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1.
Food Chem ; 308: 125666, 2020 Mar 05.
Artigo em Inglês | MEDLINE | ID: mdl-31655481

RESUMO

Nine new compounds, argutinosides A-I (1-9) together with 20 known compounds (10-29), were isolated from the fruits of Actinidia arguta. Using spectral analysis, the structures of the isolated compounds were identified as 10 succinic acid derivatives, 11 quinic acid derivatives, two shikimic acid derivatives and six citric acid derivatives. The NF-κB transcriptional inhibitory activity of the compounds was evaluated using RAW 264.7 macrophages cells induced by lipopolysaccharide. Among four groups of different organic acid derivatives, the quinic acid derivatives inhibited NF-κB transcriptional activity with an IC50 value of 4.0 µM. Fruit is rich in organic acid and secondary metabolites, which differ depending on the type of fruit. Our present study showed the presence of various organic acids conjugates including nine new 2-methylsuccinic acid phenolic conjugates in kiwiberry and compared their biological activities. This will contribute to application of kiwiberry and also the diversity of different fruits.


Assuntos
Actinidia/química , NF-kappa B/antagonistas & inibidores , Fenóis/farmacologia , Ácido Quínico/química , Animais , Linhagem Celular , Frutas/química , Lipopolissacarídeos/farmacologia , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Camundongos , Fenóis/química
2.
Biosci Biotechnol Biochem ; 84(1): 134-142, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31490096

RESUMO

Plumbagin (PLB), an alkaloid obtained from the roots of the plants of Plumbago genus, is an inhibitor of NADPH oxidase 4 (NOX4). This study aimed to investigate the beneficial effect of PLB against oxygen-glucose deprivation/reoxygenation (OGDR)-induced neuroinjury in human SH-SY5Y neuronal cultures. Our results showed that OGD/R stimulated NOX4 protein expression and reactive oxygen species (ROS) production in SH-SY5Y cells, whereas increased 4-hydroxynonenal (4-HNE) and malondialdehyde (MDA) production, resulting in the activation of the NLRP3 inflammasome. And PLB pretreatment reduced the ROS production by regulating the expression of NOX4 and downregulated NF-κB signaling which was induced by OGDR. Furthermore, PLB inhibited OGDR induced NLRP3 inflammasome activation but not PARP1. Overall, PLB improved OGDR induced neuroinjury by inhibiting NOX4-derived ROS-activated NLRP3 inflammasome.


Assuntos
Hipóxia Celular/efeitos dos fármacos , Glucose/deficiência , Inflamassomos/metabolismo , NADPH Oxidase 4/antagonistas & inibidores , Proteína 3 que Contém Domínio de Pirina da Família NLR/antagonistas & inibidores , Naftoquinonas/farmacologia , Neurônios/metabolismo , Extratos Vegetais/farmacologia , Espécies Reativas de Oxigênio/metabolismo , Apoptose/efeitos dos fármacos , Isquemia Encefálica/metabolismo , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Humanos , Potencial da Membrana Mitocondrial/efeitos dos fármacos , NF-kappa B/antagonistas & inibidores , Estresse Oxidativo/efeitos dos fármacos , Raízes de Plantas/química , Plumbaginaceae/química
3.
J Enzyme Inhib Med Chem ; 35(1): 187-198, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31752552

RESUMO

Twenty novel talmapimod analogues were designed, synthesised and evaluated for the in vivo anti-inflammatory activities. Among them, compound 6n, the most potent one, was selected for exploring the mechanisms underlying its anti-inflammatory efficacy. In RAW264.7 cells, it effectively suppressed lipopolysaccharides-induced (LPS-induced) expressions of iNOS and COX-2. As illustrated by the western blot analysis, 6n downregulated both the NF-κB signalling and p38 MAPK phosphorylation. Further enzymatic assay identified 6n as a potent inhibitor against both p38α MAPK (IC50=1.95 µM) and COX-2 (IC50=0.036 µM). By virtue of the concomitant inhibition of p38α MAPK, its upstream effector, and COX-2, along with its capability to downregulate NF-κB and MAPK-signalling pathways, 6n, a polypharmacological anti-inflammatory agent, deserves further development as a novel anti-inflammatory drug.


Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Ciclo-Oxigenase 2/metabolismo , Descoberta de Drogas , NF-kappa B/antagonistas & inibidores , Óxido Nítrico Sintase Tipo II/antagonistas & inibidores , Proteínas Quinases p38 Ativadas por Mitógeno/antagonistas & inibidores , Animais , Anti-Inflamatórios não Esteroides/síntese química , Anti-Inflamatórios não Esteroides/química , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Lipopolissacarídeos/antagonistas & inibidores , Lipopolissacarídeos/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos ICR , Estrutura Molecular , NF-kappa B/metabolismo , Óxido Nítrico Sintase Tipo II/metabolismo , Células RAW 264.7 , Transdução de Sinais/efeitos dos fármacos , Relação Estrutura-Atividade , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
4.
Anticancer Res ; 39(11): 6135-6144, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31704841

RESUMO

AIM: To investigate the effect of carnosine, an active compound of dietary beef, fish and chicken, on the regulation of cell adhesion and extravasation during metastasis. MATERIALS AND METHODS: Cell adhesion and extravasation abilities, and related regulating molecular mechanisms were analyzed in human colorectal cancer cells (HCT-116) and human umbilical vein cells (EA.hy926). RESULTS: Carnosine reduced the ability of HCT-116 cells to adhere to EA.hy926 cells. The expression levels of integrin-ß1 in HCT-116 cells, as well as of intercellular adhesion molecule-1 and E-selectin in EA.hy926 cells, were reduced after carnosine treatment. After EA.hy926 cells were treated with carnosine, phosphorylation of vascular endothelia-cadherin (VE-cadherin), protein levels of Ras homologous (RHO) and RHO-associated coiled-coil containing protein kinase, and levels of reactive oxygen species were reduced. After treating EA.hy926 cells with carnosine, phosphorylation of inhibitor of kappa B (IκB) and DNA binding activity of nuclear factor-κB (NF-κB) were reduced. CONCLUSION: Carnosine inhibits metastatic cell adhesion and extravasation by suppressing NF-κB signaling activation.


