KEY FINDINGS: HMGCR was expressed on carcinoma cells but not on normal epithelial cells in thymic tissue. Inhibition of HMGCR by fluvastatin suppressed cell proliferation and induced the death of Ty-82 human thymic carcinoma cells. Fluvastatin mediated its antitumor effects by blocking the production of geranylgeranyl-pyrophosphate (GGPP), an isoprenoid that is produced from mevalonate and binds to small GTPases, which promotes cell proliferation. SIGNIFICANCE: Fluvastatin showed marked antitumor effects on thymic carcinoma. The results suggest that the statin has clinical benefits in thymic carcinoma management.


Assuntos
Fluvastatina/uso terapêutico , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Timoma/tratamento farmacológico , Neoplasias do Timo/tratamento farmacológico , Apoptose/efeitos dos fármacos , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Humanos , Hidroximetilglutaril-CoA Redutases/biossíntese , Hidroximetilglutaril-CoA Redutases/genética , Imuno-Histoquímica , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Fosfatos de Poli-Isoprenil/antagonistas & inibidores , Fosfatos de Poli-Isoprenil/biossíntese , Prenilação/efeitos dos fármacos
5.
Cancer Sci ; 111(1): 72-83, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31691433

RESUMO

Capn4, also known as CapnS1, is a member of the calpain family, which plays a crucial role in maintaining the activity and function of calpain. We previously reported that Capn4 also plays an essential role in the migration of nasopharyngeal carcinoma (NPC) cells through regulation of (MMP-2) by nuclear factor-kappa B activation. Epstein-Barr virus latent membrane protein 1 (LMP1) is closely related to the malignant functions of NPC; however, the relationship between LMP1 and Capn4 in NPC remain unclear. Immunohistochemical studies showed that the level of LMP1 and Capn4 expression was high in both primary and metastatic NPC tissues, with a significantly positive correlation. We further found that LMP1 was able to upregulate the Capn4 promoter in a dose-dependent way through the C-terminal activation region (CTAR)1 and CTAR2 domains to activate AP-1. Moreover, we also found that LMP1 activated AP-1 through ERK/JNK phosphorylation. These findings indicate that Capn4 coordination with LMP1 promotes actin rearrangement and, ultimately, cellular migration. These results show that Capn4 coordination with LMP1 enhances NPC migration by increasing actin rearrangement involving ERK/JNK/AP-1 signaling. Therapeutically, additional and more specific LMP1 and Capn4 targeted inhibitors could be exploited to treat NPC.


Assuntos
Calpaína/genética , Sistema de Sinalização das MAP Quinases/genética , Carcinoma Nasofaríngeo/genética , Neoplasias Nasofaríngeas/genética , Metástase Neoplásica/genética , Fator de Transcrição AP-1/genética , Proteínas da Matriz Viral/genética , Linhagem Celular Tumoral , Infecções por Vírus Epstein-Barr/genética , Infecções por Vírus Epstein-Barr/virologia , Regulação Neoplásica da Expressão Gênica/genética , Herpesvirus Humano 4/patogenicidade , Humanos , NF-kappa B/genética , Carcinoma Nasofaríngeo/patologia , Carcinoma Nasofaríngeo/virologia , Neoplasias Nasofaríngeas/patologia , Neoplasias Nasofaríngeas/virologia , Metástase Neoplásica/patologia , Fosforilação/genética , Regiões Promotoras Genéticas/genética , Transdução de Sinais/genética , Regulação para Cima/genética
6.
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
7.
Gene ; 726: 144224, 2020 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-31669646

RESUMO

MicroRNA-155 (miR-155) has been identified to be overexpressed in various human cancers including osteosarcoma. However, whether the up-regulation of miR-155 is associated with osteosarcoma cancer stem cells (CSCs) is not well understood. In the present study, we showed that miR-155 induced the acquisition of stem-like features in U2OS osteosarcoma cells by increasing the expression of both CSCs surface markers (CD24, CD90, CD133) and CSC-related transcriptional factors (Nanog, SOX2, Oct4, Bim-1). Inflammatory factor TNF-α upregulated the miR-155 expression in U2OS cells and formed a feedback regulatory loop with miR-155. Furthermore, TNF-α/miR-155 axis promoted the cell proliferation, invasion and epithelial-mesenchymal transition (EMT) process in a TP53INP1 independent manner. We also revealed that TNF-α/miR-155 axis induced osteosarcoma CSCs transformation via ERK signaling pathway. These results indicate a crucial role of miR-155 in the acquisition of osteosarcoma CSC phenotype and miR-155 may serve as a potential target in future osteosarcoma therapy.


