Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 11.782
Filtrar
1.
Zhongguo Zhong Yao Za Zhi ; 46(16): 4167-4174, 2021 Aug.
Artigo em Chinês | MEDLINE | ID: mdl-34467729

RESUMO

This study aimed to explore the effects of galangin on energy metabolism and autophagy in gastric cancer MGC803 cells and the underlying mechanism. Cell counting kit-8(CCK-8) was used to detect the effects of galangin at different concentrations on via-bility of MGC803 cells after 48 h intervention. Western blot was carried out to measure the effects of galangin on expression of proteins related to autophagy, nuclear factor-κB(NF-κB) pathway and energy metabolism, followed by the determination of its effects on mRNA expression of energy metabolism-related proteins by Real-time quantitative PCR(qPCR). The impact of galangin on autophagy was explored using AutophagyGreen dye reagent, with autophagosomes and lysosomes observed under the transmission electron microscope(TEM). Nude mice transplanted with gastric cancer MGC803 cells via subcutaneous injection were randomly divided into the following three groups: control(0.5% sodium carboxymethyl cellulose, once a day), 5-fluorouracil(5-FU, 50 mg·kg~(-1), twice a week), and galangin(120 mg·kg~(-1), once a day) groups. The body weight and tumor volume were measured once every three days with a vernier caliper at the same time point by the same person. After 21-d treatment, the tumor tissue was isolated and weighed for the calculation of the tumor-suppressing rate. The comparison with the control group revealed that galangin inhibited the viability of MGC803 cells, up-regulated the protein expression of microtuble-associated protein 1 light chain 3 B(LC3 B) Ⅱ, inhibited the phosphorylation of NF-κB pathway-related proteins, and promoted the formation of autophagosomes in MGC803 cells. However, it did not obviously affect the expression of energy metabolism-related proteins. Furthermore, galangin at 120 mg·kg~(-1) significantly reduced the tumor weight and volume in mice, enhanced LC3 BⅡ protein expression, and inhibited the phosphorylation of NF-κB pathway-related proteins. All these have suggested that galangin inhibited the growth of gastric cancer MGC803 cells both in vivo and in vitro, possibly by inhibiting the NF-κB pathway and enhancing autophagy.


Assuntos
NF-kappa B , Neoplasias Gástricas , Animais , Autofagia , Flavonoides , Camundongos , Camundongos Nus , NF-kappa B/genética , Transdução de Sinais , Neoplasias Gástricas/tratamento farmacológico , Neoplasias Gástricas/genética
2.
J Biol Regul Homeost Agents ; 35(Special Issue on Internal Medicine n.1)2021 07 30.
Artigo em Inglês | MEDLINE | ID: mdl-34350747

RESUMO

In this study, MicroRNA-210 (miR-210), which was previously proved to be a potential immunomodulator in various disease, attenuated mouse myocardium ischemia/reperfusion (I/R) injury. miR-210 was increased in cardiomyocytes exposed to hypoxia/reoxygenation (H/R). The expression of IL-6 and TNF-α in both serum and supernatant were reduced in miR-210 mimics groups. Mice were randomly divided into four groups, which were pre-treated with saline (sham and ischemia/reperfusion group), miR-210 mimics and miR-210 inhibitor treatments. Three days later, the mouse IR model was established by ischemia for 30 min, followed by reperfusion for 3 h. Myocardium and plasma were harvested and assessed. The myocardium histopathological changes were reduced in miR-210 mimics groups, and serum levels of Creatine kinase isoenzyme (CK-MB) and Lactate dehydrogenase (LDH) were significantly decreased compared with I/R groups. The protein expression of proinflammatory factor interleukin (IL)-1ß and IL-6 were suppressed by the up-regulation of miR-210. The expression of miR-210 was negatively correlated with the expression of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB). In conclusion, our study indicates that miR-210 protects heart from myocardium I/R injury via suppressing NF-κB signal pathway.


Assuntos
MicroRNAs , Traumatismo por Reperfusão Miocárdica , Traumatismo por Reperfusão , Animais , Camundongos , MicroRNAs/genética , Traumatismo por Reperfusão Miocárdica/genética , Miócitos Cardíacos , NF-kappa B/genética , Ratos , Ratos Sprague-Dawley
3.
Int J Mol Sci ; 22(16)2021 Aug 18.
Artigo em Inglês | MEDLINE | ID: mdl-34445612

RESUMO

Prostate cancer is a common cause of death worldwide. Here, we isolated cancer stem cells (CSCs) from four adenocarcinomas of the prostate (Gleason scores from 3 + 3 up to 4 + 5). CSCs were characterized by the expression of the stem cell markers TWIST, the epithelial cell adhesion molecule (EPCAM), the transcription factors SNAI1 (SNAIL) and SNAI2 (SLUG) and cancer markers such as CD44 and prominin-1 (CD133). All investigated CSC populations contained a fraction highly positive for aldehyde dehydrogenase (ALDH) function and displayed robust expressions of programmed cell death 1 (PD-1) ligands. Furthermore, we investigated immunotherapeutic approaches but had no success even with the clinically used PD-1 inhibitor pembrolizumab. In addition, we studied another death-inducing pathway via interferon gamma signaling and detected high-level upregulations of human leukocyte antigen A (HLA-A) and beta 2-microglobulin (B2M) with only moderate killing efficacy. To examine further killing mechanisms in prostate cancer stem cells (PCSCs), we analyzed NF-κB signaling. Surprisingly, two patient-specific populations of PCSCs were found: one with canonical NF-κB signaling and another one with blunted NF-κB activation, which can be efficiently killed by tumor necrosis factor (TNF). Thus, culturing of PCSCs and analysis of respective NF-κB induction potency after surgery might be a powerful tool for optimizing patient-specific treatment options, such as the use of TNF-inducing chemotherapeutics and/or NF-κB inhibitors.


