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1.
Chem Pharm Bull (Tokyo) ; 68(1): 46-57, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31902901

RESUMO

Over the past decade, a number of new 1,4-naphthoquinones have been isolated from natural sources and new 1,4-naphthoquinones with diverse structural features have been synthesized. Cardioprotective, anti-ischemic, hepatoprotective, neuroprotective and some other new properties were found for these compounds; their role in protecting against neurodegenerative diseases has been established. Their anti-inflammatory, antimicrobial and antitumor activities have been studied in more detail; new, previously unknown intracellular molecular targets and mechanisms of action have been discovered. Some compounds of this class are already being used as a medicinal drugs and some substances can be used as biochemical tools and probes for non-invasive detection of pathological areas in cells and tissues in myocardial infarction and neurodegenerative diseases using modern molecular imaging techniques.


Assuntos
Anti-Infecciosos/química , Anti-Inflamatórios/química , Naftoquinonas/química , Substâncias Protetoras/química , Anti-Infecciosos/farmacologia , Anti-Inflamatórios/farmacologia , Bactérias/efeitos dos fármacos , Citocinas/metabolismo , Humanos , Leucócitos Mononucleares/citologia , Leucócitos Mononucleares/efeitos dos fármacos , Leucócitos Mononucleares/metabolismo , Naftoquinonas/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Substâncias Protetoras/farmacologia , Trypanosoma/efeitos dos fármacos
2.
Zhongguo Zhong Yao Za Zhi ; 44(16): 3520-3525, 2019 Aug.
Artigo em Chinês | MEDLINE | ID: mdl-31602917

RESUMO

The effect of triptolide( TP) on VEGFA,SDF-1,CXCR4 pathway were investigated in vitro to explore the mechanism in improving platelet activation in patients with ankylosing spondylitis( AS). Peripheral blood mononuclear cells( PBMC) were used for the experiment and divided into 4 groups: normal group( NC),model group( MC),triptolide group( TP),and AMD3100 group. The optimal concentration of TP was measured by the MTT method. The expressions of TNF-α,IL-1ß,IL-4,IL-10,VEGFA and VEGFR were detected by ELISA. The expressions of SDF-1,CXCR4 and VEGFA were detected by real-time quantitative PCR( RT-qPCR).The expressions of SDF-1,CXCR4,VEGFA and VEGFR were detected by Western blot. The expression levels of CD62 p,CD40 L and PDGFA were detected by immunofluorescence. MTT results showed that medium-dose TP had the strongest inhibitory effect on cells at24 h. The results of ELISA and PCR showed that TP inhibited mRNA expressions of IL-1ß,TNF-α,VEGFA,VEGFR and SDF-1,CXCR4 and VEGFA. The results of Western blot indicated that TP inhibited SDF-1,CXCR4 and VEGFA,VEGFR protein expressions; immunofluorescence results indicate that TP can inhibit the expressions of CD62 p,CD40 L,PDGFA. TP may regulate platelet activation by down-regulating SDF-1,CXCR4,VEGFA and VEGFR mRNA expressions,thereby down-regulating IL-1ß and TNF-αexpressions,and up-regulating the expressions of IL-4 and IL-10 cytokines.


Assuntos
Diterpenos/farmacologia , Leucócitos Mononucleares/efeitos dos fármacos , Fenantrenos/farmacologia , Ativação Plaquetária , Espondilite Anquilosante , Células Cultivadas , Quimiocina CXCL12/metabolismo , Citocinas/metabolismo , Compostos de Epóxi/farmacologia , Compostos Heterocíclicos/farmacologia , Humanos , Receptores CXCR4/metabolismo , Fator A de Crescimento do Endotélio Vascular/metabolismo
3.
Anticancer Res ; 39(9): 4687-4698, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31519568

RESUMO

BACKGROUND/AIM: Propagermanium (PG) inhibits the CCL2/CCR2 axis, and has been shown to function as an immune modulator. This study investigated its anti-tumor mechanism in patients with refractory cancers. MATERIALS AND METHODS: Five healthy volunteers and 23 patients with refractory oral (n=8) or gastric (n=15) cancer received PG (30 mg/day). We performed flow cytometry (FCM) of peripheral blood mononuclear cells and in vitro killing assays. RESULTS: FCM revealed that CD16+/CD56Dim NK cells (i.e., mature, cytolytic subset) increased, and the apoptosis induction rate of cancer cells increased after PG administration. Among gastric cancer patients, median OS was 172.0 days. Two patients showed complete remission of lung or liver metastasis. Survival of patients with oral cancer also tended to be prolonged. CONCLUSION: PG induces NK cell maturation, and may potentiate anti-tumor activity.