Assuntos
Proteínas de Transporte/genética , Transformação Celular Neoplásica/genética , Proteínas de Choque Térmico/genética , MicroRNAs/genética , Células-Tronco Neoplásicas/patologia , Osteossarcoma/genética , Fator de Necrose Tumoral alfa/genética , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células/genética , Transformação Celular Neoplásica/patologia , Transição Epitelial-Mesenquimal/genética , Regulação Neoplásica da Expressão Gênica/genética , Humanos , Sistema de Sinalização das MAP Quinases/genética , Invasividade Neoplásica/genética , Invasividade Neoplásica/patologia , Osteossarcoma/patologia , Transdução de Sinais/genética , Fatores de Transcrição/genética
8.
Life Sci ; 241: 117160, 2020 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-31837331

RESUMO

AIMS: Theanine, as a naturally occurring component in tea, has been shown to deliver benefits against various diseases. However, the exact molecular mechanisms underlying theanine's protective actions against cerebral ischemia/reperfusion (IR) injury still remains largely unknown. MAIN METHODS: In this study, rat cerebral IR injury model was established and were randomly divided into the following five groups: Sham (SH), IR, IR + Theanine (TH), IR + TH+ heme oxygenase-1 (HO-1) inducer cobalt protoporphyrin (Copp), and IR + Copp groups. KEY FINDINGS: We found that theanine significantly inhibited neuron damage and apoptosis in the hippocampus during the 48 h detection period, as detected by hematoxylin and eosin (HE) and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining. Meanwhile, reduced levels of malondialdehyde (MDA) and elevated activities of superoxide dismutase (SOD), glutathione (GSH), and glutathione peroxidase (GSH-PX) were observed in the theanine-treated group. Enzyme-linked immunosorbent (ELISA) assay also revealed that theanine markedly decreased the levels of inflammatory cytokines, such as IL-6, IL-1ß, and TNF-α, in IR rats. The anti-apoptotic effect of theanine on IR injury was further verified by flow cytometry assay. Besides, theanine dramatically inhibited HO-1 expression and activity but increased extracellular signal-regulated kinase 1/2 (ERK1/2) activity in hippocampal tissue from rats with cerebral IR injury. However, co-treatment with Copp remarkably abolished the protective effects of theanine on cerebral IR injury. SIGNIFICANCE: These findings demonstrated that the neuroprotective role of theanine was associated with its anti-oxidative, anti-inflammatory, and anti-apoptotic properties, which might be through regulation of HO-1 activation in rats with cerebral IR injury.


Assuntos
Isquemia Encefálica/prevenção & controle , Regulação da Expressão Gênica/efeitos dos fármacos , Glutamatos/farmacologia , Heme Oxigenase (Desciclizante)/antagonistas & inibidores , Hipocampo/efeitos dos fármacos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Traumatismo por Reperfusão/prevenção & controle , Animais , Apoptose/efeitos dos fármacos , Isquemia Encefálica/etiologia , Isquemia Encefálica/metabolismo , Isquemia Encefálica/patologia , Hipocampo/metabolismo , Hipocampo/patologia , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Inflamação/patologia , Masculino , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Neurônios/patologia , Estresse Oxidativo/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Traumatismo por Reperfusão/etiologia , Traumatismo por Reperfusão/metabolismo , Traumatismo por Reperfusão/patologia
9.
Eur J Med Chem ; 188: 111972, 2020 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-31884408

RESUMO

Quinolizidine alkaloids, as essential active ingredients extracted from Sophora alopecuroides Linn, have been well concerned in the past several decades owing to the unique structural features and numerous pharmacological activities. Quinolizidine alkaloids consist of matrine, oxymatrine, sophoridine, sophocarpine and aloperine etc. Additionally, quinolizidine alkaloids exert various excellent activities, including anti-cancer, anti-inflammation, anti-fibrosis, anti-virus and anti-arrhythmia regulations. In this review, we comprehensively clarify the pharmacological activities of quinolizidine alkaloids, as well as the relationship between biological function and structure-activity of substituted quinolizidine alkaloids. We believe that biological agents based on the pharmacological functions of quinolizidine alkaloids could be well applied in clinical practice.


