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1.
Int J Nanomedicine ; 14: 5323-5338, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31409990

RESUMO

Background: Candida albicans as an opportunistic fungus is one of the most important causes of late-onset morbidity and mortality in patients with major burns and severely impaired immune system. In recent years, the emergence of resistance to opportunistic fungi and toxicity of antimicrobial drugs make it necessary to develop new drugs. Methods: In the present study, we investigated anticandidal effects of indolicidin, as a representative of host defense peptide, conjugated with gold nanoparticles in fluconazole-resistant clinical isolates of C. albicans. After characterizing the conjugation of indolicidin using biophysical methodologies, the cytotoxicity and hemolytic activity of the nanocomplex were examined. In addition, the expression level of ERG11, responsible for antifungal resistance, and the immunomodulatory effect of peptide-nanomaterial conjugates were assessed. Results: Our data indicated that the nanocomplex was nontoxic for the fibroblast cells and erythrocytes. Treatment with the nanocomplex significantly reduced the expression levels of the ERG11 gene in fluconazole-resistant C. albicans isolates and the iNOS gene in macrophages. Conclusion: The study data provides a chance to develop innovative therapies for the treatment of C. albicans burn infections. However, further investigation is required to examine the efficiency of the nanocomplex.


Assuntos
Antifúngicos/farmacologia , Peptídeos Catiônicos Antimicrobianos/farmacologia , Queimaduras/microbiologia , Candida albicans/efeitos dos fármacos , Candida albicans/isolamento & purificação , Fluconazol/farmacologia , Ouro/farmacologia , Nanopartículas Metálicas/química , Animais , Peptídeos Catiônicos Antimicrobianos/química , Queimaduras/tratamento farmacológico , Candida albicans/genética , Morte Celular/efeitos dos fármacos , Farmacorresistência Fúngica/efeitos dos fármacos , Eritrócitos/efeitos dos fármacos , Eritrócitos/metabolismo , Fluconazol/química , Regulação Fúngica da Expressão Gênica/efeitos dos fármacos , Genes Fúngicos , Hemólise/efeitos dos fármacos , Humanos , Nanopartículas Metálicas/ultraestrutura , Camundongos , Camundongos Endogâmicos BALB C , Testes de Sensibilidade Microbiana , Células NIH 3T3 , Óxido Nítrico Sintase Tipo II/genética , Óxido Nítrico Sintase Tipo II/metabolismo
2.
J Agric Food Chem ; 67(32): 9009-9021, 2019 Aug 14.
Artigo em Inglês | MEDLINE | ID: mdl-31319030

RESUMO

Soybean allergy is a serious health risk to humans and animals; ß-conglycinin is the primary antigenic protein in soybean. Intestinal porcine epithelial (IPEC-J2) cells were used as an in vitro physiological model of the intestinal epithelium to study the effects of different concentrations of soybean antigen protein ß-conglycinin to identify the involved signaling pathways. The cells were divided into eight groups and either untreated or treated with different concentrations of ß-conglycinin, pyrrolidine dithiocarbamate (PDTC), Nω-nitro-l-arginine methyl ester hydrochloride (l-NAME), SP600125, and SB202190 either alone or in combination. The cells were incubated with 1, 5, and 10 mg·mL-1 ß-conglycinin or 5 mg·mL-1 ß-conglycinin and 1 µmol·L-1 nuclear factor κB (NF-κB) inhibitor (PDTC), inducible nitric oxide synthase inhibitor (l-NAME), c-Jun N-terminal kinase (JNK) inhibitor (SP600125), and p38 inhibitor (SB202190) for 24 h, separately; controls were left untreated. The mRNA, protein, and phosphorylation levels of NF-κB, p38, and JNK were higher in the treated groups than in the control group. ß-Conglycinin decreased tight junction distribution, destroyed the cytoskeleton of IPEC-J2 cells, and caused cell death. After the addition of the inhibitors, ß-conglycinin-induced IPEC-J2 cell damage was significantly reduced. ß-Conglycinin caused damage to IPEC-J2 cells via the mitogen-activated protein kinase/NF-κB signaling pathway. The results of this study are crucial for exploring the mechanisms underlying allergic reactions caused by soybean antigen proteins.


Assuntos
Antígenos de Plantas/imunologia , Células Epiteliais/imunologia , Hipersensibilidade Alimentar/imunologia , Globulinas/imunologia , Proteínas Quinases Ativadas por Mitógeno/imunologia , NF-kappa B/imunologia , Proteínas de Armazenamento de Sementes/imunologia , Proteínas de Soja/imunologia , Soja/imunologia , Animais , Humanos , Mucosa Intestinal/citologia , Mucosa Intestinal/imunologia , Proteínas Quinases JNK Ativadas por Mitógeno/genética , Proteínas Quinases JNK Ativadas por Mitógeno/imunologia , Proteínas Quinases Ativadas por Mitógeno/genética , NF-kappa B/genética , Óxido Nítrico Sintase Tipo II/genética , Óxido Nítrico Sintase Tipo II/imunologia , Fosforilação , Transdução de Sinais , Suínos , Junções Íntimas/genética , Junções Íntimas/imunologia
3.
J Agric Food Chem ; 67(30): 8339-8347, 2019 Jul 31.
Artigo em Inglês | MEDLINE | ID: mdl-31291543