Assuntos
Anticorpos Monoclonais Humanizados/farmacologia , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Células Matadoras Naturais/patologia , NF-kappa B/metabolismo , Células-Tronco Neoplásicas/patologia , Neoplasias da Próstata/patologia , Fator de Necrose Tumoral alfa/farmacologia , Antineoplásicos Imunológicos/farmacologia , Apoptose , Proliferação de Células , Humanos , Células Matadoras Naturais/efeitos dos fármacos , Células Matadoras Naturais/metabolismo , Masculino , NF-kappa B/genética , Células-Tronco Neoplásicas/efeitos dos fármacos , Células-Tronco Neoplásicas/metabolismo , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/metabolismo , Células Tumorais Cultivadas
4.
Int J Mol Sci ; 22(16)2021 Aug 13.
Artigo em Inglês | MEDLINE | ID: mdl-34445430

RESUMO

Age-related macular degeneration (AMD), the leading cause of vision loss in the elderly, is a degenerative disease of the macula, where retinal pigment epithelium (RPE) cells are damaged in the early stages of the disease, and chronic inflammatory processes may be involved. Besides aging and lifestyle factors as drivers of AMD, a strong genetic association to AMD is found in genes of the complement system, with a single polymorphism in the complement factor H gene (CFH), accounting for the majority of AMD risk. However, the exact mechanism of CFH dysregulation confers such a great risk for AMD and its role in RPE cell homeostasis is unclear. To explore the role of endogenous CFH locally in RPE cells, we silenced CFH in human hTERT-RPE1 cells. We demonstrate that endogenously expressed CFH in RPE cells modulates inflammatory cytokine production and complement regulation, independent of external complement sources, or stressors. We show that loss of the factor H protein (FH) results in increased levels of inflammatory mediators (e.g., IL-6, IL-8, GM-CSF) and altered levels of complement proteins (e.g., C3, CFB upregulation, and C5 downregulation) that are known to play a role in AMD. Moreover, our results identify the NF-κB pathway as the major pathway involved in regulating these inflammatory and complement factors. Our findings suggest that in RPE cells, FH and the NF-κB pathway work in synergy to maintain inflammatory and complement balance, and in case either one of them is dysregulated, the RPE microenvironment changes towards a proinflammatory AMD-like phenotype.


Assuntos
Citocinas/metabolismo , Inativação Gênica , Degeneração Macular/genética , Epitélio Pigmentado da Retina/imunologia , Linhagem Celular , Fator H do Complemento/genética , Proteínas do Sistema Complemento/metabolismo , Citocinas/genética , Regulação da Expressão Gênica , Humanos , Degeneração Macular/imunologia , Modelos Biológicos , NF-kappa B/genética , NF-kappa B/metabolismo , Epitélio Pigmentado da Retina/metabolismo , Transdução de Sinais
5.
J Med Food ; 24(8): 806-816, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34382859

RESUMO

Even though nasopharyngeal carcinoma (NPC) is not common worldwide, it is a major public health burden in endemic areas. Distant metastasis often leads to a poor prognosis for NPC; therefore, new and effective anticancer strategies are needed. Ginkgolic acid (GA) is small-molecule compound existing in Ginkgo biloba that has various biologically relevant activities, including antitumor properties; however, its effects and mechanism of action in NPC are unknown. The effects of GA on NPC and such underlying mechanisms were investigated using 5-8F and CNE2 cells and NP69 human immortalized nasopharyngeal epithelial cells in this study. Moreover, the xenograft models were built to examine GA's effection in vivo. GA treatment decreased the survival and invasive capacity of 5-8F and CNE2 and induced their apoptosis, which varied with dose; this was accompanied by downregulation of B cell lymphoma (Bcl)2, upregulation of Bcl2-associated X protein, and activation of poly-ADP ribose polymerase, and caspase-9/-3. G0/G1 phase arrest was induced by GA in NPCs. It also reduced the expression of cyclin-dependent kinase 6 and its regulators cyclin D2 and cyclin D3. GA inhibited the activation of protein kinase B/nuclear factor signaling; this effect was potentiated with GA and 5-fluorouracil (5-FU), which also enhanced 5-FU-induced apoptosis. In summary, GA may be effective as an adjuvant to conventional chemotherapy drugs in preventing the progression of NPC.