Assuntos
Antineoplásicos/farmacologia , Diferenciação Celular/efeitos dos fármacos , Diferenciação Celular/imunologia , Células Matadoras Naturais/efeitos dos fármacos , Células Matadoras Naturais/imunologia , Neoplasias/imunologia , Neoplasias/mortalidade , Compostos Organometálicos/farmacologia , Linhagem Celular Tumoral , Resistencia a Medicamentos Antineoplásicos , Humanos , Estimativa de Kaplan-Meier , Leucócitos Mononucleares/efeitos dos fármacos , Leucócitos Mononucleares/imunologia , Leucócitos Mononucleares/metabolismo , Subpopulações de Linfócitos/imunologia , Subpopulações de Linfócitos/metabolismo , Neoplasias/diagnóstico , Neoplasias/tratamento farmacológico , Tomografia Computadorizada por Raios X
4.
Braz Oral Res ; 33: e040, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31508724

RESUMO

The study characterizes dental implant surfaces treated with phosphoric acid to assess the effects of acid treatment on blood cells and correlate them with cytokine levels. The implant surfaces examined were divided into untreated metal surface (US; n = 50), metal surface treated with phosphoric acid (ATS; n = 50) and cement surface (CS; n = 50) groups. The samples were characterized by scanning electron microscopy (SEM) and rheometry. The implants were incubated with human blood mononuclear cells for 24 h, with surface rinsing in the ATS treatment. Cell viability was determined by colorimetric methods and cytokines in the culture supernatant were quantified using flow cytometry. In the ATS group, the surface porosity and contact surface were increased and plaques were observed on the surface. The blood flow and viscosity curves were similar among the treatments, and the high cell viability rates indicate the biocompatibility of the materials used. An increase in the levels of IL-2, IL-4, IL-6, IL-10 and TNF-α was observed in the ATS and CS groups. There were positive correlations between IL-10 and IL-2 levels and between IL-10 and IL-4 levels in the culture supernatant of the ATS group. The results suggest that implant surface treatment with phosphoric acid activates the production of inflammatory cytokines. The increased cytokine levels can modulate the immune response, thereby improving biofunctional processes and promoting the success of dental implants.


Assuntos
Citocinas/análise , Implantes Dentários , Materiais Dentários/farmacologia , Leucócitos Mononucleares/efeitos dos fármacos , Ácidos Fosfóricos/farmacologia , Anti-Inflamatórios , Sobrevivência Celular , Citocinas/metabolismo , Cimentos Dentários , Humanos , Interleucina-10/análise , Interleucina-10/metabolismo , Microscopia Eletrônica de Varredura , Reologia , Propriedades de Superfície
5.
Fitoterapia ; 138: 104297, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31404617

RESUMO

As a part of an ongoing bioprospective project, searching for potential medicinal plants from the Brazilian Atlantic Forest, Miconia willdenowii was selected for its potential leishmanicidal and antimicrobial activities. The crude ethanolic extract of M. willdenowii showed an inhibition of 99.7% of the promastigote forms of Leishmania amazonensis at the concentration of 80 µg/mL. Further investigation of its antimicrobial activity against pathogenic fungi and Gram positive and negative bacteria, revealed a significant antimicrobial activity. A bioguided study with its liquid-liquid partition fractions revealed the hexane fraction (Hex) as the most active against Leishmania, inhibiting 99.2% and 46.9% of the protozoan at concentrations of 40 and 20 µg/mL, respectively. Hex also showed significant antimicrobial activity against Staphylococcus aureus and Candida krusei with IC50 of 15.6 and 62.5 µg/mL, respectively. Purification of Hex led to the isolation of 2-methoxy-6-pentyl-benzoquinone (1, also known as primin) as the active metabolite, probably responsible for the observed antimicrobial and anti-leishmania effects. Primin (1) disclosed leishmanicidal activity (IC50 = 1.25 µM), showing higher potency than the standard drug amphotericin B (IC50 = 5.08 µM), with additional antifungal effects against all tested fungi species. Compound 1 also showed significant activity against S. aureus (IC50 = 8.94 µM), showing a comparable potency with the reference drug chloramphenicol (IC50 = 6.19 µM), but with a potential cytotoxicity towards peripheral human blood mononuclear cells (CC50 = 255.15 µM). Here in, the antimicrobial and anti-L. amazonensis effects of M. willdenowii are reported for the first time, as well as Primin (1) as its probable bioactive metabolite.