Assuntos
Carnosina/farmacologia , Adesão Celular/efeitos dos fármacos , Neoplasias Colorretais/patologia , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , NF-kappa B/antagonistas & inibidores , Apoptose/efeitos dos fármacos , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Proliferação de Células/efeitos dos fármacos , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/metabolismo , Humanos , NF-kappa B/genética , NF-kappa B/metabolismo , Células Tumorais Cultivadas
5.
Cancer Sci ; 110(12): 3802-3810, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31583781

RESUMO

The ubiquitin proteasome pathway is essential for the proliferation and survival of multiple myeloma (MM) cells. TAS4464, a novel highly potent inhibitor of NEDD8 activating enzyme, selectively inactivates cullin-RING ubiquitin E3 ligases, resulting in accumulation of their substrates. Here, we examined 14 MM cell lines treated with TAS4464. TAS4464 induced growth arrest and cell death in the MM cell lines even in the presence of bone marrow stromal cells. It also induced the accumulation of phospho-inhibitor of κBα and phospho-p100, impaired the activities of nuclear factor κB (NF-κB) transcription factors p65 and RelB, and decreased the expression of NF-κB target genes, suggesting that TAS4464 inhibits both the canonical and non-canonical NF-κB pathways. TAS4464 had similar effects in an in vivo human-MM xenograft mouse model in which it was also observed to have strong antitumor effects. TAS4464 synergistically enhanced the antitumor activities of the standard MM chemotherapies bortezomib, lenalidomide/dexamethasone, daratumumab and elotuzumab. Together, these results suggest that the anti-MM activity of TAS4464 occurs via inhibition of the NF-κB pathways, and that treatment with TAS4464 is a potential approach for treating MM by single and combination therapies.


Assuntos
Mieloma Múltiplo/tratamento farmacológico , Proteína NEDD8/antagonistas & inibidores , NF-kappa B/antagonistas & inibidores , Pirimidinas/farmacologia , Pirróis/farmacologia , Animais , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Humanos , Masculino , Camundongos , Mieloma Múltiplo/patologia , Transdução de Sinais/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
6.
J Biochem Mol Toxicol ; 33(12): e22405, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31593333

RESUMO

Ankylosing spondylitis (AS) is a high disability and greatly destructive disease. In this study, we preliminarily studied the function and mechanism of bilobalide (BIL) on interleukin (IL)-17-induced inflammatory injury in ATDC5 cells. CCK-8 and migration assays were used to detect the functions of IL-7, BIL, and microRNA (miR)-125a on cell viability and migration. The miR-125a level was changed by transfection, and tested by real-time quantitative polymerase chain reaction. Additionally, Western blot tested the levels of inflammatory factors (IL-6 and tumor necrosis factor-α), matrix metalloproteinases (MMPs), and pathway-related proteins. Moreover, the enzyme-linked immunosorbent assay also was used to detect inflammatory factor levels. IL-7 was used to construct an inflammatory injury model in ATDC5 cells. Based on this, BIL inhibited IL-17-induced cell viability, migration, and expressions of inflammatory factors and MMPs. Furthermore, we found BIL negatively regulated miR-125a, and the miR-125a mimic could partly reverse the effects of BIL on IL-17-injury. Finally, we showed that BIL inhibited the c-Jun N-terminal kinase (JNK) and nuclear factor kappa B (NF-κB) pathways, and the miR-125a mimic had the opposite effect. BIL inhibited IL-17-induced inflammatory injury in ATDC5 cells by downregulation of miR-125a via JNK and NF-κB signaling pathways.


Assuntos
Ciclopentanos/farmacologia , Regulação para Baixo/efeitos dos fármacos , Furanos/farmacologia , Ginkgolídeos/farmacologia , Inflamação/induzido quimicamente , Interleucina-17/farmacologia , MicroRNAs/metabolismo , Extratos Vegetais/farmacologia , Animais , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Modelos Animais de Doenças , Proteínas Quinases JNK Ativadas por Mitógeno/antagonistas & inibidores , Metaloproteinases da Matriz/metabolismo , Camundongos , MicroRNAs/química , MicroRNAs/genética , Mimetismo Molecular , NF-kappa B/antagonistas & inibidores , Transdução de Sinais/efeitos dos fármacos , Espondilite Anquilosante/metabolismo , Transfecção
7.
Chem Biol Interact ; 313: 108820, 2019 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-31518571