Assuntos
NF-kappa B , Neoplasias Nasofaríngeas , Apoptose , Linhagem Celular Tumoral , Proliferação de Células , Humanos , NF-kappa B/genética , Carcinoma Nasofaríngeo/tratamento farmacológico , Carcinoma Nasofaríngeo/genética , Neoplasias Nasofaríngeas/tratamento farmacológico , Neoplasias Nasofaríngeas/genética , Proteínas Proto-Oncogênicas c-akt/genética , Salicilatos
6.
J Med Food ; 24(8): 852-859, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34382871

RESUMO

CYJ-27, a synthetic analog of decursin, prevents the generation of proinflammatory cytokines and oxidative stress. In this study, the effects of CYJ-27 on the regulation of inducible nitric oxide synthase (iNOS), heme oxygenase (HO)-1, and cyclooxygenase (COX-)2 were characterized in lipopolysaccharide (LPS)-treated human umbilical vein endothelial cells (HUVECs). In addition, the effects of CYJ-27 on the production of iNOS and representative proinflammatory cytokines, such as tumor necrosis factor (TNF)-α and interleukin (IL)-1ß, were tested in the lung tissues of LPS-treated mice. CYJ-27 promoted the expression of HO-1, suppressed NF-κB-luciferase activity, and reduced COX-2/PGE2 and iNOS/NO, resulting in a diminution in phosphorylated-STAT-1. Furthermore, CYJ-27 promoted the nuclear translocation of Nrf2, enhanced the combination of Nrf2 to antioxidant response elements, and diminished IL-1ß production in LPS-activated HUVECs. CYJ-27-downregulated iNOS/NO expression was rescued after the RNAi suppression of HO-1. In LPS-treated mice, CYJ-27 significantly diminished iNOS production in the lung tissues and TNF-α expression in the bronchoalveolar lavage fluid. These findings indicate that CYJ-27 exerts anti-inflammatory activities by regulating iNOS through downregulation of both NF-κB activation and phosphorylated-STAT-1. Hence, it can act as a template for the development of novel substances to treat inflammatory diseases.


Assuntos
Inflamação , NF-kappa B , Animais , Benzopiranos , Butiratos , Ciclo-Oxigenase 2/metabolismo , Regulação para Baixo , Heme Oxigenase-1/genética , Heme Oxigenase-1/metabolismo , Células Endoteliais da Veia Umbilical Humana/metabolismo , Humanos , Inflamação/tratamento farmacológico , Inflamação/genética , Lipopolissacarídeos , Camundongos , Fator 2 Relacionado a NF-E2/genética , Fator 2 Relacionado a NF-E2/metabolismo , NF-kappa B/genética , NF-kappa B/metabolismo , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase Tipo II/genética , Óxido Nítrico Sintase Tipo II/metabolismo
7.
J Agric Food Chem ; 69(35): 10151-10162, 2021 Sep 08.
Artigo em Inglês | MEDLINE | ID: mdl-34432454

RESUMO

Inflammatory bowel disease (IBD) is a disease characterized by intestinal inflammation with immune dysregulation and intestinal microecological imbalance. In a dextran sulfate sodium salt (DSS)-induced IBD mouse model, noni (Morinda citrifolia L.) fruit polysaccharides (NFP) with homogalacturonan and rhamnogalacturonan-I domain decreased the concentration of serum LPS, TNF-α, and IL-17 by 84, 42, and 65%, respectively. It was abolished when intestinal microbiota were depleted by antibiotics. Sequencing analysis of gut microbiota showed an attenuated disruption of the microbial composition in the DSS+NFP group. Targeted metabolomic analysis revealed that NFP upregulated the content of acetic acid, propionic acid, and butyric acid by onefold but reduced isobutyric acid and isovaleric acid contents. NFP also inhibited JNK, ERK, and NF-κB phosphorylation of IBD mice. Taken together, the mechanism of NFP alleviating IBD is related to the intestinal microecological balance to inhibit inflammatory signaling pathways. This study provides a basis for NFP as a cheap intervention for the prevention and treatment of IBD patients.


Assuntos
Microbioma Gastrointestinal , Doenças Inflamatórias Intestinais , Morinda , Animais , Sulfato de Dextrana , Frutas , Humanos , Doenças Inflamatórias Intestinais/tratamento farmacológico , Doenças Inflamatórias Intestinais/genética , Camundongos , NF-kappa B/genética , Polissacarídeos
8.
Ecotoxicol Environ Saf ; 223: 112566, 2021 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-34340153

RESUMO

Artemisia ordosica is one of the main shrubby perennials belonging to Artemisia species of Asteraceae and could be used in folk Chinese/Mongolian medicine to treat symptoms of various inflammatory ailments. The present study was conducted to investigate the protective effects of dietary Artemisia ordosica polysaccharide (AOP) against lipopolysaccharide (LPS) induced oxidative stress in broilers via Nrf2/Keap1 and TLR4/NF-κB pathway. A total of 192 1-day-old Arbor Acres male broilers were randomly allotted to four treatments with 6 replicates (n = 8): (1) CON group, non-challenged broilers fed basal diet; (2) LPS group, LPS-challenged broilers fed basal diet; (3) AOP group, non-challenged broilers fed basal diet supplemented with 750 mg/kg AOP; (4) LPS+AOP group, LPS-challenged broilers fed basal diet supplemented with 750 mg/kg AOP. The trial included starter phase (d 1-14), stress period Ⅰ (d 15-21), convalescence Ⅰ (d 22-28), stress period Ⅱ (d 29-35) and convalescence Ⅱ (d 36-42). During stress period Ⅰ (on d 15, 17, 19 and 21) and stress period Ⅱ (on d 29, 31, 33 and 35), broilers were injected intra-abdominally either with LPS solution or with an equal amount of sterile saline. The results showed that dietary AOP supplementation alleviated LPS-induced reduction in antioxidant enzyme activity and excessive production of ROS, 8-OHdG and PC in serum of broilers challenged with LPS. Moreover, dietary AOP supplementation alleviated the decrease of T-AOC and activities of SOD, CAT and GPx in liver of broilers challenged with LPS by increasing expression of Nrf2, and inhibiting over-expression of Keap1 both at gene and protein level. Additionally, dietary AOP supplementation decreased the over-production of IL-1ß and IL-6 in liver of broilers challenged by LPS through decreasing mRNA expression of TLR4, MyD88, NF-κB P65, IL-1ß and IL-6, and alleviating the increase of protein expression of TLR4, IKKß, NF-κB P65, IL-1ß, IL-6, and the decrease of protein expression of IkBα. In conclusion, dietary AOP supplementation could alleviate LPS-induced oxidative stress through Nrf2/Keap1 and TLR4/NF-κB pathway.