Assuntos
Antibacterianos/farmacologia , Antiprotozoários/farmacologia , Benzoquinonas/farmacologia , Melastomataceae/química , Extratos Vegetais/farmacologia , Antibacterianos/isolamento & purificação , Antiprotozoários/isolamento & purificação , Benzoquinonas/isolamento & purificação , Brasil , Humanos , Leishmania/efeitos dos fármacos , Leucócitos Mononucleares/efeitos dos fármacos , Folhas de Planta/química , Plantas Medicinais/química , Staphylococcus aureus/efeitos dos fármacos
6.
BMC Complement Altern Med ; 19(1): 168, 2019 Jul 10.
Artigo em Inglês | MEDLINE | ID: mdl-31291937

RESUMO

BACKGROUND: Several immunological pathways, particularly skin inflammation via various pro-inflammatory cytokines have been reported to be involved in the pathogenesis and clinical manifestations of psoriasis. The aim of the study was to investigate the potential role of naringin from Citrus maxima (Burm.) Merr and sericin from Bombyx mori combination in the treatment of psoriasis. Inhibitory effects on the expression of mRNA and the production of pro-inflammatory cytokines (TNF-α, IL-6, IL-23, and IL-12p40) were investigated. METHODS: Human peripheral blood mononuclear cells (hPBMCs) were isolated from 10 healthy subjects and 10 patients with psoriasis. The hPBMCs from each group were exposed to naringin or sericin alone, and the combination of naringin and sericin. The expression levels of mRNA and the production of all cytokines were determined using quantitative RT-PCR and ELISA, respectively. RESULTS: Naringin/sericin combination significantly decreased the expression of mRNA and the production of all pro-inflammatory cytokines in hPBMCs from patients with psoriasis. The potency of inhibitory activity was markedly higher than naringin or sericin alone. CONCLUSION: The activity of naringin/sericin combination on down-regulation of these pro-inflammatory cytokines suggested its potential clinical use in psoriasis as well as other inflammation-associated diseases. The combination might be used as a complementary therapy with conventional treatment in psoriasis to improve clinical efficacy and tolerability.


Assuntos
Citrus/química , Flavanonas/farmacologia , Leucócitos Mononucleares/efeitos dos fármacos , Extratos Vegetais/farmacologia , Psoríase/tratamento farmacológico , Sericinas/farmacologia , Adulto , Anti-Inflamatórios/farmacologia , Citocinas/biossíntese , Citocinas/genética , Quimioterapia Combinada , Feminino , Flavanonas/uso terapêutico , Humanos , Técnicas In Vitro , Mediadores da Inflamação/metabolismo , Masculino , Pessoa de Meia-Idade , Extratos Vegetais/uso terapêutico , Sericinas/uso terapêutico , Adulto Jovem
7.
Am J Vet Res ; 80(7): 663-669, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31246122

RESUMO

OBJECTIVE: To evaluate effects of poly(ADP-ribose) polymerase-1 (PARP1) inhibitors on the production of tumor necrosis factor-α (TNF-α) by interferon-γ (IFN-γ)- and lipopolysaccharide (LPS)-stimulated peripheral blood mononuclear cells (PBMCs) of horses as an in vitro model of inflammation in horses. SAMPLE: 1,440 samples of PBMCs from 6 healthy research horses. PROCEDURES: From heparinized whole blood samples, PBMC cultures were obtained. An initial dose-response trial on 48 PBMC samples from 2 horses (24 samples each) was used to determine concentrations of IFN-γ and LPS for use as low- and high-level stimulation concentrations. Seventy-two PBMC samples from 6 horses were assigned equally to 1 of 4 PARP1 inhibition categories: no PARP1 inhibitor (PARP1 inhibition control); 2-((R)-2-methylpyrrolidin-2-yl)-1H-benzimidazole-4-carbozamide dihydrochloride (ABT888);4-(3-(1-(cyclopropanecarbonyl)piperazine-4-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one (AZD2281); or N-(6-oxo-5,6-dihydrophenanthridin-2-yl) -N,N-dimethylacetamide hydrochloride (PJ34). Samples of PBMCs from each horse and each PARP1 inhibition category were then assigned to 1 of 3 levels of IFN-γ and LPS stimulation: none (control), low stimulation, or high stimulation. After a 24-hour incubation period, a TNF-α ELISA was used to measure TNF-α concentration in the supernatant. Results were compared across treatments and for each horse. Data were analyzed with repeated-measures ANOVA. RESULTS: Median TNF-α concentration was significantly lower for PJ34-treated, high-level stimulated PBMCs than for PARP1 inhibition control, high-level stimulated PBMCs; however, no other meaningful differences in TNF-α concentration were detected among the inhibition and stimulation combinations. CONCLUSIONS AND CLINICAL RELEVANCE: Findings suggested that PJ34 PARP1 inhibition may reduce TNF-α production in horses, a potential benefit in reducing inflammation and endotoxin-induced damage in horses.