RESUMO

The dried seeds of Cuminum cyminum L. have been traditionally used as food and medicine. To explore its chemical composition and anti-inflammatory activity, four new compounds (1-4) along with five known compounds (5-9) were isolated from the seeds in the present study. The chemical structures of the new compounds were identified as follows: methyl 3-((7H-purin-2-yl) amino)-3-(4-isopropylphenyl) propanoate (1), 8-(amino(4-isopropylphenyl)methyl)-5-hydroxy-2-(4-hydroxyphenyl)-7-methoxy-4-oxo-4H-chromene-6-carboxylic acid (2), (3,4,5-trihydroxy-6-((4-isopropylbenzyl)oxy)tetrahydro-2H-pyran-2-yl)methyl (E)-3-(4-propoxyphenyl)acrylate (3), and (3,4,5-trihydroxy-6-((5-hydroxy-2-(4-hydroxyphenyl)-4-oxo-4H-chromen-7-yl)oxy)tetrahydro-2H-pyran-2-yl)methyl 3-(4-isopropylphenyl)-2-methoxypropanoate (4). Compound 2, an atypical nitrogen-containing flavonoid, exhibited the most active inhibitory effect on nitride oxide, with IC50 of 5.25 µM in the lipopolysaccharide-stimulated RAW264.7 cell assay. Compound 2 was found to suppress the expression levels of inducible nitric oxide synthase and cyclooxygenase-2. Furthermore, it was revealed that both nuclear factor κB and mitogen-activated protein kinase were involved in the anti-inflammatory process of compound 2.


Assuntos
Anti-Inflamatórios/química , Anti-Inflamatórios/farmacologia , Cuminum/química , Flavonoides/química , Flavonoides/farmacologia , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Animais , Sobrevivência Celular/efeitos dos fármacos , Frutas/química , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Camundongos , Proteínas Quinases Ativadas por Mitógeno/genética , Proteínas Quinases Ativadas por Mitógeno/imunologia , Estrutura Molecular , NF-kappa B/genética , NF-kappa B/imunologia , Óxido Nítrico Sintase Tipo II/genética , Óxido Nítrico Sintase Tipo II/imunologia , Células RAW 264.7 , Sementes/química
4.
Mar Drugs ; 17(6)2019 Jun 03.
Artigo em Inglês | MEDLINE | ID: mdl-31163615

RESUMO

Sea hares of Aplysia genus are recognized as a source of a diverse range of metabolites. 5α,8α-Endoperoxides belong to a group of oxidized sterols commonly found in marine organisms and display several bioactivities, including antimicrobial, anti-tumor, and immunomodulatory properties. Herein we report the isolation of 5α,8α-epidioxycholest-6-en-3ß-ol (EnP(5,8)) from Aplysia depilans Gmelin, based on bioguided fractionation and nuclear magnetic resonance (NMR) analysis, as well as the first disclosure of its anti-inflammatory properties. EnP(5,8) revealed capacity to decrease cellular nitric oxide (NO) levels in RAW 264.7 macrophages treated with lipopolysaccharide (LPS) by downregulation of the Nos2 (inducible nitric oxide synthase, iNOS) gene. Moreover, EnP(5,8) also inhibited the LPS-induced expression of cyclooxygenase-2 (COX-2), interleukin 6 (IL-6), and tumor necrosis factor alpha (TNF-α) at the mRNA and protein levels. Mild selective inhibition of COX-2 enzyme activity was also evidenced. Our findings provide evidence of EnP(5,8) as a potential lead drug molecule for the development of new anti-inflammatory agents.


Assuntos
Anti-Inflamatórios/química , Anti-Inflamatórios/farmacologia , Aplysia/química , Ésteres do Colesterol/química , Ésteres do Colesterol/farmacologia , Macrófagos/efeitos dos fármacos , Adjuvantes Imunológicos/farmacologia , Animais , Anti-Inflamatórios/isolamento & purificação , Fracionamento Químico , Ésteres do Colesterol/isolamento & purificação , Regulação para Baixo/efeitos dos fármacos , Ativação Enzimática/efeitos dos fármacos , Lipopolissacarídeos/farmacologia , Espectroscopia de Ressonância Magnética , Camundongos , Óxido Nítrico Sintase Tipo II/genética , Células RAW 264.7
5.
Mar Drugs ; 17(6)2019 May 30.
Artigo em Inglês | MEDLINE | ID: mdl-31151271

RESUMO

In our previous study, a synthetic compound, (+)-(R,E)-6a1, that incorporated the key structures of anti-inflammatory algal metabolites and the endogenous peroxisome proliferator-activated receptor γ (PPAR-γ) ligand 15-deoxy-∆12,14-prostaglandin J2 (15d-PGJ2), exerted significant PPAR-γ transcriptional activity. Because PPAR-γ expressed in macrophages has been postulated as a negative regulator of inflammation, this study was designed to investigate the anti-inflammatory effect of the PPAR-γ agonist, (+)-(R,E)-6a1. Compound (+)-(R,E)-6a1 displayed in vitro anti-inflammatory activity in lipopolysaccharides (LPS)-stimulated murine RAW264.7 macrophages. Compound (+)-(R,E)-6a1 suppressed the expression of proinflammatory factors, such as nitric oxide (NO), inducible NO synthase (iNOS), cyclooxygenase-2 (COX-2), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α), possibly by the inhibition of the nuclear factor-κB (NF-κB) pathway. In macrophages, (+)-(R,E)-6a1 suppressed LPS-induced phosphorylation of NF-κB, inhibitor of NF-κB α (IκBα), and IκB kinase (IKK). These results indicated that PPAR-γ agonist, (+)-(R,E)-6a1, exerts anti-inflammatory activity via inhibition of the NF-κB pathway.