RESUMO

Natural products with potent activity and less toxicity provide major sources for development of novel anti-cancer drugs. Herein, we evaluated the effects and the underlying mechanisms of a novel piperlongumine (PL) analogue L50377 on non-small-cell lung cancer (NSCLC) cells. The results revealed that L50377 displayed greater potentials of suppressing cell growth than PL. In addition, L50377 promoted cell apoptosis and pyroptosis via stimulating reactive oxygen species (ROS) generation in NSCLC cells. More interestingly, ROS mediated NF-κB suppression might be implicated in the mechanisms of L50377-induced pyroptosis in NSCLC cells. Taken together, our results suggested that L50377 served as a novel chemical agent might have great potentials for NSCLC treatment.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Dioxolanos/farmacologia , Neoplasias Pulmonares/tratamento farmacológico , Piroptose/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Carcinoma Pulmonar de Células não Pequenas/patologia , Linhagem Celular Tumoral , Dioxolanos/química , Humanos , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , NF-kappa B/antagonistas & inibidores , NF-kappa B/metabolismo
8.
J Enzyme Inhib Med Chem ; 34(1): 1678-1689, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31530032

RESUMO

A series of novel 4-ferrocenylchroman-2-one derivatives were designed and synthesised to discover potent anti-inflammatory agents for treatment of arthritis. All the target compounds had been screened for their anti-inflammatory activity by evaluating the inhibition effect of LPS-induced NO production in RAW 264.7 macrophages. Among them, 4-ferrocenyl-3,4-dihydro-2H-benzo[g]chromen-2-one (3h) was found to be the most potent compound in inhibiting the productions of NO with low toxicity. This compound also exhibited significant inhibition of the productions of IL-6 and TNF-α in RAW 264.7 macrophages. Preliminary mechanism studies indicated that compound 3h could inhibit the activation of LPS-induced NF-κB and MAPKs signalling pathways. The in vivo anti-inflammatory effect of this compound was determined in the rat adjuvant-induced arthritis model.


Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Artrite/tratamento farmacológico , Cromonas/farmacologia , Interleucina-6/antagonistas & inibidores , Proteínas Quinases Ativadas por Mitógeno/antagonistas & inibidores , NF-kappa B/antagonistas & inibidores , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Animais , Anti-Inflamatórios não Esteroides/síntese química , Anti-Inflamatórios não Esteroides/química , Artrite/metabolismo , Sobrevivência Celular/efeitos dos fármacos , Cromonas/síntese química , Cromonas/química , Relação Dose-Resposta a Droga , Adjuvante de Freund , Interleucina-6/biossíntese , Lipopolissacarídeos/antagonistas & inibidores , Lipopolissacarídeos/farmacologia , Masculino , Camundongos , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Estrutura Molecular , NF-kappa B/metabolismo , Células RAW 264.7 , Ratos , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacos , Relação Estrutura-Atividade , Fator de Necrose Tumoral alfa/biossíntese
9.
Int J Med Sci ; 16(8): 1180-1187, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31523181

RESUMO

Objective: The effects of pre-treatments from s-methyl cysteine (SMC) alone, syringic acid (SA) alone and SMC plus SA against kainic acid (KA) induced injury in nerve growth factor (NGF) differentiated PC12 cells were investigated. Methods: NGF-differentiated PC12 cells were treated with 1 µM SMC, 1 µM SA or 0.5 µM SMC plus 0.5 µM SA for 2 days. Subsequently, cells were further treated by 150 µM KA. Results: KA suppressed Bcl-2 mRNA expression, enhanced Bax mRNA expression and casued cell death. SMC was greater than SA, and similar as SMC+SA in increasing Bcl-2 mRNA expression. SMC+SA led to greater increase in mitochondrial membrane potential and cell survival than SMC or SA alone. SMC+SA resulted in more reduction in reactive oxygen species and tumor necrosis factor-alpha generation, more increase in glutathione content and glutathione reductase activity than SMC or SA alone. KA up-regulated protein expression of nuclear factor kappa B (NF-κB) p65 and phosphorylated p38 (p-p38). SMC or SA pre-treatments alone limited protein expression of both factors. SMC+SA resulted in more suppression in NF-κB p65 and p-p38 expression. KA decreased glutamine level, increased glutamate level and stimulated calcium release. SMC pre-treatments alone reversed these alterations. SMC alone elevated glutamine synthetase (GS) activity and mRNA expression. SMC+SA led to greater GS activity and mRNA expression than SMC pre-treatments alone. Conclusion: These findings suggested that this combination, SMC+SA, might provide greater protective potent for neuronal cells.


Assuntos
Cisteína/análogos & derivados , Ácido Gálico/análogos & derivados , Fator de Crescimento Neural/farmacologia , Fármacos Neuroprotetores/farmacologia , Animais , Cálcio/metabolismo , Diferenciação Celular/efeitos dos fármacos , Membrana Celular/efeitos dos fármacos , Membrana Celular/patologia , Sobrevivência Celular , Cisteína/farmacologia , Sinergismo Farmacológico , Ácido Gálico/farmacologia , Ácido Caínico/toxicidade , Potencial da Membrana Mitocondrial/efeitos dos fármacos , NF-kappa B/antagonistas & inibidores , NF-kappa B/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Células PC12 , Ratos , Proteínas Quinases p38 Ativadas por Mitógeno/antagonistas & inibidores , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
10.
Cell Mol Biol (Noisy-le-grand) ; 65(6): 85-90, 2019 Aug 05.
Artigo em Inglês | MEDLINE | ID: mdl-31472052