Assuntos
Cavalos/sangue , Interferon gama/metabolismo , Leucócitos Mononucleares/efeitos dos fármacos , Inibidores de Poli(ADP-Ribose) Polimerases/farmacologia , Poli(ADP-Ribose) Polimerases/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Animais , Modelos Animais de Doenças , Doenças dos Cavalos/fisiopatologia , Técnicas In Vitro , Inflamação/fisiopatologia , Leucócitos Mononucleares/enzimologia , Lipopolissacarídeos/farmacologia
8.
J Appl Oral Sci ; 27: e20180529, 2019 Jun 03.
Artigo em Inglês | MEDLINE | ID: mdl-31166413

RESUMO

OBJECTIVES: Dental composites release unreacted resin monomers into the oral environment, even after polymerization. Periodontal cells are, therefore, exposed to substances that potentially elicit the immune inflammatory response. The underlying molecular mechanisms associated with the interaction between resin monomers and human immune cells found in the gingival crevicular fluid are not fully understood yet. This study investigated the ability of bisphenol A-glycidyl methacrylate (BISGMA), urethane dimethacrylate (UDMA) and triethylene glycol dimethacrylate (TEGDMA) to induce apoptosis and cytokine release by human leukocytes stimulated with a periodontal pathogen. METHODOLOGY: Peripheral blood mononuclear cells (PBMC) from 16 healthy individuals were included in this study. To determine the toxicity, the PBMC were incubated for 20 hours, with monomers, for the analysis of cell viability using MTT assay. To evaluate cell death in the populations of monocytes and lymphocytes, they were exposed to sub-lethal doses of each monomer and of heat-inactivated Porphyromonas gingivalis (P. gingivalis) for 5 hours. Secretions of IL-1ß, IL-6, IL-10 and TNF-α were determined by ELISA after 20 hours. RESULTS: UDMA and TEGDMA induced apoptosis after a short-time exposure. Bacterial challenge induced significant production of IL-1ß and TNF-α (p<0.05). TEGDMA reduced the bacterial-induced release of IL-1ß and TNF-α, whereas UDMA reduced IL-1ß release (p<0.05). These monomers did not affect IL-10 and IL-6 secretion. BISGMA did not significantly interfere in cytokine release. CONCLUSIONS: These results show that resin monomers are toxic to PBMC in a dose-dependent manner, and may influence the local immune inflammatory response and tissue damage mechanisms via regulation of bacterial-induced IL-1ß and TNF-α secretion by PBMC.


Assuntos
Bis-Fenol A-Glicidil Metacrilato/farmacologia , Citocinas/metabolismo , Leucócitos Mononucleares/efeitos dos fármacos , Metacrilatos/farmacologia , Polietilenoglicóis/farmacologia , Ácidos Polimetacrílicos/farmacologia , Poliuretanos/farmacologia , Porphyromonas gingivalis/fisiologia , Análise de Variância , Apoptose/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Citocinas/análise , Citocinas/efeitos dos fármacos , Ensaio de Imunoadsorção Enzimática , Humanos , Leucócitos Mononucleares/metabolismo , Necrose , Valores de Referência , Reprodutibilidade dos Testes , Estatísticas não Paramétricas , Fatores de Tempo
9.
Chin J Nat Med ; 17(4): 252-263, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31076129