Assuntos
Anti-Inflamatórios/farmacologia , Macrófagos/efeitos dos fármacos , NF-kappa B/agonistas , PPAR gama/antagonistas & inibidores , Prostaglandinas Sintéticas/farmacologia , Animais , Ciclo-Oxigenase 2/genética , Regulação da Expressão Gênica/efeitos dos fármacos , Inflamação/induzido quimicamente , Interleucina-6/genética , Lipopolissacarídeos , Camundongos , Óxido Nítrico/genética , Óxido Nítrico Sintase Tipo II/genética , Células RAW 264.7 , Rodófitas/química , Fator de Necrose Tumoral alfa/genética
6.
Life Sci ; 233: 116525, 2019 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-31158376

RESUMO

BACKGROUND: Impaired wound healing in diabetes foot ulcers (DFUs) brings a great burden to diabetic patients. Pro-angiogenesis through elevating nitric oxide (NO) is beneficial to the wound healing process. Ginsenoside Rg1, the main active in Notoginseng, is reported to regulate the angiogenesis in endothelial cells through modulating miR-23a. However, the effect of Rg1 in diabetes remains elusive. METHODS: High fat diet combined with streptozotocin-induced diabetic rats were treated with Rg1. Then incision area and tissue NO level were measured to evaluate the wound closure efficacy of Rg1. Then high glucose cultured HUVECs were employed to mimic diabetic environment in vitro. Overexpression and knockdown plasmids of miR-23a or IRF-1 were constructed and transfected in HUVECs. qPCR and western blot were used to determine the mRNA and protein level, respectively. Dual-luciferase reporter assay was utilized to determine the interaction of IRF-1/miR-23a. RESULTS: Rg1 accelerated the wound closure speed in diabetic rats and increased NO level through elevating iNOS expression. Knockdown of iNOS reversed Rg1-induced VEGF expression, cell proliferation, anti-apoptotic efficacy and cell migration ability in high glucose cultured HUVECs. Further investigation revealed that Rg1 mediated iNOS through miR-23a. miR-23a inhibited the expression of IRF-1, a protein which could directly bind to the iNOS mRNA 3'UTR. CONCLUSION: Rg1 promoted angiogenesis in diabetic wound healing process through NO signaling via miR-23a, providing a novel candidate for DFUs treatment.


Assuntos
Diabetes Mellitus Experimental/complicações , Pé Diabético/tratamento farmacológico , Ginsenosídeos/farmacologia , Fator Regulador 1 de Interferon/metabolismo , MicroRNAs/genética , Óxido Nítrico Sintase Tipo II/metabolismo , Cicatrização/efeitos dos fármacos , Animais , Apoptose , Movimento Celular , Proliferação de Células , Fármacos do Sistema Nervoso Central/farmacologia , Pé Diabético/etiologia , Pé Diabético/metabolismo , Pé Diabético/patologia , Regulação da Expressão Gênica , Células Endoteliais da Veia Umbilical Humana , Humanos , Fator Regulador 1 de Interferon/genética , Masculino , Óxido Nítrico Sintase Tipo II/genética , Ratos , Ratos Sprague-Dawley
7.
J Microbiol Biotechnol ; 29(7): 1022-1032, 2019 Jul 28.
Artigo em Inglês | MEDLINE | ID: mdl-31216608

RESUMO

Probiotics are known to provide the host with immune-modulatory effects and are therefore of remarkable interest for therapeutic and prophylactic applications against various disorders, including inflammatory diseases. Weissella cibaria JW15 (JW15) has been reported to possess probiotic and antioxidant properties. However, the effect of JW15 on inflammatory responses has not yet been reported. Therefore, the objective of the current study was to evaluate the anti-inflammatory potential of JW15 against lipopolysaccharide (LPS) stimulation. The production of pro-inflammatory factors and the cellular signaling pathways following treatment with heat-killed JW15 was examined in LPS-induced RAW 264.7 cells. Treatment with heat-killed JW15 decreased nitric oxide and prostaglandin E2 production via downregulation of the inducible nitric oxide synthase and cyclooxygenase-2. In addition, treatment with heat-killed JW15 suppressed the expression of pro-inflammatory cytokines, interleukin (IL)-1ß, IL-6, and tumor necrosis factor-α. The anti-inflammatory properties of treating with heat-killed JW15 were associated with mitogen-activated protein kinase signaling pathwaymediated suppression of nuclear factor-κB. These results indicated that JW15 possesses antiinflammatory potential and provide a molecular basis regarding the development of functional probiotic products.


Assuntos
Anti-Inflamatórios/farmacologia , Macrófagos/efeitos dos fármacos , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Probióticos/farmacologia , Fator de Transcrição RelA/metabolismo , Weissella/fisiologia , Animais , Sobrevivência Celular , Ciclo-Oxigenase 2/genética , Citocinas/genética , Citocinas/metabolismo , Dinoprostona/metabolismo , Alimentos Fermentados/microbiologia , Lipopolissacarídeos/toxicidade , Macrófagos/imunologia , Macrófagos/metabolismo , Camundongos , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase Tipo II/genética , Fosforilação/efeitos dos fármacos , Células RAW 264.7 , Transdução de Sinais/efeitos dos fármacos
8.
Eur J Med Chem ; 177: 457-466, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31181405

RESUMO

Histone deacetylases (HDACs) play an important role in cancer, degenerative diseases and inflammation. The currently applied HDAC inhibitors in the clinic lack selectivity among HDAC isoforms, which limits their application for novel indications such as inflammatory diseases. Recent, literature indicates that HDAC 3 plays an important role among class I HDACs in gene expression in inflammation. In this perspective, the development and understanding of inhibitory selectivity among HDACs 1, 2 and 3 and their respective influence on gene expression need to be characterized to facilitate drug discovery. Towards this aim, we synthesized nine structural analogues of the class I HDAC inhibitor Entinostat and investigated their selectivity profile among HDACs 1, 2 and 3. We found that we can explain the observed structure activity relationships by small structural and conformational differences between HDAC 1 and HDAC 3 in the 'lid' interacting region. Cell-based studies indicated, however, that application of inhibitors with improved HDAC 3 selectivity did not provide an anti-inflammatory response in contrast to expectations from biochemical evidence in literature. Altogether, in this study, we identified structure activity relationships among class I HDACs and we connected isoform selectivity among class I HDACs with pro- and anti-inflammatory gene transcription in macrophages.