RESUMO

To investigate the effect of gentiopicrin on the expressions of inflammatory factors in human fibroblast-like synoviocytes (HFLS) and the underlying mechanism. Human fibroblast-like synoviocytes (HFLS) were cultured in vitro at 37 °C in Dulbecco's modified Eagle's medium (DMEM) supplemented with 5 % fetal bovine serum (FBS) in a humidified incubator containing 5 % CO2. Cell viability was determined using 3-(4, 5-dimethylthiazol-2-yl)-2, 5-tetrazolium bromide (MTT) assay, while real-time quantitative polymerase chain reaction (qRT-PCR) was used to determine the expressions of interleukin 1ß (IL-1ß) and interleukin 6 (IL-6) mRNAs. The expressions of p38 mitogen-activated protein kinase (p38 MAPK) and nuclear factor kappa light chain enhancer of activated B cells (NF-κB) were determined using Western blotting. Enzyme-linked immunosorbent assay (ELISA) was used to determine the levels of IL-1ß and IL-6 in cell lysate. Treatment with 5-25 µM gentiopicrin did not significantly affect the number of viable cells, when compared with control group (p > 0.05). However, at 50 and 100 µM gentiopicrin, the number of viable cells were significantly increased, relative to control group (p < 0.05). Results of qRT-PCR showed that the expression levels of IL-1ß and IL-6 mRNAs were significantly higher in TNF-α group than in control group (p < 0.05). However, treatment with gentiopicrin significantly and dose-dependently decreased their expression levels compared with TNF-α group (p < 0.05). Western blotting results showed that the expressions of p-p38MAPK and NF-κB-p65 proteins were significantly upregulated in TNF-α group, when compared with control group (p < 0.05). However, treatment with gentiopicrin significantly and dose-dependently down-regulated the expression of these proteins compared with TNF-α group (p < 0.05). The levels of IL-1ß and IL-6 in cell lysate were significantly higher in TNF-α group than in control group (p < 0.05). However, treatment with gentiopicrin, and p38MAPK/NF-κB pathway inhibitors (SB203580 and BAY11-7082) significantly reduced the levels of these inflammatory factors compared with TNF-α group (p < 0.05).  Gentiopicrin has therapeutic potential for Rheumatoid arthritis (RA  ) through a mechanism involving the inhibition of p38MAPK/NF-κB pathway.


Assuntos
Fibroblastos/metabolismo , Glucosídeos Iridoides/farmacologia , NF-kappa B/antagonistas & inibidores , Extratos Vegetais/farmacologia , Sinoviócitos/efeitos dos fármacos , Proteínas Quinases p38 Ativadas por Mitógeno/antagonistas & inibidores , Artrite Reumatoide/metabolismo , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Humanos , Imidazóis/farmacologia , Interleucina-1beta/metabolismo , Interleucina-6/metabolismo , Glucosídeos Iridoides/administração & dosagem , NF-kappa B/metabolismo , Nitrilos/farmacologia , Extratos Vegetais/administração & dosagem , Piridinas/farmacologia , RNA Mensageiro/metabolismo , Transdução de Sinais/efeitos dos fármacos , Sulfonas/farmacologia , Fator de Transcrição RelA/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
11.
Virol J ; 16(1): 97, 2019 08 05.
Artigo em Inglês | MEDLINE | ID: mdl-31382996

RESUMO

BACKGROUND: Transmissible gastroenteritis virus (TGEV), a member of the family Coronaviridae, causes lethal watery diarrhea in piglets. Previous studies have revealed that the coronaviruses develop various strategies to evade the host innate immunity through the inhibition of nuclear factor kappa B (NF-κB) signaling pathway. However, the ability of TGEV to inhibit the host innate immune response by modulating the NF-κB signaling pathway is not clear. METHODS: In this study, a dual luciferase reporter assay was used to confirm the inhibition of NF-κB by TGEV infection and to identify the major viral proteins involved in the inhibition of NF-κB signaling. Real-time quantitative PCR was used to quantify the mRNA expression of inflammatory factors. The deubiquitination of Nsp3 domains and its effect on IκBα and p65 were analyzed by western blotting. The ubiquitination level of IκBα was analyzed by immunoprecipitation. RESULTS: In ST and IPEC-J2 cells, TGEV exhibited a dose-dependent inhibition of NF-κB activity. Individual TGEV protein screening revealed the high potential of non-structural protein 3 (Nsp3) to inhibit NF-κB signaling, and leading to the downregulation of the NF-κB-induced cytokine production. We demonstrated that the inhibitory effect of Nsp3 was mainly mediated through the suppression of IκBα degradation as well as the inhibition of p65 phosphorylation and nuclear translocation. Furthermore, the amino acid residues at positions 590-1,215 in Nsp3 were demonstrated to inhibit the degradation of IκBα by inhibiting the IκBα ubiquitination. CONCLUSION: TGEV infection can inhibit the activation of the NF-κB signaling pathway, which is mainly mediated by Nsp3 through the canonical pathway. The amino acid residues at positions 590-1,215 in Nsp3 compose the critical domain that mediates NF-κB inhibition. We speculate that this inhibitory effect is likely to be related to the structure of PLP2 with deubiquitinating enzyme activity of the amino acid residues at positions 590-1,215 in Nsp3. Our study provides a better understanding of the TGEV-mediated innate immune modulation and lays the basis for studies on the pathogenesis of coronavirus.