Assuntos
Artemisia , Lipopolissacarídeos , Ração Animal/análise , Animais , Artemisia/metabolismo , Galinhas/metabolismo , Dieta , Suplementos Nutricionais , Proteína 1 Associada a ECH Semelhante a Kelch/genética , Lipopolissacarídeos/toxicidade , Masculino , Fator 2 Relacionado a NF-E2/genética , NF-kappa B/genética , NF-kappa B/metabolismo , Estresse Oxidativo , Polissacarídeos , Receptor 4 Toll-Like/genética
9.
Int J Mol Sci ; 22(16)2021 Aug 10.
Artigo em Inglês | MEDLINE | ID: mdl-34445305

RESUMO

Pulmonary arterial hypertension (PAH) is characterized by pulmonary vascular remodeling. Recent evidence supports that inflammation plays a key role in triggering and maintaining pulmonary vascular remodeling. Recent studies have shown that garlic extract has protective effects in PAH, but the precise role of allicin, a compound derived from garlic, is unknown. Thus, we used allicin to evaluate its effects on inflammation and fibrosis in PAH. Male Wistar rats were divided into three groups: control (CON), monocrotaline (60 mg/kg) (MCT), and MCT plus allicin (16 mg/kg/oral gavage) (MCT + A). Right ventricle (RV) hypertrophy and pulmonary arterial medial wall thickness were determined. IL-1ß, IL-6, TNF-α, NFκB p65, Iκß, TGF-ß, and α-SMA were determined by Western blot analysis. In addition, TNF-α and TGF-ß were determined by immunohistochemistry, and miR-21-5p and mRNA expressions of Cd68, Bmpr2, and Smad5 were determined by RT-qPCR. Results: Allicin prevented increases in vessel wall thickness due to TNF-α, IL-6, IL-1ß, and Cd68 in the lung. In addition, TGF-ß, α-SMA, and fibrosis were lower in the MCT + A group compared with the MCT group. In the RV, allicin prevented increases in TNF-α, IL-6, and TGF-ß. These observations suggest that, through the modulation of proinflammatory and profibrotic markers in the lung and heart, allicin delays the progression of PAH.


Assuntos
Anti-Inflamatórios/uso terapêutico , Dissulfetos/uso terapêutico , Hipertensão Pulmonar/tratamento farmacológico , Ácidos Sulfínicos/uso terapêutico , Animais , Antígenos CD/genética , Antígenos CD/metabolismo , Antígenos de Diferenciação Mielomonocítica/genética , Antígenos de Diferenciação Mielomonocítica/metabolismo , Receptores de Proteínas Morfogenéticas Ósseas Tipo II/genética , Receptores de Proteínas Morfogenéticas Ósseas Tipo II/metabolismo , Citocinas/genética , Citocinas/metabolismo , Fibrose , Ventrículos do Coração/efeitos dos fármacos , Ventrículos do Coração/metabolismo , Ventrículos do Coração/patologia , Masculino , NF-kappa B/genética , NF-kappa B/metabolismo , Artéria Pulmonar/efeitos dos fármacos , Artéria Pulmonar/metabolismo , Artéria Pulmonar/patologia , Ratos , Ratos Wistar , Proteína Smad5/genética , Proteína Smad5/metabolismo
10.
In Vivo ; 35(5): 2569-2576, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34410944

RESUMO

BACKGROUND/AIM: The combination of regorafenib with cisplatin/pemetrexed has indicated controllable safety and encouraging antitumor activity in non-small cell lung cancer (NSCLC) patients. However, the anti-NSCLC effects and action mechanisms of regorafenib combined with cisplatin is ambiguous. The major goal of the study was to study the inhibitory effects and action mechanisms of regorafenib combined with cisplatin in NSCLC cells. MATERIALS AND METHODS: Cell viability, flow cytometry, immunofluorescence staining, western blotting, migration, and invasion assays were employed to verify the anti-NSCLC effects and mechanisms of regorafenib in combination with cisplatin. RESULTS: Cisplatin-induced epidermal growth factor receptor (EGFR)/nuclear factor κB (NF-κB) signaling was effectively inhibited by regorafenib treatment. Regorafenib, erlotinib (EGFR inhibitor) and QNZ (NF-κB inhibitor) may all enhance the cytotoxicity effect of cisplatin. The invasion ability was effectively decreased by combination treatment. Caspase-dependent and -independent apoptosis was activated by cisplatin combined with regorafenib. CONCLUSION: Apoptosis induction and EGFR/NF-κB inactivation correlate with regorafenib-enhanced anti-NSCLC efficacy of cisplatin. This study provides evidence of the therapeutic efficacy of regorafenib in combination with cisplatin on NSCLC.


Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Apoptose , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Linhagem Celular Tumoral , Proliferação de Células , Cisplatino , Receptores ErbB/genética , Humanos , Neoplasias Pulmonares/tratamento farmacológico , NF-kappa B/genética , Compostos de Fenilureia , Piridinas
11.
Int J Mol Sci ; 22(16)2021 Aug 17.
Artigo em Inglês | MEDLINE | ID: mdl-34445559

RESUMO

Scutellarein (SCU) is a well-known flavone with a broad range of biological activities against several cancers. Human hepatocellular carcinoma (HCC) is major cancer type due to its poor prognosis even after treatment with chemotherapeutic drugs, which causes a variety of side effects in patients. Therefore, efforts have been made to develop effective biomarkers in the treatment of HCC in order to improve therapeutic outcomes using natural based agents. The current study used SCU as a treatment approach against HCC using the HepG2 cell line. Based on the cell viability assessment up to a 200 µM concentration of SCU, three low-toxic concentrations of (25, 50, and 100) µM were adopted for further investigation. SCU induced cell cycle arrest at the G2/M phase and inhibited cell migration and proliferation in HepG2 cells in a dose-dependent manner. Furthermore, increased PTEN expression by SCU led to the subsequent downregulation of PI3K/Akt/NF-κB signaling pathway related proteins. In addition, SCU regulated the metastasis with EMT and migration-related proteins in HepG2 cells. In summary, SCU inhibits cell proliferation and metastasis in HepG2 cells through PI3K/Akt/NF-κB signaling by upregulation of PTEN, suggesting that SCU might be used as a potential agent for HCC therapy.


Assuntos
Apigenina/farmacologia , Carcinoma Hepatocelular/tratamento farmacológico , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , NF-kappa B/metabolismo , PTEN Fosfo-Hidrolase/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Apoptose , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patologia , Movimento Celular , Proliferação de Células , Humanos , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , NF-kappa B/genética , PTEN Fosfo-Hidrolase/genética , Fosfatidilinositol 3-Quinases/genética , Proteínas Proto-Oncogênicas c-akt/genética , Células Tumorais Cultivadas
12.
Oxid Med Cell Longev ; 2021: 5520644, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34457115

RESUMO

Age-related macular degeneration (AMD) is a common and severe blinding disease among people worldwide. Retinal inflammation and neovascularization are two fundamental pathological processes in AMD. Recent studies showed that P2X7 receptor was closely involved in the inflammatory response. Here, we aim to investigate whether A740003, a P2X7 receptor antagonist, could prevent retinal inflammation and neovascularization induced by oxidized low-density lipoprotein (ox-LDL) and explore the underlying mechanisms. ARPE-19 cells and C57BL/6 mice were treated with ox-LDL and A740003 successively for in vitro and in vivo studies. In this research, we found that A740003 suppressed reactive oxygen species (ROS) generation and inhibited the activation of Nod-like receptor pyrin-domain protein 3 (NLRP3) inflammasome and nuclear factor-κB (NF-κB) pathway. A740003 also inhibited the generation of angiogenic factors in ARPE-19 cells and angiogenesis in mice. The inflammatory cytokines and phosphorylation of inhibitor of nuclear factor-κB alpha (IKBα) were repressed by A740003. Besides, ERG assessment showed that retinal functions were remarkably preserved in A740003-treated mice. In summary, our results revealed that the P2X7 receptor antagonist reduced retinal inflammation and neovascularization and protected retinal function. The protective effects were associated with regulation of NLRP3 inflammasome and the NF-κB pathway, as well as inhibition of angiogenic factors.


Assuntos
Inflamação/tratamento farmacológico , Lipoproteínas LDL/toxicidade , Neovascularização Patológica/tratamento farmacológico , Estresse Oxidativo , Antagonistas do Receptor Purinérgico P2X/farmacologia , Receptores Purinérgicos P2X7/química , Retinite/tratamento farmacológico , Animais , Citocinas/metabolismo , Inflamação/induzido quimicamente , Inflamação/metabolismo , Inflamação/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , NF-kappa B/genética , NF-kappa B/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Neovascularização Patológica/induzido quimicamente , Neovascularização Patológica/metabolismo , Neovascularização Patológica/patologia , Espécies Reativas de Oxigênio/metabolismo , Receptores Purinérgicos P2X7/metabolismo , Retinite/induzido quimicamente , Retinite/metabolismo , Retinite/patologia , Transdução de Sinais
13.
Oxid Med Cell Longev ; 2021: 9932099, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34457120

RESUMO

Oxidative stress, inflammation, and apoptosis are crucial in the pathogenesis of acute liver failure (ALF). 4-Octyl itaconate (OI) showed antioxidative and anti-inflammatory properties in many disease models. However, its role in lipopolysaccharide- (LPS-)/D-galactosamine- (D-GalN-) induced ALF is still not investigated. Here, we established an ALF murine model induced by LPS/D-GalN administration. And we found that OI improved survival rate in the murine ALF model. Our results also showed that OI alleviated LPS/D-GalN-induced hepatic histopathological injury and reduced the serum activities of alanine transaminase and aspartate transaminase. Moreover, OI reduced serum levels of proinflammatory cytokines such as monocyte chemotactic protein-1, tumor necrosis factors-α, and interlukin-6. Additionally, OI mitigated oxidative stress and alleviated lipid peroxidation in a murine model of ALF. This was evaluated by a reduction of thiobarbituric acid reactive substances (TBARS) in liver tissues. In addition, OI increased the ratio of reduced glutathione/oxidized glutathione and the activities of antioxidant enzymes including catalase and superoxide dismutase. Moreover, the apoptosis of hepatocytes in the liver was inhibited by OI. Furthermore, we found that OI inhibited LPS-induced nuclear translocation and activation of factor-kappa B (NF-κB) p65 in macrophages which could be inhibited by OI-induced activation of nuclear factor erythroid-2-related factor (Nrf2) signaling. Additionally, D-GalN-induced reactive oxygen species (ROS) generation and apoptosis in hepatocytes were inhibited by OI-induced activation of Nrf2 signaling. Therefore, the underlying mechanism for OI's protective effect in LPS/D-GalN-induced ALF may be associated with deactivation of NF-κB signaling in macrophages to reduce inflammation and inhibition of ROS-related hepatocyte apoptosis by activating Nrf2. In conclusion, OI showed a protective role in LPS/D-GalN-induced ALF by reducing inflammation, enhancing antioxidant capacity, and inhibiting cell apoptosis.