Assuntos
Anilidas/farmacologia , Benzamidas/farmacologia , Expressão Gênica/efeitos dos fármacos , Inibidores de Histona Desacetilases/farmacologia , Macrófagos/efeitos dos fármacos , Anilidas/síntese química , Anilidas/química , Anilidas/metabolismo , Animais , Benzamidas/síntese química , Benzamidas/química , Benzamidas/metabolismo , Domínio Catalítico , Histona Desacetilase 1/química , Histona Desacetilase 1/metabolismo , Histona Desacetilase 2/metabolismo , Inibidores de Histona Desacetilases/síntese química , Inibidores de Histona Desacetilases/química , Inibidores de Histona Desacetilases/metabolismo , Histona Desacetilases/química , Histona Desacetilases/metabolismo , Humanos , Inflamação/genética , Interleucina-10/genética , Interleucina-6/genética , Camundongos , Simulação de Acoplamento Molecular , Subunidade p50 de NF-kappa B/metabolismo , Óxido Nítrico Sintase Tipo II/genética , Ligação Proteica , Células RAW 264.7 , Estereoisomerismo , Relação Estrutura-Atividade , Fator de Necrose Tumoral alfa/genética
9.
Arch Virol ; 164(9): 2231-2241, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31177351

RESUMO

Viral persistence alters cellular antiviral activities. Nitric oxide (NO), a highly reactive free radical and a potent antiviral molecule, can inhibit replication of RNA and DNA viruses, but its production and effect during viral persistence are largely unknown. NO synthesis is stimulated in epithelial cells during acute infection with respiratory syncytial virus (RSV) and interferes with viral replication. In this study, we compared the levels of production of NO and expression of its regulatory enzymes, inducible nitric oxide synthase (NOS II) and arginase 1 (Arg-1), during acute and persistent RSV infection in a macrophage cell line to investigate their role in the control and maintenance of viral infection. We observed that NO and NOS II mRNA were induced at higher levels in acutely infected macrophages than in persistently infected macrophages, while the kinetics of NOS II protein expression were similar in both types of infected cultures, except that its disappearance was delayed during acute infection. Thus, NOS II was inducible and expressed at high levels during persistent infection, but production of NO was low relative to acute infection. This was not associated with a lack of enzymatic activity but instead was due to constitutive expression of the Arg-1 enzyme at the mRNA and protein levels, suggesting that arginase restricts availability of L-arginine as a substrate for NOS II to synthesize NO. This hypothesis was supported by showing that arginase enzymatic activity was inhibited in persistently RSV-infected cells by Nω-hydroxy-nor-L-arginine, increasing L-arginine availability in conditioned medium and producing increased levels of nitrites, concurrently with a significant reduction in virus genome replication, implying that Arg-1 overexpression contributes to the maintenance of the RSV genome in the host in persistent infection.


Assuntos
Arginase/metabolismo , Óxido Nítrico/metabolismo , Infecções por Vírus Respiratório Sincicial/virologia , Vírus Sincicial Respiratório Humano/fisiologia , Arginase/genética , Arginina/metabolismo , Regulação para Baixo , Humanos , Óxido Nítrico Sintase Tipo II/genética , Óxido Nítrico Sintase Tipo II/metabolismo , Nitritos/metabolismo , Infecções por Vírus Respiratório Sincicial/enzimologia , Infecções por Vírus Respiratório Sincicial/genética , Vírus Sincicial Respiratório Humano/genética , Replicação Viral
10.
Parasitol Int ; 72: 101928, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31108221

RESUMO

The successful control and eradication of leishmaniasis are still challenging in view of the lack of adequate chemotherapy and potential prophylaxis. Research is going on for finding an appropriate anti-leishmanial drug which should be acceptable in terms of cost and safety. In view of this, the current study investigated the anti-leishmanial efficacy of salidroside (SAL) which is a phenylpropanoid glycoside. The leishmanicidal capacity of SAL was verified in vitro as well as in vivo. The SAL exhibited leishmanicidal activity against the promastigotes of L. donovani which was further validated by propidium iodide staining and its ability to arrest the promastigotes at the sub G0/G1 stage. SAL decreased and controlled the VL infection in mice as estimated by real-time PCR. Active immunomodulation was exhibited upon SAL treatment in BALB/c mice. The characteristic features like pronounced DTH reaction, polarization of immune status to Th1 type of immune response, increased the production of CD4+ and CD8+ T cells indicated the immune-stimulatory property of SAL. In addition to this the expression of NF-ĸB, iNOS genes along with the levels of leishmanicidal species, NO and ROS were found to be augmented in SAL treated infected animals. Moreover, SAL exhibited minimal toxicity to the THP-1 cells and it revealed no toxicity against liver and kidney. The capability of SAL in promoting the immune status in favor of host during VL infection without causing any side-effects may be used as an effective strategy to fight the disease.