Assuntos
Gastroenterite Suína Transmissível/imunologia , Evasão da Resposta Imune , Imunidade Inata , NF-kappa B/antagonistas & inibidores , Transdução de Sinais , Vírus da Gastroenterite Transmissível/imunologia , Proteínas não Estruturais Virais/genética , Animais , Linhagem Celular , Regulação para Baixo , Interações entre Hospedeiro e Microrganismos , NF-kappa B/genética , Suínos , Vírus da Gastroenterite Transmissível/fisiologia , Proteínas não Estruturais Virais/imunologia , Replicação Viral
12.
Oral Dis ; 25(8): 1945-1953, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31393636

RESUMO

OBJECTIVE: There are challenges in the treatment of chronic inflammatory diseases of oral mucosa. Both paeoniflorin (PF) and baicalin (BAI) exert anti-inflammatory effects, but the mechanism underlying their combined effects is still unclear. Here, we explored the anti-inflammatory function of the PF-BAI combination in the oral inflammatory response. MATERIALS AND METHODS: The CCK-8 assay was used to determine the proliferative capacity of HOKs with PF and BAI. Enzyme-linked immunosorbent (ELISA), Western blotting, reverse transcription polymerase chain reaction, and confocal immunofluorescence were performed to study the anti-inflammatory effects of PF-BAI in LPS-stimulated human oral keratinocytes (HOKs). Immunohistochemistry and ELISA were performed to detect the levels of NF-κB p65, IKKα and IL-6, TNF-α in OLP and healthy tissues. RESULTS: Compared to PF or BAI alone, the combination of PF-BAI at 5 µg/ml downregulated secretion of inflammatory cytokines more effectively (p < .05). Combined PF-BAI decreased NF-κB p65 and IκBα protein phosphorylation, leading to reduce nuclear translocation of NF-κB p65. Higher expression of TNF-α, IL-6, NF-κB p65, and IKKα were observed in OLP than in HC tissues (p < .01). CONCLUSION: The optimal combination concentration of PF and BAI at 5 µg/ml may have a positive effect on the treatment of oral inflammatory diseases, providing a novel therapeutic approach.


Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Flavonoides/farmacologia , Glucosídeos/farmacologia , Mediadores da Inflamação/metabolismo , Líquen Plano Bucal/tratamento farmacológico , Monoterpenos/farmacologia , NF-kappa B/metabolismo , Periodontite/tratamento farmacológico , Citocinas , Humanos , Inflamação/induzido quimicamente , Inflamação/metabolismo , Lipopolissacarídeos , NF-kappa B/antagonistas & inibidores
13.
Phytother Res ; 33(10): 2775-2782, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31373419

RESUMO

Diabetic nephropathy (DN) is one of the major complications of diabetes mellitus. The progression of DN has been found to be associated with high glucose (HG)-induced oxidative stress and inflammation in diabetes mellitus. Eriodictyol is a flavonoid that possesses antioxidant and anti-inflammatory effects. However, the effect of eriodictyol on DN remains unknown. In the present study, we evaluated the role of eriodictyol in mesangial cells (MCs) in response to HG condition. The results showed that eriodictyol repressed cell proliferation of HG-stimulated MCs. Treatment with eriodictyol attenuated oxidative stress, which was evidenced by increased superoxide dismutase activity as well as decreased production of reactive oxygen species (ROS) and malondialdehyde. Besides, eriodictyol suppressed the expressions of two NADPH oxidase (NOX) isoforms, NOX2 and NOX4, which are responsible for the generation of ROS. Eriodictyol suppressed the production of extracellular matrix proteins including fibronectin and Collagen IV, as well as the secretion of inflammatory cytokines including TNF-α, IL-1ß, and IL-6 in HG-induced MCs. Moreover, the HG-induced activation of Akt/NF-κB pathway was mitigated by eriodictyol. In conclusion, eriodictyol protected MCs from HG stimulation though inhibition of Akt/NF-κB pathway.


Assuntos
Matriz Extracelular/metabolismo , Flavanonas/farmacologia , Inflamação/prevenção & controle , Células Mesangiais/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Células Cultivadas , Citocinas/metabolismo , Matriz Extracelular/efeitos dos fármacos , Fibronectinas/metabolismo , Humanos , Células Mesangiais/metabolismo , NF-kappa B/antagonistas & inibidores , NF-kappa B/fisiologia , Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-akt/fisiologia
14.
Phytother Res ; 33(10): 2737-2748, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31338905

RESUMO

Coriolus versicolor (CV) is a traditional medicine and food mushroom. Our previous study demonstrated that CV extract exhibited anti-hyperglycemia and anti-insulin resistance effects. However, the effect of CV on cardiac function in diabetic cardiomyopathy (DCM) remains unclear. Therefore, we aimed to investigate the effect of CV on cardiac function in diabetes mellitus (DM) rats. We found that the cardiac dysfunction of DM rats was markedly improved by CV extract treatment. CV extract administration significantly attenuated cardiac fibrosis in DM rats, which was accompanied by suppressed transforming growth factor beta 1 (TGF-ß1)/Smad signaling as indicated by decreased levels of TGF-ß1, p-Smad2, and p-Smad3 and increased Smad7 expression. Moreover, CV extract treatment significantly alleviated cardiac inflammation as shown by decreased levels of NLRP3 receptor, cleaved caspase-1, IL-1ß, and IL-18 in DM rats at least partly due to the inhibition of the NF-κB. In addition, high-glucose treatment induced cardiac fibrosis and increased cardiac inflammation in cardiac fibroblast cells, but these effects were ameliorated by CV extract treatment. Therefore, we conclude that the protective effect of CV on DCM is associated with the suppression of TGF-ß1/Smad signaling and attenuation of NLRP3 inflammasome activation, suggesting that CV extract may be a potential therapeutic agent for DCM.