Assuntos
Apoptose , Galactosamina/toxicidade , Inflamação/prevenção & controle , Lipopolissacarídeos/toxicidade , Falência Hepática Aguda/tratamento farmacológico , Estresse Oxidativo , Succinatos/farmacologia , Animais , Anti-Inflamatórios/farmacologia , Antioxidantes/farmacologia , Inflamação/induzido quimicamente , Inflamação/metabolismo , Inflamação/patologia , Falência Hepática Aguda/induzido quimicamente , Falência Hepática Aguda/metabolismo , Falência Hepática Aguda/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Fator 2 Relacionado a NF-E2/genética , Fator 2 Relacionado a NF-E2/metabolismo , NF-kappa B/genética , NF-kappa B/metabolismo , Substâncias Protetoras/farmacologia , Transdução de Sinais
14.
Vet Microbiol ; 261: 109189, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34375914

RESUMO

Transmissible gastroenteritis (TGE) is an acute viral disease and characterized as severe acute inflammation response that leads to diarrhea, vomiting, and high lethality of piglets. Transmissible gastroenteritis virus (TGEV), a member of coronavirus, is the pathogen of TGE. We previously found NF-κB pathway was activated and 65 miRNAs were changed in response to inflammation caused by TGEV in cell line porcine intestinal epithelial cells-jejunum 2 (IPEC-J2). Bioinformatics results showed that these altered miRNAs were relevant to inflammation. In this study, the candidate targets of differentially expressed (DE) miRNAs were predicted and analyzed using Kyoto Encyclopedia of Genes and Genomes (KEGG) database. Based on the results of KEGG analysis, miR-885-3p might participate in regulating activation of NF-κB pathway and TNF pathway. To study the function of miR-885-3p, miR-885-3p mimics and inhibitors were artificially synthesized and respectively used for overexpression and silence of miR-885-3p in cells. Our results showed that miR-885-3p inhibited NF-κB signaling pathway and tumor necrosis factor-α (TNF-α) production. B-cell CLL/lymphoma 10 (Bcl-10) was identified as the target of miR-885-3p, and promoted NF-κB pathway activation and TNF-α production. It was found that TGEV open reading frame 3b (TGEV-ORF3b) suppressed Bcl-10 expression, activation of NF-κB pathway, and TNF-α production by uniquely up-regulated miR-885-3p expression. Overall, the results indicated that TGEV-ORF3b counteracted NF-κB pathway and TNF-α via regulating miR-885-3p and Bcl-10.


Assuntos
Proteína 10 de Linfoma CCL de Células B/metabolismo , Gastroenterite Suína Transmissível/virologia , MicroRNAs/metabolismo , NF-kappa B/metabolismo , Vírus da Gastroenterite Transmissível/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Animais , Proteína 10 de Linfoma CCL de Células B/genética , Linhagem Celular , Células Epiteliais/metabolismo , Células Epiteliais/virologia , Regulação da Expressão Gênica , Mucosa Intestinal/citologia , MicroRNAs/genética , NF-kappa B/antagonistas & inibidores , NF-kappa B/genética , Suínos , Regulação para Cima , Proteínas Virais
15.
J Agric Food Chem ; 69(32): 9313-9325, 2021 Aug 18.
Artigo em Inglês | MEDLINE | ID: mdl-34370469

RESUMO

PSPP-1 was obtained from purple sweet potato, and the effects of PSPP-1 on the immune modulation on macrophage cells were investigated for the first time. PSPP-1 promoted RAW264.7 proliferation and increased the total cell percentage in DNA synthesis and mitosis phases, and the cell morphology changed in volume and appearance. Additionally, the RAW264.7 immune functions of phagocytic activity and nitric oxide, reactive oxygen species, and cytokine production were improved by PSPP-1. The western blot experiment showed that PSPP-1 could activate toll-like receptor 2 and toll-like receptor 4-mediated pathways, and the expressions of proteins in MyD88-dependent, mitogen-activated protein kinase (MAPK)-signaling, NF-κB-signaling, AP-1 signaling, and TRIF-dependent pathways were improved markedly. Molecular docking and Biolayer Interferometry study further indicated that PSPP-1 could recognize and bind TLR2 and TLR4 by targeting the binding sites with a strong affinity. It suggested that PSPP-1 could enhance immunity via TLR2- and TLR4-mediated pathways, and it could be explored as an immunomodulatory agent.