Assuntos
Antiprotozoários/farmacologia , Glucosídeos/farmacologia , Leishmania donovani/efeitos dos fármacos , Fenóis/farmacologia , Animais , Linfócitos T CD8-Positivos/imunologia , Citocinas/imunologia , Humanos , Imunomodulação , Leishmaniose Visceral/tratamento farmacológico , Macrófagos/imunologia , Camundongos , Camundongos Endogâmicos BALB C , Subunidade p50 de NF-kappa B/genética , Óxido Nítrico Sintase Tipo II/genética , Baço/imunologia , Baço/parasitologia , Células THP-1 , Células Th1/imunologia
11.
Int J Mol Sci ; 20(9)2019 05 05.
Artigo em Inglês | MEDLINE | ID: mdl-31060340

RESUMO

Heme oxygenase 1 (HO-1) and carbon monoxide were shown to normalize oxidative stress and inflammatory reactions induced by neuropathic pain in the central nervous system, but their effects in the locus coeruleus (LC) of animals with peripheral inflammation and their interaction with nitric oxide are unknown. In wild-type (WT) and knockout mice for neuronal (NOS1-KO) or inducible (NOS2-KO) nitric oxide synthases with inflammatory pain induced by complete Freund's adjuvant (CFA), we assessed: 1) antinociceptive actions of cobalt protoporphyrin IX (CoPP), an HO-1 inducer; 2) effects of CoPP and tricarbonyldichlororuthenium(II)dimer (CORM-2), a carbon monoxide-liberating compound, on the expression of HO-1, NOS1, NOS2, CD11b/c, GFAP,and mitogen-activated protein kinases (MAPK)in the LC. CoPP reduced inflammatory pain in different time-dependent manners in WT and KO mice. Peripheral inflammation activated astroglia in the LC of all genotypes and increased the levels of NOS1 and phosphorylated extracellular signal-regulated kinase 1/2 (p-ERK 1/2) in WT mice. CoPP and CORM-2 enhanced HO-1 and inhibited astroglial activationin all genotypes. Both treatments blocked NOS1 overexpression,and CoPP normalized ERK 1/2 activation. This study reveals an interaction between HO-1 and NOS1/NOS2 during peripheral inflammation andshows that CoPP and CORM-2 improved HO-1 expression and modulated the inflammatory and/or plasticity changes caused by peripheral inflammation in the LC.


Assuntos
Inflamação/etiologia , Inflamação/metabolismo , Óxido Nítrico/metabolismo , Compostos Organometálicos/farmacologia , Protoporfirinas/farmacologia , Animais , Biomarcadores , Inflamação/patologia , Masculino , Camundongos , Camundongos Knockout , Óxido Nítrico Sintase Tipo I/genética , Óxido Nítrico Sintase Tipo II/genética , Compostos Organometálicos/química , Protoporfirinas/química
12.
Chem Biol Interact ; 308: 120-129, 2019 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-31129132

RESUMO

A preclinical study using DEN-induced HCC rat model was attempted to evaluate the antitumor potential of zolmitriptan (ZOL). The molecular insights were investigated using ELISA, qRT-PCR and Western blot techniques. The result confirmed that the HCC condition was developed in response to lower expressions of caspase 3 and 9 which, in turn, was due to the upstream regulation of iNOS, Bcl-xl and Bcl-2, and downstream regulation of eNOS, BAX, BAD and Cyt C. The treatment with ZOL caused the significant activation of caspase mediated apoptotic signals that could be responsible for its anti-HCC potential. Later, 1H NMR based serum metabolomics study confirmed that ZOL restored the perturbed metabolites associated with DEN-induced HCC. The antineoplastic potential of ZOL was found comparable or to some degree better than the marketed chemotherapeutics, 5-flurouracil.


Assuntos
Apoptose/efeitos dos fármacos , Caspase 3/metabolismo , Caspase 9/metabolismo , Oxazolidinonas/farmacologia , Triptaminas/farmacologia , Animais , Carcinoma Hepatocelular/induzido quimicamente , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/patologia , Citocinas/análise , Modelos Animais de Doenças , Glutationa/metabolismo , Lipídeos/sangue , Fígado/efeitos dos fármacos , Fígado/metabolismo , Fígado/patologia , Neoplasias Hepáticas/induzido quimicamente , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/patologia , Masculino , Óxido Nítrico Sintase Tipo II/genética , Óxido Nítrico Sintase Tipo II/metabolismo , Oxazolidinonas/uso terapêutico , Estresse Oxidativo/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-bcl-2/genética , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Ratos , Ratos Wistar , Triptaminas/uso terapêutico , Proteína X Associada a bcl-2/genética , Proteína X Associada a bcl-2/metabolismo
13.
Int J Mol Sci ; 20(9)2019 Apr 29.
Artigo em Inglês | MEDLINE | ID: mdl-31035654

RESUMO

Several clinical studies have suggested the impact of sinusoidal and pulsed electromagnetic fields in quickening wound repair processes and tissue regeneration. The clinical use of extremely low-frequency electromagnetic fields could represent a novel frontier in tissue repair and oral health, with an interesting clinical perspective. The present study aimed to evaluate the effect of an extremely low-frequency sinusoidal electromagnetic field (SEMF) and an extremely low-frequency pulsed electromagnetic field (PEMF) with flux densities of 1 mT on a model of oral healing process using gingival fibroblasts. An in vitro mechanical injury was produced to evaluate wound healing, migration, viability, metabolism, and the expression of selected cytokines and protease genes in fibroblasts exposed to or not exposed to the SEMF and the PEMF. Interleukin 6 (IL-6), transforming growth factor beta 1 (TGF-ß), metalloproteinase 2 (MMP-2), monocyte chemoattractant protein 1 (MCP-1), inducible nitric oxide synthase (iNOS), and heme oxygenase 1 (HO-1) are involved in wound healing and tissue regeneration, favoring fibroblast proliferation, chemotaxis, and activation. Our results show that the exposure to each type of electromagnetic field increases the early expression of IL-6, TGF-ß, and iNOS, driving a shift from an inflammatory to a proliferative phase of wound repair. Additionally, a later induction of MMP-2, MCP-1, and HO-1 was observed after electromagnetic field exposure, which quickened the wound-healing process. Moreover, electromagnetic field exposure influenced the proliferation, migration, and metabolism of human gingival fibroblasts compared to sham-exposed cells. This study suggests that exposure to SEMF and PEMF could be an interesting new non-invasive treatment option for wound healing. However, additional studies are needed to elucidate the best exposure conditions to provide the desired in vivo treatment efficacy.