Assuntos
Alcaloides/farmacologia , Quinolizidinas/farmacologia , Sophora/química , Alcaloides/química , Apoptose/efeitos dos fármacos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Estrutura Molecular , Quinolizidinas/química , Relação Estrutura-Atividade
10.
Life Sci ; 242: 117191, 2020 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-31863775

RESUMO

Melatonin is an indole neuroendocrine hormone that is mainly secreted by the pineal gland to regulate circadian rhythm, antioxidation, and immune regulation. Melatonin plays an important role in T cell-mediated immune responses against cancer, infections, and the development of many autoimmune diseases. The aim of this study was to investigate the immunomodulatory effects of melatonin on T/B cell activation in pinealectomy mice. The improved pinealectomy procedure for mice presented in this study is a good animal model to be used in follow-up studies on melatonin. After pinealectomy, the tissue removed was identified as the pineal body using HE staining. The effects of melatonin supplementation on T cell activation and activation-related changes to the MAPK/NF-κ B pathways were analyzed by flow cytometry and real-time PCR. We found that expression levels of Th1, Th2 and Th17-related cytokines in peripheral blood were lower in mice that had undergone pinealectomy, compared with normal mice. After melatonin supplementation, cytokine levels rapidly increased within a short period of time, which resulted in the gradual recovery of cytokine expression levels. Moreover, activation of T/B cells in mice was weakened and decreased after pineal gland removal. Melatonin was found to inhibit the expression of TLR3, p38, JNK, and MAPK/NF-κ B within a short period (2 weeks) of melatonin replenishment. This inhibition gradually weakened with time, since the degree of inhibition is negatively related with the dosage of melatonin. In conclusion, melatonin may regulate the activation of T/B cells, playing a critical role in the regulation of immune balance.


Assuntos
Linfócitos B/efeitos dos fármacos , Imunidade Celular/efeitos dos fármacos , Fatores Imunológicos/farmacologia , Ativação Linfocitária/efeitos dos fármacos , Melatonina/farmacologia , Pinealectomia , Linfócitos T/efeitos dos fármacos , Animais , Citocinas/metabolismo , Citometria de Fluxo , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Glândula Pineal/anatomia & histologia , Reação em Cadeia da Polimerase em Tempo Real
11.
Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi ; 35(11): 979-985, 2019 Nov.
Artigo em Chinês | MEDLINE | ID: mdl-31878993

RESUMO

Objective To investigate the role of mitogen activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK) pathway in the salidroside (SAL)-regulated antitumor immunity of dendritic cells (DCs). Methods Lewis lung cancer-bearing mouse model was established and treated with normal saline (NS) (0.2 mL/d), SAL [500 mg/(kg.d)] and cyclophosphamide (CTX) [10 mg/(kg.d)] in corresponding groups. Then their survival and tumor quality were recorded. Meanwhile, the bone marrow-derived DCs from the Lewis lung cancer-bearing mice were isolated in vitro and cultured for 7 days before collection. After sorted with magnetic beads, cells were co-cultured with PBS, SAL (0.05 mg/mL), LPS (200 ng/mL) or SAL combined with ERK inhibitor U0126 separately for 48 hours, followed by detection of the expression of phosphorylated ERK (p-ERK) by flow cytometry. In addition, after the stimulation of DCs by SAL, the expression of p38 MAPK and phosphorylated c-jun N-terminal kinase (p-JNK) was detected by flow cytometry. Moreover, after sorted with magneticbeads, DCs were co-cultured with PBS, SAL (0.05 mg/mL), LPS (200 ng/mL) or SAL combined with U0126. Then, the supernatant was collected, and IL-12p70 secretion ability of DCs was detected by ELISA. Finally, sensitized bone marrow-derived DCs from Lewis lung cancer-bearing mice were stimulated with SAL and co-cultured with spleen T lymphocytes purified by nylon fiber column from C57BL/6 mice as effector cells. 3LL target cells were then added at the target ratio of 10:1, 25:1, 50:1, followed by the detection of cell viability of cytotoxic T lymphocytes (CTLs) using CCK-8 assay. Results SAL could significantly inhibit tumor growth and improve the survival rate. Compared with PBS group, the phosphorylation of ERK protein on DC was enhanced significantly, and then reduced significantly after U0126 treatment. The phosphorylation of p38MAPK and c-jun N-terminal kinase (JNK) protein was not statistically affected by SAL. The level of IL-12p70 significantly increased in SAL group, and became remarkably higher after U0126 treatment. Finally, the killing ability of CTL was significantly enhanced by SAL. Conclusion SAL can inhibit the tumor growth of Lewis lung cancer-bearing mice and activate the ERK signaling pathway, thereby promoting IL-12p70 secretion in DCs and enhancing the cytotoxicity of CTL.