RESUMO

Astragalus membranaceus may be a potential therapy for childhood asthma but its driving mechanism remains elusive. The main components of A. membranaceus were identified by HPLC. The children with asthma remission were divided into two combination group (control group, the combination of budesonide and terbutaline) and A. membranaceus group (treatment group, the combination of budesonide, terbutaline and A. membranaceus). The therapeutic results were compared between two groups after 3-month therapy. Porcine peripheral blood mononuclear cells (PBMCs) were isolated from venous blood by using density gradient centrifugation on percoll. The levels of FoxP3, EGF-ß, IL-17 and IL-23 from PBMCs and serum IgE were measured. The relative percentage of Treg/Th17 cells was determined using flow cytometry. The main components of A. membranaceus were calycosin-7-O-glucoside, isoquercitrin, ononin, calycosin, quercetin, genistein, kaempferol, isorhamnetin and formononetin, all of which may contribute to asthma therapy. Lung function was significantly improved in the treatment group when compared with a control group (P < 0.05). The efficacy in preventing the occurrence of childhood asthma was higher in the treatment group than the control group (P < 0.05). The levels of IgE, IL-17 and IL-23 were reduced significantly in the treatment group when compared with the control group, while the levels of FoxP3 and TGF-ß were increased in the treatment group when compared with the control group (P < 0.05). A. membranaceus increased the percentage of Treg cells and reduced the percentage of Th17 cells. A. membranaceus is potential natural product for improving the therapeutic efficacy of combination therapy of budesonide and terbutaline for the children with asthma remission by modulating the balance of Treg/Th17 cells.


Assuntos
Asma/tratamento farmacológico , Astragalus propinquus/química , Medicamentos de Ervas Chinesas/administração & dosagem , Medicamentos de Ervas Chinesas/farmacologia , Fatores Imunológicos/administração & dosagem , Linfócitos T Reguladores/efeitos dos fármacos , Células Th17/efeitos dos fármacos , Animais , Asma/imunologia , Budesonida/administração & dosagem , Células Cultivadas , Criança , Pré-Escolar , Citocinas/metabolismo , Feminino , Humanos , Fatores Imunológicos/farmacologia , Leucócitos Mononucleares/efeitos dos fármacos , Leucócitos Mononucleares/metabolismo , Pulmão/efeitos dos fármacos , Pulmão/fisiologia , Masculino , Suínos , Linfócitos T Reguladores/citologia , Terbutalina/administração & dosagem , Células Th17/citologia , Resultado do Tratamento
10.
Int J Mol Sci ; 20(10)2019 May 16.
Artigo em Inglês | MEDLINE | ID: mdl-31100865

RESUMO

Adult metabolic syndrome is considered to be elicited by the developmental programming which is regulated by the prenatal environment. The maternal excess intake of fructose, a wildly used food additive, is found to be associated with developmental programing-associated cardiovascular diseases. To investigate the effect of maternal fructose exposure (MFE) on endothelial function and repair, which participate in the initiation and progress of cardiovascular disease, we applied a rat model with maternal fructose excess intake during gestational and lactational stage and examined the number and function of endothelial progenitor cells (EPCs) in 3-month-old male offspring with induction of critical limb ischemia (CLI). Results showed that the circulating levels of c-Kit+/CD31+ and Sca-1+/KDR+ EPC were reduced by MFE. In vitro angiogenesis analysis indicated the angiogenic activity of bone marrow-derived EPC, including tube formation and cellular migration, was reduced by MFE. Western blots further indicated the phosphorylated levels of ERK1/2, p38-MAPK, and JNK in circulating peripheral blood mononuclear cells were up-regulated by MFE. Fourteen days after CLI, the reduced blood flow recovery, lowered capillary density, and increased fibrotic area in quadriceps were observed in offspring with MFE. Moreover, the aortic endothelium-mediated vasorelaxant response in offspring was impaired by MFE. In conclusion, maternal fructose intake during gestational and lactational stage modulates the number and angiogenic activity of EPCs and results in poor blood flow recovery after ischemic injury.


Assuntos
Células Progenitoras Endoteliais/metabolismo , Frutose/metabolismo , Frutose/farmacologia , Isquemia/metabolismo , Neovascularização Fisiológica/efeitos dos fármacos , Fluxo Sanguíneo Regional , Animais , Ataxina-1 , Medula Óssea/metabolismo , Doenças Cardiovasculares , Movimento Celular , Modelos Animais de Doenças , Extremidades/patologia , Isquemia/patologia , Leucócitos Mononucleares/efeitos dos fármacos , Leucócitos Mononucleares/metabolismo , Sistema de Sinalização das MAP Quinases , Masculino , Quinases de Proteína Quinase Ativadas por Mitógeno/metabolismo , Molécula-1 de Adesão Celular Endotelial a Plaquetas , Proteínas Proto-Oncogênicas c-kit , Ratos , Receptor 2 de Fatores de Crescimento do Endotélio Vascular
11.
Int J Nanomedicine ; 14: 2371-2381, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31040662