Assuntos
Campos Eletromagnéticos , Fibroblastos/metabolismo , Fibroblastos/efeitos da radiação , Gengiva/citologia , Biomarcadores , Proliferação de Células , Citocinas , Expressão Gênica , Humanos , Metaloproteinase 2 da Matriz/genética , Metaloproteinase 2 da Matriz/metabolismo , Óxido Nítrico Sintase Tipo II/genética , Óxido Nítrico Sintase Tipo II/metabolismo , Cicatrização/efeitos da radiação
14.
Int J Nanomedicine ; 14: 2945-2959, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31114201

RESUMO

Background: Gold nanoparticles (AuNPs) have potential applications in the treatment and diagnosis process, which are attributed to their biocompatibility and high efficiency of drug delivery. In the current study, we utilized an extract of Euphrasia officinalis, a traditional folk medicine, to synthesize gold nanoparticles (EO-AuNPs), and investigated their anti-inflammatory effects on lipopolysaccharide (LPS)-stimulated RAW 264.7 macrophages. Materials and methods: The AuNPs were synthesized from an ethanol extract of E. officinalis leaves and characterized using several analytical techniques. Anti-inflammatory activities of EO-AuNPs were detected by a model of LPS-induced upregulation of inflammatory mediators and cytokines including nitric oxide (NO), inducible nitric oxide synthase (iNOS), tumor necrosis factor-α (TNF-α), IL-1ß, and IL-6 in RAW 264.7 cells. The activation of nuclear factor (NF)-κB and Janus kinase/signal transducer and activators of transcription (JAK/STAT) signaling pathways was investigated by Western blot. Results: The results confirmed the successful synthesis of AuNPs by E. officinalis. Transmission electron microscopy images showed obvious uptake of EO-AuNPs and internalization into intracellular membrane-bound compartments, resembling endosomes and lysosomes by RAW 264.7 cells. Cell viability assays showed that EO-AuNPs exhibited little cytotoxicity in RAW 264.7 cells at 100 µg/mL concentration after 24 hours. EO-AuNPs significantly suppressed the LPS-induced release of NO, TNF-α, IL-1ß, and IL-6 as well as the expression of the iNOS gene and protein in RAW 264.7 cells. Further experiments demonstrated that pretreatment with EO-AuNPs significantly reduced the phosphorylation and degradation of inhibitor kappa B-alpha and inhibited the nuclear translocation of NF-κB p65. In addition, EO-AuNPs suppressed LPS-stimulated inflammation by blocking the activation of JAK/STAT pathway. Conclusion: The synthesized EO-AuNPs showed anti-inflammatory activity in LPS-induced RAW 264.7 cells, suggesting they may be potential candidates for treating inflammatory-mediated diseases.


Assuntos
Euphrasia/química , Ouro/química , Química Verde/métodos , Macrófagos/patologia , Nanopartículas Metálicas/química , Extratos Vegetais/farmacologia , Folhas de Planta/química , Transdução de Sinais , Animais , Anti-Inflamatórios/farmacologia , Sobrevivência Celular/efeitos dos fármacos , Citocinas/metabolismo , Inflamação/metabolismo , Inflamação/patologia , Mediadores da Inflamação/metabolismo , Janus Quinases/metabolismo , Lipopolissacarídeos , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Macrófagos/ultraestrutura , Nanopartículas Metálicas/ultraestrutura , Camundongos , NF-kappa B/metabolismo , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase Tipo II/genética , Óxido Nítrico Sintase Tipo II/metabolismo , Células RAW 264.7 , Fatores de Transcrição STAT/metabolismo , Transdução de Sinais/efeitos dos fármacos
15.
Mol Med Rep ; 19(6): 5153-5161, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31059087

RESUMO

Parkinson's disease (PD) is a common progressive neurodegenerative disorder occurring in older individuals. Mechanistically, neuroinflammation is a central pathological change in the progression of PD. Activation of microglia is widely considered to be a major trigger for neuroinflammation. Certain microRNAs (miRs) are key factors in inhibiting or stimulating inflammation during the occurrence and development of PD, among which miR­195 may be a potential crucial biomarker. However, the underlying pathological mechanisms remain unclear. To investigate the pathogenesis of PD, lipopolysaccharide (LPS) was used to establish an in vitro model of microglia activation in the present study. It was revealed that miR­195 expression was decreased in LPS­stimulated BV2 cells, suggesting a potential mechanism of action of miR­195 on microglia activation. Furthermore, gain­ and loss­of­function experiments were performed by successful transfection of microglia with miR­195 mimics or inhibitors. The results demonstrated that miR­195 overexpression inhibited the release of pro­inflammatory cytokines, including inducible nitric oxide synthase, interleukin­6 (IL­6) and tumor necrosis factor­α, but induced the release of anti­inflammatory cytokines in LPS­treated BV2 cells, including IL­4 and IL­10. In addition, Rho­associated kinase 1 (ROCK1), which is negatively regulated by miR­195, was increased in LPS­stimulated BV2 cells. ROCK1 knockdown with small interfering RNA exhibited the same effect as miR­195 overexpression on regulating microglia status, suggesting that the miR­195/ROCK1 interaction serves a central role in inducing microglia activation. Furthermore, inhibition of ROCK1 impaired cell viability and proliferation but induced cell apoptosis in LPS­treated miR­195­deficient BV2 cells. The present results suggest that miR­195 is a potential therapeutic target for PD.