Assuntos
Carcinoma Pulmonar de Lewis/imunologia , Células Dendríticas/efeitos dos fármacos , Glucosídeos/farmacologia , Sistema de Sinalização das MAP Quinases , Fenóis/farmacologia , Animais , Células Cultivadas , Células Dendríticas/imunologia , Interleucina-12/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Linfócitos T Citotóxicos/imunologia
12.
BMC Complement Altern Med ; 19(1): 371, 2019 Dec 16.
Artigo em Inglês | MEDLINE | ID: mdl-31842849

RESUMO

BACKGROUND: Canscora lucidissima (Levl. & Vaniot) Hand.-Mazz. (C. lucidissima), mainly distributed in southern China, has been shown to be effective in the treatment of inflammatory diseases. However, the underlying mechanism of its anti-inflammatory effect is not fully understood. METHODS: In this study, we investigated the anti-inflammatory mechanism of ethanol extract of C. lucidissima (Cl-EE) in lipopolysaccharide (LPS)-induced inflammatory models. ELISA, real-time PCR, Western blot and luciferase reporter assay were used for the experiments in vitro, and ICR mouse endotoxemia model was used for in vivo test. RESULTS: Our data showed that Cl-EE reduced the production of NO by down-regulating the mRNA and protein expression of inducible nitric oxide synthase (iNOS) in LPS-activated RAW 264.7 cells. Meanwhile, it potently decreased other proinflammatory mediators, such as TNF-α, IL-6, MCP-1 and IL-1ß at the transcriptional and translational levels. Further study indicated that Cl-EE did not affect NF-κB signaling pathway but significantly suppressed the phosphorylation of ERK1/2, rather than JNK or p38. In a LPS-induced endotoxemia mouse model, a single intraperitoneal injection of Cl-EE (75-300 mg/kg) could lower circulatory TNF-α, IL-6 and MCP-1 levels. CONCLUSIONS: Collectively, our results indicated that Cl-EE suppressed the phosphorylation level of ERK1/2 thus reducing the transcription and translation of inflammatory genes, thereby exerted anti-inflammatory activity. This study reveals the anti-inflammatory mechanism of C. lucidissima and may provide an effective treatment option for a variety of inflammatory diseases.


Assuntos
Anti-Inflamatórios/farmacologia , Gentianaceae , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Extratos Vegetais/farmacologia , Animais , Citocinas/metabolismo , Feminino , Inflamação/metabolismo , Lipopolissacarídeos/efeitos adversos , Macrófagos/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos ICR , Fosforilação/efeitos dos fármacos , Células RAW 264.7
13.
Chem Commun (Camb) ; 56(2): 179-196, 2019 Dec 19.
Artigo em Inglês | MEDLINE | ID: mdl-31782422