Assuntos
Agaricales , Cardiomiopatias Diabéticas/tratamento farmacológico , Miocárdio/patologia , Proteína 3 que Contém Domínio de Pirina da Família NLR/antagonistas & inibidores , Animais , Fibrose , Masculino , NF-kappa B/antagonistas & inibidores , Proteína 3 que Contém Domínio de Pirina da Família NLR/fisiologia , Ratos , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacos
15.
BMC Cancer ; 19(1): 706, 2019 Jul 18.
Artigo em Inglês | MEDLINE | ID: mdl-31319814

RESUMO

BACKGROUND: Glioblastoma (GBM) is an extremely deadly form of brain cancer with limited treatment options and thus novel therapeutic modalities are necessary. Histone deacetylase inhibitors (HDACi) have demonstrated clinical and preclinical activities against GBM. (Silent mating type information regulation 2 homolog, Sirt1) abbreviated as Sirtuin 1, has been implicated in GBM. We explored the activity of the Sirt1 activator SRT2183 in glioma cell lines in terms of biological response. METHODS: The effects of SRT2183 on glioma cell growth and neurosphere survival were evaluated in vitro using the CCK-8, clonogenic and neurosphere assays, respectively. Glioma cell cycle arrest and apoptosis were determined by flow cytometry. SRT2183-induced autophagy was investigated by detection of GFP-microtubule-associated protein 1 light chain 3 (GFP-LC3) puncta, conversion of the nonlipidated form of LC3 (LC3-I) to the phosphatidylethanolamine-conjugated form (LC3-II). Acetylation of STAT3 and NF-κB in SRT2183-treated glioma cells was examined using immunoprecipitation. The expression levels of anti-apoptotic proteins were assayed by immunoblotting. RESULTS: SRT2183 suppressed glioma cell growth and destroyed neurospheres in vitro. Furthermore, SRT2183 induced glioma cell cycle arrest and apoptosis, accompanying by upregulation of the pro-apoptotic Bim and downregulation of Bcl-2 and Bcl-xL. Notably, ER stress was triggered in glioma cells upon exposure to SRT2183 while the pre-exposure to 4-PBA, an ER stress inhibitor, significantly antagonized SRT2183-mediated growth inhibition in glioma cells. In addition, SRT2183 induced autophagy in glioma cells and pharmacological modulation of autophagy appeared not to affect SRT2183-inhibited cell growth. Of interest, the acetylation and phosphorylation of p65 NF-κB and STAT3 in glioma cells were differentially affected by SRT2183. CONCLUSIONS: Our data suggest the ER stress pathway is involved in SRT2183-mediated growth inhibition in glioma. Further investigation in vivo is needed to consolidate the data.


Assuntos
Neoplasias Encefálicas/patologia , Proliferação de Células/efeitos dos fármacos , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Glioblastoma/patologia , Compostos Heterocíclicos de 4 ou mais Anéis/farmacologia , Sirtuína 1/metabolismo , Acetilação , Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Células Endoteliais da Veia Umbilical Humana , Humanos , Proteínas Associadas aos Microtúbulos/metabolismo , NF-kappa B/antagonistas & inibidores , Fosforilação , Fator de Transcrição STAT3/antagonistas & inibidores , Transdução de Sinais/efeitos dos fármacos
16.
Environ Toxicol ; 34(11): 1191-1198, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31313480

RESUMO

The phthalate plasticizer, di(2-ethyl-hexyl) phthalate (DEHP), and its derived metabolites are common anthropogenic environmental toxins, which are known to act as endocrine disruptors. Numerous studies have associated DEHP with disruption of sex hormones, abnormal development of reproductive organs, allergies, and inflammation. Its role in promoting inflammation has been reported by both human epidemiological and animal studies. In stomach tissue, chronic inflammation is known to accompany mucosal damage, and pave the way to gastritis, stomach ulcers, and ultimately gastric cancer. Eastern Asian populations possess the highest gastric cancer incidences in the world. Coincidentally, East Asia is one of the world's major sites for plastics manufacture and export. Thus, possible correlations between DEHP, a common plasticizer, and gastric cancer are of great interest. Our study revealed several critical findings. First, even at very low dosage, mimicking the residual plasticizer exposure, detrimental effects of DEHP on gastric cells can be detected. Second, gastric cells treated with DEHP increased cyclooxygenase-2 (COX-2) in a time-dependent manner. Third, promoter deletion studies revealed a critical role of nuclear factor-kappa B (NF-κB) for COX-2 gene responses. Finally, our results indicated that a low concentration of DEHP is able to trigger COX-2 activation via the extracellular signal-regulated kinase (ERK1/2) and NF-κB signaling pathway. Taken together, we demonstrate that very low doses of DEHP enhance the expression of the prototypical inflammatory gene, COX-2, in gastric cancer cells via ERK1/2 and NF-κB activation. This study provides important insights into the inflammatory process and damages associated with phthalate plasticizers exposure.