Assuntos
MicroRNAs/metabolismo , Quinases Associadas a rho/metabolismo , Animais , Antagomirs/metabolismo , Apoptose/efeitos dos fármacos , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Inflamação , Interleucina-6/genética , Interleucina-6/metabolismo , Lipopolissacarídeos/farmacologia , Camundongos , MicroRNAs/antagonistas & inibidores , MicroRNAs/genética , Microglia/citologia , Microglia/efeitos dos fármacos , Microglia/metabolismo , Óxido Nítrico Sintase Tipo II/genética , Óxido Nítrico Sintase Tipo II/metabolismo , Doença de Parkinson/metabolismo , Doença de Parkinson/patologia , Interferência de RNA , RNA Interferente Pequeno/metabolismo , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/metabolismo , Quinases Associadas a rho/antagonistas & inibidores , Quinases Associadas a rho/genética
16.
Int J Biol Macromol ; 132: 844-851, 2019 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-30936009

RESUMO

Moringa oleifera is a mutli-purpose herbal plant which has attained enormous attention as a natural source of nutrients and folk medicine. This work aimed to get a novel polysaccharide, termed MRP-1, which was isolated from Moringa oleifera roots with hot water extraction method followed by ethanol precipitation and purified with DEAE-Sepharose Fast Flow column. Monosaccharide composition analysis based on GC-MS showed that MRP-1 mainly consisted of Rha, Ara, Fru, Xyl, Man and Gal in the molar ratio of 1.5:2.0:3.1:6.0:5.3:1.1. The Roman spectra, FT-IR and NMR analysis showed that the typical features of carbohydrates, such as α-Araf, α-Gly, ß-Galp, α-GalpA and ß-Gly was contained by MRP-1. The LPS-induced RAW264.7 macrophage cells were used to evaluate the anti-inflammatory activity of MRP-1. The result demonstrated that the increasing of NO and TNF-α production induced by LPS could be prevented by different concentrations of MRP-1 treatment. Moreover, the mRNA expression level of iNOS induced by LPS was decreased significantly (p < 0.05) by MRP-1 treatment while show no obvious effect on the COX-2 mRNA expression. This study may provide new possible application of Moringa oleifera root polysaccharide related to anti-inflammation.


Assuntos
Anti-Inflamatórios não Esteroides/química , Anti-Inflamatórios não Esteroides/farmacologia , Moringa oleifera/química , Raízes de Plantas/química , Polissacarídeos/química , Polissacarídeos/farmacologia , Animais , Sobrevivência Celular/efeitos dos fármacos , Ciclo-Oxigenase 2/genética , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Macrófagos/citologia , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Camundongos , Monossacarídeos/análise , Óxido Nítrico/biossíntese , Óxido Nítrico Sintase Tipo II/genética , Células RAW 264.7 , Fator de Necrose Tumoral alfa/biossíntese , Fator de Necrose Tumoral alfa/genética
17.
Int J Biol Macromol ; 132: 1024-1030, 2019 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-30959132

RESUMO

ADPs-1a and ADPs-3a were two kinds of pure polysaccharide in Angelica dahurica. The immunomodulatory effects of ADPs-1a and ADPs-3a were assayed on phagocytosis, nitric oxide (NO) and cytokines of RAW264.7 cells, and the mechanism was investigated through NF-κB and MAPKs signaling pathway. RAW264.7 cells were stimulated by different concentrations of ADPs-1a and ADPs-3a with LPS (1 µg/mL) as positive control. The results showed that ADPs-1a and ADPs-3a could significantly enhance the phagocytic activity of RAW264.7 cells, and enhance the ability of RAW264.7 cells to release NO, TNF-α and IL-6 in a concentration-dependent manner. At the same time, ADPs-1a and ADPs-3a could significantly up-regulate the mRNA expression of iNOS, TNF-α, IL-6 and the phosphorylation level of p65, p38, ERK, JNK proteins. The immunomodulatory mechanism of ADPs-1a and ADPs-3a on macrophages was related to the up-regulation of phosphorylation of MAPKs and NF-kB.


Assuntos
Angelica/química , Fatores Imunológicos/farmacologia , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Proteínas Quinases Ativadas por Mitógeno/metabolismo , NF-kappa B/metabolismo , Polissacarídeos/farmacologia , Animais , Sobrevivência Celular/efeitos dos fármacos , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Interleucina-6/genética , Camundongos , Óxido Nítrico/biossíntese , Óxido Nítrico Sintase Tipo II/genética , Fagocitose/efeitos dos fármacos , Células RAW 264.7 , Fator de Transcrição RelA/metabolismo , Fator de Necrose Tumoral alfa/genética
18.
Molecules ; 24(7)2019 Apr 11.
Artigo em Inglês | MEDLINE | ID: mdl-30978947

RESUMO

Mulberry fruit (Morus alba L.) contains abundant bioactive compounds, including anthocyanins and flavonols, and has been reported to possess potent beneficial properties including anticancer, antidiabetic, and anti-oxidant effects. High hydrostatic pressure (HHP) processing, a nonthermal food processing technology, is suitable for the extraction of bioactive compounds from plants. Nevertheless, the anti-inflammatory effects of HHP extract of mulberry fruit (HM) in RAW264.7 cells remain unclear. The present study aimed to investigate the anti-inflammatory effects of HM on lipopolysaccharide (LPS)-induced inflammation in vitro. RAW264.7 cells were treated with various concentrations (0.1-1 µg/mL) of HM in the presence or absence of LPS. HM inhibited the inflammatory mediator, nitric oxide (NO) release, and mRNA expression of nitric oxide synthase 2 (NOS2) in LPS-induced RAW264.7 cells. In addition, HM suppressed both mRNA and protein expressions of prostaglandin-endoperoxide synthase 2 (PTGS2). Moreover, it reduced the LPS-induced secretion of proinflammatory cytokines such as interleukin (IL)-6 and tumor necrosis factor (TNF)-α. These results revealed that HM exerts anti-inflammatory effects by inhibiting several mediators and cytokines involved in the inflammatory process.