RESUMO

Organo-seleno compounds (org-Se) have been widely used in antitumor, antiviral, and antiinflammatory therapy; antioxidation and other biological fields. As such, they have made an important contribution to overcoming various kinds of diseases, and researchers are increasingly attracted to org-Se's synthesis and functional design. This review is mainly focused on the design and synthesis of various kinds of org-Se, followed by their anticancer mechanisms such as the mitochondria mediated pathway induced by ROS, death receptor mediated pathways involving p53 phosphorylation, and the activation of the AMPK pathway to promote apoptosis. Org-Se also serves as a sensitizer in chemotherapy and radiotherapy, and an antagonist against the cytotoxic effects induced by chemotherapeutic agents. Finally, we will summarize the development of cancer-targeted org-Se containing complexes, and nanotechnology-based org-Se for anticancer application. This review could provide information for the future design of chemically innovative org-Se with anticancer potential, and shed light on the discovery of nanomaterial-based pharmaceuticals to improve drug development and formation.


Assuntos
Antineoplásicos/uso terapêutico , Neoplasias/tratamento farmacológico , Compostos Organosselênicos/uso terapêutico , Animais , Antineoplásicos/química , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Complexos de Coordenação/química , Complexos de Coordenação/farmacologia , Complexos de Coordenação/uso terapêutico , Desenho de Drogas , Humanos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Nanopartículas/química , Neoplasias/radioterapia , Compostos Organosselênicos/química , Compostos Organosselênicos/farmacologia , Espécies Reativas de Oxigênio/metabolismo , Receptores de Morte Celular/metabolismo , Proteína Supressora de Tumor p53/metabolismo
14.
Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi ; 35(9): 794-799, 2019 Sep.
Artigo em Chinês | MEDLINE | ID: mdl-31750820

RESUMO

Objective To explore the inhibitory effects of polyphenols from Toona sinensis seeds (PTSS) on neuroinflammation and the underlying mechanism in rats with Parkinson's disease (PD). Methods PD rat models were prepared by stereotaxic injection of 6-hydroxydopamine (6-OHDA) into one side of striatum of Sprague-Dawley male rats. Model rats were randomly divided into model group and PTSS group (n=10), and a normal control group was set as well (n=10). The rotational behavior of rats was induced by intraperitoneal injection of apomorphine (APO) after 30 days, and the behavioral changes of rats from each group were investigated. The morphological and quantity changes of DA neurons (tyrosine hydroxylase positive, TH-positive), microglia cells (ionized calcium binding adaptor molecule-1, Iba1-positive) and astrocytes (glial fibrillary acidic protein, GFAP-positive) in substantia nigra (SN) of rats from each group were examined by immunohistochemistry. Inducible nitric oxide synthase (iNOS), nuclear factor-κB p65 (NF-κBp65), p38 mitogen-activated protein kinase (p38MAPK) and phosphor-p38 mitogen-activated protein kinase (p-p38MAPK) levels were evaluated through immunohistochemical staining. The protein levels of TH, GFAP, p38MAPK and p-p38MAPK in SN were examined by Western blot analysis. Results The number of rotations in the rats of the PTSS group was significantly reduced compared with that in the model group. The number of TH-positive cells in the model group was much less than that in the control group. The number and protein levels of TH-positive cells were enhanced significantly by PTSS intervention. Compared with the control group, the protein levels of Iba1, GFAP, iNOS, NF-κB, p38MAPK and p-p38MAPK in the injured side of the model group significantly increased, which could be suppressed significantly by PTSS intervention. Conclusion PTSS demonstrates protective effects on DA neurons by inhibiting p38MAPK signaling pathway and reducing the expression of inflammatory factors in PD rats.


Assuntos
Neurônios Dopaminérgicos/efeitos dos fármacos , Sistema de Sinalização das MAP Quinases , Meliaceae/química , Doença de Parkinson/tratamento farmacológico , Polifenóis/farmacologia , Sementes/química , Animais , Masculino , Oxidopamina , Compostos Fitoquímicos/farmacologia , Ratos , Ratos Sprague-Dawley , Substância Negra
15.
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
16.
Life Sci ; 239: 117035, 2019 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-31697952