Assuntos
Ciclo-Oxigenase 2/metabolismo , Dietilexilftalato/toxicidade , Regulação da Expressão Gênica/efeitos dos fármacos , Plastificantes/toxicidade , Adenocarcinoma , Animais , Linhagem Celular Tumoral , Dietilexilftalato/metabolismo , Poluentes Ambientais/química , Poluentes Ambientais/metabolismo , Poluentes Ambientais/toxicidade , Humanos , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , NF-kappa B/antagonistas & inibidores , NF-kappa B/genética , NF-kappa B/metabolismo , Plastificantes/metabolismo , Interferência de RNA , RNA Interferente Pequeno/metabolismo , Transdução de Sinais/efeitos dos fármacos , Neoplasias Gástricas
17.
J Surg Res ; 243: 316-324, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31255931

RESUMO

BACKGROUND: 3-amino-2-hydroxy-4-phenyl-valyl-isoleucine (LYRM03) has been shown to be beneficial in a rat model of acute lung injury (ALI). Nonetheless, the pharmacologic action of LYRM03 interference has not been demonstrated to occur through oxidative stress and apoptosis in a rat lipopolysaccharide (LPS)-induced ALI model, and the potential pathogenic mechanism needs to be clarified. Our research intended to explore the mechanism of action using an in vivo rat LPS-induced ALI model and highlight the associated pathogenesis. METHODS: Sprague-Dawley rats were randomly assigned to the following five groups: Sham; LPS (5 mg/kg); LPS + LYRM03 (5 mg/kg); LPS + LYRM03 (10 mg/kg); and LPS + LYRM03 (20 mg/kg). Pulmonary injury indicators were documented at 24 h after LPS-induced ALI. Morphologic alterations, such as the extent of the injury, were determined using hematoxylin-eosin staining. Furthermore, expression levels of oxidative stress indicators (malondialdehyde, superoxide dismutase, and glutathione peroxidase) and inflammatory molecules (tumor necrosis factor-α, interleukin-8, and interleukin-6) in circulation were observed. The production of apoptosis-associated proteins (poly ADP-ribose polymerase, c-caspase 3, B-cell lymphoma-2, and Bcl2 associated X), inflammatory mediators (high mobility group box-1, toll-like receptor 4, nuclear factor-kappa B p65, and myeloid differentiation primary response 88), and inhibitor of kappa B-α were determined through Western blotting. Real-time polymerase chain reaction was applied to assess the messenger RNA expression of the inflammatory mediators. RESULTS: The LPS-treated group exhibited a remarkable increase in the extent of the pulmonary injury, oxidative stress indicator secretion, inflammatory molecule release, and inflammatory mediator production and an increase in the inhibitor of kappa B-α levels relative to the Sham group. The LYRM03 (5 and 10 mg/kg)-treated groups exhibited a remarkable decrease relative to the LPS group. In addition, treatment with LYRM03 (20 mg/kg) powerfully limited the extent of the injury and demonstrated anti-inflammatory actions. CONCLUSIONS: The results of this investigation indicated that treatment with LYRM03 plays a role in lung defense by inhibiting the NF-κB/MyD88/TLR4 pathway.


Assuntos
Lesão Pulmonar Aguda/prevenção & controle , Fator 88 de Diferenciação Mieloide/antagonistas & inibidores , NF-kappa B/antagonistas & inibidores , Oligopeptídeos/uso terapêutico , Receptor 4 Toll-Like/antagonistas & inibidores , Lesão Pulmonar Aguda/sangue , Lesão Pulmonar Aguda/patologia , Animais , Apoptose/efeitos dos fármacos , Avaliação Pré-Clínica de Medicamentos , Lipopolissacarídeos , Pulmão/enzimologia , Pulmão/patologia , Masculino , Fator 88 de Diferenciação Mieloide/metabolismo , NF-kappa B/metabolismo , Oligopeptídeos/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Peroxidase/metabolismo , Distribuição Aleatória , Ratos Sprague-Dawley , Receptor 4 Toll-Like/metabolismo
18.
Phytomedicine ; 63: 153037, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31357075

RESUMO

BACKGROUND: Non-Small-Cell Lung Cancer (NSCLC) is the most-frequent cause of cancer death, and novel chemotherapeutic drugs for treating NSCLC are urgently needed. 2α, 3α, 23-trihydroxy-13α, 27-cyclours-11-en-28-oic acid (euscaphic acid G) is a new hexacyclic triterpene acid isolated by our group from Glechoma longituba (Nakai) Kupr. However, the underlying mechanisms responsible for the anticancer effects of hexacyclic triterpene acid have not been elucidated. PURPOSE: In the present work, we evaluated growth inhibitory effect of the new isolated hexacyclic triterpene acid and explored the underlying molecular mechanisms. METHODS/STUDY DESIGNS: Herbs were extracted and constituents were purified by chromatographic separation, including silica gel, ODS, MCI, Sephadex LH-20 and preparative HPLC. The compound structures were elucidated by the use of UV, NMR and MS spectral data. The anticancer activity of euscaphic acid G was evaluated by MTT assay. Cell cycle, apoptosis, reactive oxygen species and mitochondrial membrane potential were determined by flow cytometry. To display the possible mechanism of euscaphic acid G on NCI-H460 cells, RT-PCR, immunofluorescence and Western blot analysis were carried out. RESULTS: A new hexacyclic triterpene acid, euscaphic acid G, together with fifteen known triterpenoids, was isolated from the aerial parts of G. longituba. Our results showed that euscaphic acid G exerted strong anti-proliferative activity against NCI-H460 cells in a concentration- and time-dependent manner. Flow cytometry demonstrated euscaphic acid G arrested the cell cycle at G1 phase, induced cellular apoptosis, accompanied by ROS generation and mitochondrial membrane potential reduction. Mechanistic studies revealed that euscaphic acid G treatment inhibited IKKα/ß phosphorylation and IκBα phosphorylation, which subsequently caused the blockage of NF-κB p65 phosphorylation and nuclear translocation. CONCLUSION: In conclusion, these results suggested that euscaphic acid G from G. longituba showed potential anticancer effects against lung cancer cells via inducing cell cycle arrest and apoptosis, at least partly, through NF-κB signaling pathways.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Lamiaceae/química , NF-kappa B/antagonistas & inibidores , Triterpenos/farmacologia , Apoptose/efeitos dos fármacos , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Potencial da Membrana Mitocondrial/efeitos dos fármacos , NF-kappa B/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais/efeitos dos fármacos , Triterpenos/química
19.
J Immunol Res ; 2019: 1982570, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31355296