RESUMO

Purpose: HIV-1 and herpes simplex virus type-2 (HSV-2) represent two of the most relevant sexually transmitted diseases (STDs) worldwide. Moreover, each year there are >200 million pregnancies worldwide, and more than half are unintended. Continued high rates of unintended pregnancies and spread of HIV-1 and HSV-2 require new approaches to address these problems. G1-S4 and G2-S16 dendrimers emerge as potential candidates for the development of a topical microbicide due to their safety and effectivity against HIV-1 and HSV-2 infection, both in vitro and in vivo. Our goal is to develop a dual topical microbicide to prevent the transmission of STDs and unintended pregnancies. Platycodin D (PD) was selected for its great spermicidal activity, topical application, and biocompatibility. Materials and methods: Toxicology and inhibitory profile of G1-S4/PD and G2-S16/PD were evaluated in vitro and in vivo. Spermicidal activity was assessed by a computer-assisted sperm analysis system (CASA). Results: G1-S4/PD and G2-S16/PD presented >95% of HIV-1 inhibition in TZM-bl cells and peripheral blood mononuclear cells. CASA assessment determined that 0.25 mM of PD with therapeutic concentrations of G1-S4 or G2-S16 was able to induce 100% immobilization of the sperm in 30 seconds. To evaluate the toxicity in vivo, a vaginal toxicity assay was performed in BALB/c mice. No significant changes or damage to the vaginal epithelium after 7 consecutive days of application were observed. Conclusion: Our data indicate that G1-S4/PD and G2-S16/PD combinations are promising candidates to be developed for vaginal microbicides with contraceptive activity.


Assuntos
Anti-Infecciosos/farmacologia , Anticoncepcionais/farmacologia , Dendrímeros/farmacologia , Saponinas/farmacologia , Silanos/farmacologia , Triterpenos/farmacologia , Vagina/microbiologia , Animais , Proliferação de Células/efeitos dos fármacos , Feminino , Herpesvirus Humano 2/efeitos dos fármacos , Humanos , Leucócitos Mononucleares/efeitos dos fármacos , Masculino , Camundongos Endogâmicos BALB C , Capacitação Espermática/efeitos dos fármacos , Espermatozoides/efeitos dos fármacos , Testes de Toxicidade , Vagina/efeitos dos fármacos , Células Vero
12.
Mediators Inflamm ; 2019: 6217548, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30944547

RESUMO

Liver X receptors (LXRs) have emerged as important regulators of inflammatory gene expression. Previously, we had reported that an LXRα gene promoter polymorphism (-1830 T > C) is associated with systemic lupus erythematosus (SLE). Therefore, we assessed cytokine expression in relation to LXRα polymorphism in monocyte-derived macrophages from patients with SLE. Macrophages were obtained after 72 hours of culture of human monocytes supplemented with phorbol 12-myristate 13-acetate. Cells were transfected with LXRα promoter constructs. Additionally, peripheral blood mononuclear cell- (PBMC-) derived macrophages from the patients were evaluated for proinflammatory cytokines in relation to the genotypes of LXRα -1830 T > C. The expression of LXRα was increased in macrophages; levels of proinflammatory cytokines were decreased with LXRα expression. Production of proinflammatory cytokines varied depending on LXRα -1830 T > C genotype. In particular, expression of LXRα was decreased and that of proinflammatory cytokines was increased for LXRα -1830 TC genotype compared to that for TT genotype. The data were consistent in PBMC-derived macrophages from patients with SLE. Increased proinflammatory cytokines is related to TLR7 and TLR9 expression. These data suggest that the expression levels of LXRα, according to LXRα -1830 T > C genotype, may contribute to the inflammatory response by induction of inflammatory cytokines in SLE.