RESUMO

AIMS: The purpose of this study was to investigate the role of long non-coding RNA taurine-upregulated gene 1 (TUG1) in colon cancer (Cc) and related molecular mechanisms. MATERIALS AND METHODS: RT-qPCR, Western blot and immunohistochemistry were used to detect the expression of related proteins. BrdU and Transwell assays were used to detect cell proliferation and invasion, respectively. Immunofluorescence was used to detect the expression of Vimentin. KEY FINDINGS: TUG1 expression was up-regulated in CaCO-2, SW620 and HT-29 cells, while miR-26a-5p was down-regulated. Bioinformatics analysis showed that miR-26a-5p was the target of TUG1, and the targeting relationship was further confirmed by dual-luciferase report analysis. Besides, matrix metalloproteinases-14 (MMP-14) was a target of mir-26a-5p. Knockdown of TUG1 by shRNA (sh-TUG1) inhibited MMP-14 expression. Functional analysis showed that sh-TUG1 significantly inhibited Cc cell proliferation, invasion and epithelial-mesenchymal transformation (EMT). Notably, miR-26a-5p inhibitor reversed the promotion of Cc caused by sh-TUG1. Mechanically, the overexpression of TUG1 significantly up-regulated the levels of MMP-14, VEGF, p-p38 mitogen-activated protein kinase (p-p38 MAPK) and p-HSP27 (heat shock protein 27), and promoted the proliferation, invasion and EMT of Cc cells. However, MAPK pathway inhibitor SB203580 has shown the opposite effect. Additionally, animal studies have shown that sh-TUG1 inhibited tumor growth and motility in vivo in the same way. SIGNIFICANCE: This study demonstrated that TUG1 accelerates the development of colon cancer by regulating miR-26a-5p/MMP14/p38 MAPK/Hsp27 axis in vitro and in vivo. Therefore, TUG1 provides a new direction for the treatment of Cc.


Assuntos
Carcinogênese/genética , Neoplasias do Colo/genética , Proteínas de Choque Térmico/biossíntese , Sistema de Sinalização das MAP Quinases/genética , Metaloproteinase 14 da Matriz/biossíntese , MicroRNAs/biossíntese , Chaperonas Moleculares/biossíntese , RNA Longo não Codificante/genética , Animais , Linhagem Celular Tumoral , Neoplasias do Colo/patologia , Biologia Computacional , Transição Epitelial-Mesenquimal/genética , Proteínas de Choque Térmico/genética , Humanos , Masculino , Metaloproteinase 14 da Matriz/genética , Camundongos , Camundongos Endogâmicos BALB C , MicroRNAs/genética , Chaperonas Moleculares/genética , Regulação para Cima
17.
Zhongguo Ying Yong Sheng Li Xue Za Zhi ; 35(4): 366-370, 2019 Jul 28.
Artigo em Chinês | MEDLINE | ID: mdl-31701725

RESUMO

OBJECTIVE: To investigate the effects of Acorus tatarinowii Schott and its active component 5- hydroxymethyl furfural (HMF) on learning and memory and ERK/CREB signal in hippocampus of rats with exercise-induced fatigue. METHODS: SD rats were randomly divided into normal group (A), exercise group (B), exercise + HMF low, middle and high dose treatment group (C, D, E), exercise + acorus tatarinowii Schott low, middle and high dose treatment group (F, G, H), with ten rats in each group. The rats in group C, D and E were treated with HMF at the doses of 0.10, 1.00 and 3.00 mg. kg-1 by ig. The rats in group F, G and H were treated with the extracts of Acorus tatarinowii Schott at the doses of 0.12, 1.20 and 4.80 g. kg-1 by ig. Learning and memory of rats were tested by the method of water maze experiment, and the expression levels of p-ERK1/2 and p-CREB protein in hippocampus of rats were tested by the method of Western blot in the end of the experiment. RESULTS: The escape latencies of E and H groups were lower than those of groups B, C, D, F and G; and the numbers of plateau crossing were more than those of groups B, C, D, F and G and the expression levels of p-ERK1/2, p-CREB protein were higher than those of groups B, C, D, F and G , respectively(P < 0.01). There was no significant difference in the above indexes among groups A, E and H(P>0.05) except that the expression levels of p-ERK2 protein in group E were lower than those in group A and H (P<0.05). CONCLUSION: Acorus tatarinowii and its active component- HMF can improve the learning and memory of rats with exercise-induced fatigue, and the mechanism is related to the up-regulation of ERK / CREB signal in hippocampus of rats with exercise-induced fatigue.