RESUMO

Dendritic cells (DCs) have the ability to induce tolerance or inflammation in response to self-antigens, which makes them fundamental players in autoimmunity. In this regard, immunogenic DCs produce IL-12 and IL-23 favouring the acquisition of Th1 and Th17 inflammatory phenotypes, respectively, by autoreactive CD4+ T-cells, thus promoting autoimmunity. Conversely, tolerogenic DCs produce IL-10 and TGF-ß, inducing the generation of CD4+ T-cells with suppressive activity (Treg), which promote tolerance to self-constituents. Previous studies have shown that STAT3 signalling in DCs attenuates the production of proinflammatory cytokines, whilst NF-κB activation promotes it. In this study, we aimed to generate DCs displaying strong and constitutive tolerogenic profile to be used as immunotherapy in autoimmunity. To this end, we transduced bone marrow-derived DCs with lentiviral particles codifying for a constitutively active version of STAT3 (constitutively active STAT3 (STAT3ca)) or with a constitutive repressor of NF-κB (IκBα superrepressor (IκBαSR)), and their therapeutic potential was evaluated in a mouse model of arthritis induced by collagen (CIA). Our results show that STAT3ca transduction favoured the production of the anti-inflammatory mediator IL-10, whereas IκBαSR transduction attenuated the expression of the proinflammatory cytokine IL-23 in DCs. Moreover, both STAT3ca-transduced and IκBαSR-transduced DCs separately exerted a mild but significant therapeutic effect reducing the severity of CIA development. Furthermore, when DCs were transduced with both STAT3ca and IκBαSR together, they reduced CIA manifestation significantly stronger than when transduced with only STAT3ca or IκBαSR separately. These results show STAT3 and NF-κB as two important and complementary regulators of the tolerogenic behaviour of DCs, which should be considered as molecular targets in the design of DC-based suppressive immunotherapies for the treatment of autoimmune disorders.


Assuntos
Artrite Experimental/terapia , Células Dendríticas/transplante , Tolerância Imunológica/imunologia , NF-kappa B/antagonistas & inibidores , Fator de Transcrição STAT3/genética , Animais , Artrite Experimental/imunologia , Artrite Experimental/metabolismo , Autoimunidade , Linfócitos T CD4-Positivos/imunologia , Células Dendríticas/imunologia , Células Dendríticas/metabolismo , Humanos , Inflamação , Interleucina-10/metabolismo , Interleucina-12/metabolismo , Masculino , Camundongos , Fator de Transcrição STAT3/metabolismo , Células Th1/imunologia , Células Th17/imunologia
20.
Blood ; 134(5): 445-455, 2019 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-31167801

RESUMO

Therapeutic options for cutaneous T-cell lymphoma (CTCL) are limited and curative treatment regimens are not available. Thus, new targeted and well-tolerated therapeutic approaches are urgently needed. In this respect, we have recently shown that dimethyl fumerate (DMF) inhibits NF-κB acting as a survival factor in CTCL. Similarly, inhibition of the antiapoptotic protein B-cell lymphoma 2 (Bcl-2) has been shown to induce cell death in CTCL especially when combined with histone deacetylase inhibitors. Therefore, we hypothesized that inhibition of Bcl-2 should potentiate NF-κB inhibition in a novel combination treatment of CTCL. We show that, in vitro, the Bcl-2 inhibitors ABT-199 and ABT-263 induced specific cell death in primary CD4+ cells from CTCL patients as well as in the CTCL cell line SeAx, but not in T cells of healthy donors nor in the CTCL cell line HH, which lacks Bcl-2. Combined treatment with ABT-199 and DMF caused synergistic cell death specifically in CTCL cells engaging 2 independent signaling pathways. To verify these findings in vivo, we performed combined ABT-199 and DMF treatment in a xenograft mouse model for CTCL. The combined treatment effectively reduced tumor growth and increased overall survival via synergistic induction of CTCL cell death and suppression of tumor cell proliferation. Essentially, the combination treatment was superior to ABT-199 monotherapy with respect to both efficacy and tolerability. To sum up, our data provide proof of principle for the therapeutic potential of combining Bcl-2 and NF-κB inhibitors in treating CTCL. Next, this potential should be explored further in a clinical study.


Assuntos
Antineoplásicos/farmacologia , Inibidores de Histona Desacetilases/farmacologia , Linfoma Cutâneo de Células T/metabolismo , NF-kappa B/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-bcl-2/antagonistas & inibidores , Animais , Apoptose , Morte Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Sinergismo Farmacológico , Humanos , Linfoma Cutâneo de Células T/diagnóstico , Linfoma Cutâneo de Células T/tratamento farmacológico , Linfoma Cutâneo de Células T/genética , Camundongos , NF-kappa B/genética , Estadiamento de Neoplasias , Ligação Proteica , Proteínas Proto-Oncogênicas c-bcl-2/genética , Interferência de RNA , RNA Interferente Pequeno/genética , Ensaios Antitumorais Modelo de Xenoenxerto
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