Assuntos
Ipomoea batatas , Receptor 2 Toll-Like , Animais , Glucanos , Macrófagos , Camundongos , Simulação de Acoplamento Molecular , NF-kappa B/genética , Células RAW 264.7 , Receptor 2 Toll-Like/genética , Receptor 4 Toll-Like/genética
16.
J Agric Food Chem ; 69(31): 8747-8757, 2021 Aug 11.
Artigo em Inglês | MEDLINE | ID: mdl-34337939

RESUMO

High-purity Fab fragment and immunoglobulin Y (IgY) were prepared to evaluate their anti-inflammatory activity in the lipopolysaccharide (LPS)-induced Raw 264.7 macrophage system. Compared with IgY, the Fab fragment possessed a greater potency in inhibiting the inflammation by nitric oxide (NO)/inducible nitric oxide synthase (iNOS) and prostaglandin-E2 (PGE2)/cyclooxygenase-2 (COX-2) pathways. The Fab fragment attenuated the levels of tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and interleukin-10 (IL-10) to 38.07 ± 1.86-48.39 ± 11.33 pg/mL (63.1-71.0% inhibition), 31.59 ± 3.91-38.08 ± 4.44 pg/mL (72.4-77.1% inhibition), and 20.62 ± 0.46-21.91 ± 0.65 pg/mL (50-53% inhibition), respectively. Additionally, the Fab fragment significantly inhibited the translocation of nuclear transcription factor-κB (NF-κB) p65 and the phosphorylation of mitogen-activated protein kinase (MAPK) proteins, including ERK1/2 (41.5/33.2%), JNK1/2 (44.2/39.6%), and p38 (42.2%). The Fab fragment could be internalized into cells, and the pretreatment of RAW 264.7 macrophages with the Fab fragment reduced the mRNA expression of the Toll-like receptor (TLR4, 32.7-44.4% inhibition) and αVß3 integrin (76.1% inhibition). In conclusion, Fab fragments regulated the TLR4 and αVß3 integrin-mediated inflammatory processes by blocking the NF-κB and MAPKs pathways in the LPS-induced RAW 264.7 macrophage system.


Assuntos
Fragmentos Fab das Imunoglobulinas/imunologia , NF-kappa B , Receptor 4 Toll-Like , Animais , Ciclo-Oxigenase 2/metabolismo , Imunoglobulinas , Integrina alfa5 , Integrinas , Lipopolissacarídeos , Macrófagos/metabolismo , Camundongos , Proteínas Quinases Ativadas por Mitógeno/genética , NF-kappa B/genética , NF-kappa B/metabolismo , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase Tipo II/metabolismo , Células RAW 264.7 , Receptor 4 Toll-Like/genética , Receptor 4 Toll-Like/metabolismo
17.
Int J Mol Sci ; 22(14)2021 Jul 11.
Artigo em Inglês | MEDLINE | ID: mdl-34299049

RESUMO

Over the last several decades, colorectal cancer (CRC) has been one of the most prevalent cancers. While significant progress has been made in both diagnostic screening and therapeutic approaches, a large knowledge gap still remains regarding the early identification and treatment of CRC. Specifically, identification of CRC biomarkers that can help with the creation of targeted therapies as well as increasing the ability for clinicians to predict the biological response of a patient to therapeutics, is of particular importance. This review provides an overview of CRC and its progression stages, as well as the basic types of CRC biomarkers. We then lay out the synopsis of signaling pathways related to CRC, and further highlight the pivotal and multifaceted role of nuclear factor (NF) κB signaling in CRC. Particularly, we bring forth knowledge regarding the tumor microenvironment (TME) in CRC, and its complex interaction with cancer cells. We also provide examples of NF-κB signaling-related CRC biomarkers, and ongoing efforts made at targeting NF-κB signaling in CRC treatment. We conclude and anticipate that with more emerging novel regulators of the NF-κB pathway being discovered, together with their in-depth characterization and the integration of large groups of genomic, transcriptomic and proteomic data, the day of successful development of more ideal NF-κB inhibitors is fast approaching.


Assuntos
Biomarcadores Tumorais/metabolismo , Neoplasias Colorretais/diagnóstico , Regulação Neoplásica da Expressão Gênica , NF-kappa B/metabolismo , Animais , Biomarcadores Tumorais/genética , Neoplasias Colorretais/genética , Neoplasias Colorretais/metabolismo , Humanos , NF-kappa B/genética , Transdução de Sinais
18.
Mol Med Rep ; 23(5)2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-34240224

RESUMO

Atopic dermatitis (AD) is a chronic inflammatory skin disease that seriously affects quality of life. Quinine is a bitter taste receptor agonist that exhibits antimalarial effects. The aim of the present study was to examine the therapeutic effects of quinine in AD­like mice. AD was induced with 2,4­dinitrochlorobenzene, and the mice were treated with 10 mg/kg quinine for 1, 4 and 7 days. A total of 60 BALB/c mice were divided into the following groups: Healthy, AD­like, AD­like + quinine and healthy + quinine, with 1, 4 and 7 days groups for each treatment. Blood was extracted from all mice and ELISA was performed to detect immunoglobulin E (IgE) levels. H&E­stained tissue sections were prepared from skin lesions on the backs of the mice and pathological changes were observed. Cytokines were detected via ELISA, and the filaggrin (FLG) and kallikrein­7 (KLK7) proteins were detected via western blotting and immunohistochemistry. IKKα and NF­κB mRNA were analyzed via reverse transcription­quantitative PCR. Quinine ameliorated skin damage in the AD­like mice, reduced IgE expression in the blood, inhibited expression of IKKα and NF­κB, reduced cytokine secretion, reduced KLK7 expression, reduced scratching frequency, increased FLG expression and repaired the skin barrier. These results suggested that quinine exhibited therapeutic effects in AD­like mice.