Assuntos
Acorus/química , Fadiga/tratamento farmacológico , Furaldeído/análogos & derivados , Condicionamento Físico Animal , Animais , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Furaldeído/farmacologia , Hipocampo/metabolismo , Sistema de Sinalização das MAP Quinases , Aprendizagem em Labirinto/efeitos dos fármacos , Memória/efeitos dos fármacos , Compostos Fitoquímicos/farmacologia , Distribuição Aleatória , Ratos , Ratos Sprague-Dawley
18.
BMC Complement Altern Med ; 19(1): 310, 2019 Nov 12.
Artigo em Inglês | MEDLINE | ID: mdl-31718640

RESUMO

BACKGROUND: Heracleum moellendorffii roots (HM-R) have been long treated for inflammatory diseases such as arthritis, backache and fever. However, an anti-inflammatory effect and the specific mechanism of HM-R were not yet clear. In this study, we for the first time explored the anti-inflammatory of HM-R. METHODS: The cytotoxicity of HM-R against RAW264.7 cells was evaluated using MTT assay. The inhibition of NO and PGE2 production by HM-R was evaluated using Griess reagent and Prostaglandin E2 ELISA Kit, respectively. The changes in mRNA or protein level following HM-R treatment were assessed by RT-PCR and Western blot analysis, respectively. RESULTS: HM-R dose-dependently blocked LPS-induced NO and PGE2 production. In addition, HM-R inhibited LPS-induced overexpression of iNOS, COX-2, IL-1ß and IL-6 in RAW264.7 cells. HM-R inhibited LPS-induced NF-κB signaling activation through blocking IκB-α degradation and p65 nuclear accumulation. Furthermore, HM-R inhibited MAPK signaling activation by attenuating the phosphorylation of ERK1/2, p38 and JNK. HM-R increased nuclear accumulation of Nrf2 and HO-1 expression. However, NAC reduced the increased nuclear accumulation of Nrf2 and HO-1 expression by HM-R. In HPLC analysis, falcarinol was detected from HM-R as an anti-inflammatory compound. CONCLUSIONS: These results indicate that HM-R may exert anti-inflammatory activity by inhibiting NF-κB and MAPK signaling, and activating ROS/Nrf2/HO-1 signaling. These findings suggest that HM-R has a potential as a natural material for the development of anti-inflammatory drugs.


Assuntos
Anti-Inflamatórios/farmacologia , Medicamentos de Ervas Chinesas/farmacologia , Heme Oxigenase-1/imunologia , Heracleum/química , Fator 2 Relacionado a NF-E2/imunologia , NF-kappa B/imunologia , Espécies Reativas de Oxigênio/imunologia , Animais , Ciclo-Oxigenase 2/genética , Ciclo-Oxigenase 2/imunologia , Heme Oxigenase-1/genética , Lipopolissacarídeos/farmacologia , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Camundongos , Fator 2 Relacionado a NF-E2/genética , NF-kappa B/genética , Raízes de Plantas/química , Células RAW 264.7
19.
Mol Immunol ; 116: 191-198, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31710976

RESUMO

BACKGROUND: Scars affects the appearance and results in tissue damage. In this research, we preliminarily studied the function and mechanism of curcumin (CUR) on cell proliferation and soluble collagen synthesis in NIH-3T3 cells. METHODS: CCK-8 was used to detect the IC50 of CUR. Moreover, Western blot was used to measure the expression of cell proliferation-related, soluble collagen synthesis and pathway-related proteins. Sircol assay was determined the expression of soluble collagen. Furthermore, reverse transcription quantitative PCR (RT-qPCR) was used to determined miR-29a, α-smooth muscle aorta (α-SMA), soluble collagen 1 (Col 1) and Col 3 expression. RESULTS: CUR inhibited cell viability and proliferation-related proteins expression. Transforming growth factor-ß (TGFß1)-induced heightened the expression of proliferation-related proteins and soluble collagen synthesis-related proteins. CUR inhibited TGFß1-induced proliferation and soluble collagen synthesis. Furthermore, CUR positively related miR-29a and miR-29a mimic inhibited TGFß1-induced proliferation and soluble collagen synthesis. Besides, transfection with miR-29a inhibitor could partly reverse the effects of CUR. CUR inhibited the ERK1/2 and ß-catenin pathways and the miR-29a inhibitor reversed the above results. Otherwise, soluble collagen 1 (Col 1) partly reversed the effects of CUR on proliferation and soluble collagen synthesis and silenced Col 1/3 could inhibit ERK1/2 and ß-catenin signaling pathways. CONCLUSION: CUR restrained TGFß1-induced proliferation and soluble collagen synthesis in NIH-3T3 cells by up-regulation of miR-29a via ERK1/2 and ß-catenin signaling pathways.