Assuntos
Frutas/química , Inflamação/tratamento farmacológico , Lipopolissacarídeos/farmacologia , Morus/química , Animais , Ciclo-Oxigenase 2/genética , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Pressão Hidrostática , Inflamação/patologia , Interleucina-6/genética , Lipopolissacarídeos/química , Camundongos , Óxido Nítrico/genética , Óxido Nítrico Sintase Tipo II/genética , Células RAW 264.7 , RNA Mensageiro/genética , Fator de Necrose Tumoral alfa/genética
19.
J Sci Food Agric ; 99(11): 5112-5121, 2019 Aug 30.
Artigo em Inglês | MEDLINE | ID: mdl-30982967

RESUMO

BACKGROUND: Salmon bones, a waste by-product from the salmon industry, were used as a protein hydrolysate source for the production of bioactive peptides. The aim of this work was to evaluate the potential antioxidant and anti-inflammatory properties of salmon bone protein hydrolysate (SBPH). RESULTS: Salmon bones were hydrolyzed by separately using one of four proteases (Alcalase, Favourzyme, Neutrase and papain) at various concentrations (10, 25 and 50 mg mL-1 ), where the SBPH derived from 10 mg mL-1 papain hydrolysis exhibited the highest nitric oxide (NO) radical scavenging activity. After ultrafiltration, the MW < 0.65 kDa fraction showed the strongest NO inhibitory activity and was further fractionated by gel filtration chromatography (G1 and G2 fractions) and reverse-phase high-performance liquid chromatographic fractionation of the G1 fraction, from which the three main peaks (H1, H2 and H3) were found to have a marked NO-inhibitory activity and their peptide sequences were determined. Moreover, the G1 fraction was shown to inhibit both the lipopolysaccharide (LPS)-induced NO production and the LPS-induced inducible NO synthase , interleukin-6, tumor necrosis factor-α and induced NO production and the LPSCOX-2 mRNA levels in RAW 264.7 cells. CONCLUSIONS: Salmon bones from the salmon fisheries and farming industry were utilized by enzymatic hydrolysis for the production of valuable peptides. The results of this study suggested that bioactive peptides derived from salmon bones would be alternative anti-inflammation materials in functional resources. © 2019 Society of Chemical Industry.


Assuntos
Anti-Inflamatórios/farmacologia , Osso e Ossos/química , Proteínas de Peixes/química , Depuradores de Radicais Livres/farmacologia , Hidrolisados de Proteína/farmacologia , Salmão , Animais , Anti-Inflamatórios/química , Anti-Inflamatórios/isolamento & purificação , Biocatálise , Cromatografia em Gel , Cromatografia Líquida de Alta Pressão , Depuradores de Radicais Livres/química , Depuradores de Radicais Livres/isolamento & purificação , Hidrólise , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Camundongos , Óxido Nítrico/imunologia , Óxido Nítrico Sintase Tipo II/genética , Óxido Nítrico Sintase Tipo II/imunologia , Peptídeo Hidrolases/química , Peptídeos/química , Peptídeos/isolamento & purificação , Peptídeos/farmacologia , Hidrolisados de Proteína/química , Células RAW 264.7
20.
Eur J Pharmacol ; 852: 207-217, 2019 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-30930248

RESUMO

Bovine endometritis is the most common uterine disease following parturition. The role of prostaglandin E2 (PGE2) in regulating normal physiological function in the bovine endometrium has been clearly established. Although PGE2 accumulation is observed in multiple inflammatory diseases, such as endometritis, its association with pathogen-induced inflammatory damage in the endometrium is unclear. To clarify the role of PGE2 in lipopolysaccharide (LPS)-induced endometritis in cultured bovine endometrial explants, the levels of PGE2 secretion, prostaglandin synthetases, pro-inflammatory factors, and damage-associated molecular patterns (DAMPs) were evaluated in the present study. Significant PGE2 accumulation in response to LPS stimulation, up-regulation of prostaglandin-endoperoxide synthase-2 (PTGS-2), microsomal prostaglandin E synthase-1 (mPGES-1), pro-inflammatory factors including interleukin-6 (IL-6), tumor necrosis factor (TNF-α), and induced nitric oxide synthase (iNOS)/nitric oxide (NO) and DAMPs including hyaluronan binding protein 1 (HABP1) and high mobility group box-1 (HMGB1), were observed compared to the control group. LPS induced distinct damage in the bovine endometrium, characterized by morphological changes and increases in HABP1 and HMGB1 expression. PTGS-2 inhibitors CAY10404 and NS398 effectively decreased the secretion of PGE2 and the expression of prostaglandin synthetases, pro-inflammatory factors and DAMPs, and alleviated LPS-induced tissue damage. These results indicate that PGE2 accumulates via PTGS-2 and mPGES-1 and induces tissue damage by upregulating pro-inflammatory factors and DAMPs in LPS-treated bovine endometrial explants. These findings provide a basis for the effect of PGE2 on LPS-treated bovine endometrium, and suggest a potential target for curing endometritis.


Assuntos
Dinoprostona/metabolismo , Endométrio/efeitos dos fármacos , Endométrio/patologia , Lipopolissacarídeos/farmacologia , Animais , Bovinos , Ciclo-Oxigenase 2/genética , Endométrio/metabolismo , Feminino , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Proteína HMGB1/metabolismo , Interleucina-6/genética , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase Tipo II/genética , Prostaglandina-E Sintases/genética , Fator de Necrose Tumoral alfa/genética
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