Assuntos
Dermatite Atópica/tratamento farmacológico , Quinina/farmacologia , Quinina/uso terapêutico , Animais , Citocinas/metabolismo , Dermatite Atópica/induzido quimicamente , Dermatite Atópica/metabolismo , Dermatite Atópica/patologia , Dinitroclorobenzeno/toxicidade , Modelos Animais de Doenças , Quinase I-kappa B/genética , Quinase I-kappa B/metabolismo , Imunoglobulina E/sangue , Calicreínas/genética , Calicreínas/metabolismo , Masculino , Camundongos Endogâmicos BALB C , Inibidor de NF-kappaB alfa/genética , Inibidor de NF-kappaB alfa/metabolismo , NF-kappa B/genética , NF-kappa B/metabolismo , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/genética , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/metabolismo , Transdução de Sinais/efeitos dos fármacos , Pele/efeitos dos fármacos , Pele/patologia
19.
FASEB J ; 35(8): e21821, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34325487

RESUMO

Skeletal muscle atrophy is a debilitating complication of many chronic disease states and disuse conditions including denervation. However, molecular and signaling mechanisms of muscle wasting remain less understood. Here, we demonstrate that the levels of several toll-like receptors (TLRs) and their downstream signaling adaptor, myeloid differentiation primary response 88 (MyD88), are induced in skeletal muscle of mice in response to sciatic nerve denervation. Muscle-specific ablation of MyD88 mitigates denervation-induced skeletal muscle atrophy in mice. Targeted ablation of MyD88 suppresses the components of ubiquitin-proteasome system, autophagy, and FOXO transcription factors in skeletal muscle during denervation. We also found that specific inhibition of MyD88 reduces the activation of canonical nuclear factor-kappa (NF-κB) pathway and expression of receptors for inflammatory cytokines in denervated muscle. In contrast, inhibition of MyD88 stimulates the activation of non-canonical NF-κB signaling in denervated skeletal muscle. Ablation of MyD88 also inhibits the denervation-induced increase in phosphorylation of AMPK without having any effect on the phosphorylation of mTOR. Moreover, targeted ablation of MyD88 inhibits the activation of a few components of the unfolded protein response (UPR) pathways, especially X-box protein 1 (XBP1). Importantly, myofiber-specific ablation of XBP1 mitigates denervation-induced skeletal muscle atrophy in mice. Collectively, our experiments suggest that TLR-MyD88 signaling mediates skeletal muscle wasting during denervation potentially through the activation of canonical NF-κB signaling, AMPK and UPR pathways.


Assuntos
Músculo Esquelético/inervação , Atrofia Muscular/metabolismo , Fator 88 de Diferenciação Mieloide/metabolismo , NF-kappa B/metabolismo , Transdução de Sinais/fisiologia , Animais , Biomarcadores/sangue , Estresse do Retículo Endoplasmático/fisiologia , Regulação da Expressão Gênica/fisiologia , Camundongos , Camundongos Knockout , Fator 88 de Diferenciação Mieloide/genética , NF-kappa B/genética , Receptores Toll-Like/genética , Receptores Toll-Like/metabolismo , Resposta a Proteínas não Dobradas
20.
Int J Mol Sci ; 22(14)2021 Jul 16.
Artigo em Inglês | MEDLINE | ID: mdl-34299224

RESUMO

Inflammation is important for the initiation and progression of breast cancer. We have previously reported that in monocytes, estrogen regulates TLR4/NFκB-mediated inflammation via the interaction of the Erα isoform ERα36 with GPER1. We therefore investigated whether a similar mechanism is present in breast cancer epithelial cells, and the effect of ERα36 expression on the classic 66 kD ERα isoform (ERα66) functions. We report that estrogen inhibits LPS-induced NFκB activity and the expression of downstream molecules TNFα and IL-6. In the absence of ERα66, ERα36 and GPER1 are both indispensable for this effect. In the presence of ERα66, ERα36 or GPER1 knock-down partially inhibits NFκB-mediated inflammation. In both cases, ERα36 overexpression enhances the inhibitory effect of estrogen on inflammation. We also verify that ERα36 and GPER1 physically interact, especially after LPS treatment, and that GPER1 interacts directly with NFκB. When both ERα66 and ERα36 are expressed, the latter acts as an inhibitor of ERα66 via its binding to estrogen response elements. We also report that the activation of ERα36 leads to the inhibition of breast cancer cell proliferation. Our data support that ERα36 is an inhibitory estrogen receptor that, in collaboration with GPER1, inhibits NFκB-mediated inflammation and ERα66 actions in breast cancer cells.


Assuntos
Receptor alfa de Estrogênio/metabolismo , Receptores de Estrogênio/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Neoplasias da Mama , Linhagem Celular Tumoral , Células Epiteliais/metabolismo , Estradiol/farmacologia , Receptor alfa de Estrogênio/genética , Receptor alfa de Estrogênio/fisiologia , Estrogênios/metabolismo , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Inflamação/metabolismo , Interleucina-6/metabolismo , Células MCF-7 , Monócitos/metabolismo , NF-kappa B/genética , NF-kappa B/metabolismo , Receptores de Estrogênio/fisiologia , Receptores Acoplados a Proteínas G/fisiologia , Receptor 4 Toll-Like/genética , Receptor 4 Toll-Like/metabolismo , Fator de Necrose Tumoral alfa/metabolismo
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...