Assuntos
Proliferação de Células/efeitos dos fármacos , Colágeno Tipo I/metabolismo , Curcumina/farmacologia , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , MicroRNAs/metabolismo , Transdução de Sinais/efeitos dos fármacos , beta Catenina/metabolismo , Animais , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Camundongos , Células NIH 3T3 , Fator de Crescimento Transformador beta1/metabolismo , Via de Sinalização Wnt/efeitos dos fármacos
20.
Invest Ophthalmol Vis Sci ; 60(14): 4596-4605, 2019 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-31675076

RESUMO

Purpose: Choroidal neovascularization (CNV) is the principal pathological factor contributing to blindness in neovascular age-related macular degeneration (nAMD). Infiltration of M2 macrophage is thought to contribute to CNV progress, although the way that regulates its differentiation remains unclear. Here, we investigate the role of CHI3L1 in M2 differentiation and angiogenesis in CNV. Methods: Serums from nAMD patients were tested for CHI3L1 expression. Mice were subjected to laser injury to induce CNV, and lesion expansion were tracked using fundus fluorescence angiography (FFA) and immunofluorescence analysis. Several strategies were taken to verify the contribution of M2 macrophage and CHI3L1: macrophage depletion by clodrosome, local CHI3L1 inhibition using intravitreally injection neutralize antibody (mAY), and depletion of CHI3L1 receptor (IL13-Ra2) by small-interfering RNA (siRNA). Tuber analysis was used to further determine angiogenetic effect of CHI3L1. Anti-VEGFA was used as positive control for mAY. Results: Serum levels of CHI3L1 were highly elevated in nAMD patients. CHI3L1 was expressed by infiltrating M2 macrophages and was elevated as CNV progress in a mice model. System macrophage depletion and local suppression of CHI3L1 alleviated CNV formation while enhancing anti-VEGFA therapeutic effect. Stimulation of macrophage with recombinant CHI3L1 activated MAPK signaling cascade and induced transition to M2, while siRNA knockdown of IL13-Ra2 abolished it. In an in vitro coculture system, supernatants from CHI3L1-stimulated M2 macrophages and promoted tube vascularization. Conclusions: These results unveil novel angiogenic regulation of CHI3L1 and M2 polarized macrophages in CNV development. These mechanistic insights may point to CHI3L1 as a new therapeutic target for treatment for nAMD.


Assuntos
Diferenciação Celular/fisiologia , Proteína 1 Semelhante à Quitinase-3/fisiologia , Neovascularização de Coroide/fisiopatologia , Macrófagos/fisiologia , Degeneração Macular Exsudativa/fisiopatologia , Idoso , Animais , Anticorpos Neutralizantes/farmacologia , Western Blotting , Neovascularização de Coroide/sangue , Neovascularização de Coroide/prevenção & controle , Modelos Animais de Doenças , Angiofluoresceinografia , Técnica Indireta de Fluorescência para Anticorpo , Humanos , Separação Imunomagnética , Injeções Intravítreas , Sistema de Sinalização das MAP Quinases/fisiologia , Masculino , Camundongos Endogâmicos C57BL , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Fator A de Crescimento do Endotélio Vascular/antagonistas & inibidores , Degeneração Macular Exsudativa/sangue , Degeneração Macular Exsudativa/prevenção & controle
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