Assuntos
Leucócitos Mononucleares/metabolismo , Receptores X do Fígado/genética , Receptores X do Fígado/metabolismo , Macrófagos/metabolismo , Benzoatos/farmacologia , Benzilaminas/farmacologia , Diferenciação Celular/efeitos dos fármacos , Diferenciação Celular/genética , Linhagem Celular Tumoral , Citocinas/metabolismo , Genótipo , Humanos , Hidrocarbonetos Fluorados/farmacologia , Immunoblotting , Leucócitos Mononucleares/efeitos dos fármacos , Receptores X do Fígado/agonistas , Macrófagos/efeitos dos fármacos , Reação em Cadeia da Polimerase em Tempo Real , Sulfonamidas/farmacologia , Receptor 7 Toll-Like/genética , Receptor 7 Toll-Like/metabolismo , Receptor Toll-Like 9/genética , Receptor Toll-Like 9/metabolismo
13.
Int Immunopharmacol ; 72: 1-11, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30953868

RESUMO

BACKGROUND: Autism spectrum disorder (ASD) is a neurodevelopmental disorder defined by Diagnosis and Statistic Manual 5 (DSM-5) as persistent social interaction and communication deficient across multiple contexts. Various immunological findings have been reported in children with ASD, and co-existing allergic problems have been recorded in children diagnosed with ASD. Osthole, the effective component of Chinese traditional medicine, is reported to have anti-inflammatory effects. This study assessed the anti-inflammatory effect of osthole on the histamine-induced inflammatory responses in PBMC cells. METHODS: Peripheral blood mononuclear cells (PBMC's) from children with: (1) ASD group with co-existing allergies/asthma (n = 29); (2) ASD group without allergy/asthma (n = 29); (3) Allergy group (n = 30) and from typically developing age-matched control subjects (n = 28) were stimulated with either histamine, FXF, osthole or mixture of this substances. mRNA COX-2 gene expression, COX-2 production and inhibitory effect of tested substances on COX-2 were assessed after stimulation. RESULTS: Children with ASD may show either an innate proinflammatory response or increased activity of COX-2 which could display more impaired behavioral profile than children with non-inflamed. This study indicated that COX-2 may be involved in pathogenesis of ASD and/or allergy, and osthole could be used to decrease the effects of COX-2 in inflammation and ASD development. High incidence of allergy in ASD patients may indicate immune dysregulation that could be of relevance to the pathophysiology, symptomatology or neuroimmunology of ASD. CONCLUSIONS: This study shows that fexofenadine (FXF - antihistamine drug) and osthole exhibit selective COX-2 enzyme inhibitory activity. The selective COX-2 activity of osthole may explain further the anti-inflammatory properties of osthole in relieving congestion in allergic rhinitis, and as distinctive effects between FXF and osthole were observed, individual antihistamines may have different modes of action via the COX enzyme system.


Assuntos
Anti-Inflamatórios/farmacologia , Transtorno do Espectro Autista/imunologia , Cumarínicos/farmacologia , Hipersensibilidade/imunologia , Leucócitos Mononucleares/efeitos dos fármacos , Transtorno do Espectro Autista/genética , Transtorno do Espectro Autista/metabolismo , Criança , Pré-Escolar , Ciclo-Oxigenase 2/genética , Ciclo-Oxigenase 2/metabolismo , Feminino , Histamina/imunologia , Antagonistas dos Receptores Histamínicos/farmacologia , Humanos , Hipersensibilidade/genética , Hipersensibilidade/metabolismo , Lactente , Leucócitos Mononucleares/imunologia , Masculino , Terfenadina/análogos & derivados , Terfenadina/farmacologia
14.
BioDrugs ; 33(3): 321-333, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30972630

RESUMO

BACKGROUND: ABP 980 has been developed as a biosimilar to Herceptin® (trastuzumab). Comprehensive analytical characterization incorporating orthogonal analytical techniques was used to compare ABP 980 to trastuzumab reference products sourced from the United States (US) and the European Union (EU). METHODS: Physicochemical property comparisons included the following: primary structure related to amino acid sequence and post-translational modifications, including glycans; higher-order structure; product-related substances and impurities, including size and charge variants; subvisible and submicron particles, and protein content. In addition, functional similarity was assessed for Fab-mediated, Fc-mediated, and combined Fab- and Fc-mediated activities. RESULTS: ABP 980 has the same amino acid sequence as and similar post-translational modification profiles to trastuzumab (US) and trastuzumab (EU). Importantly, ABP 980 was found to be highly similar to trastuzumab for all functional activities related to the mechanism(s) of action. Higher-order structure, product-related substances and impurities, particles and aggregates were also highly similar between ABP 980 and trastuzumab. Where minor differences were noted, they were evaluated and found unlikely to impact clinical performance. The totality of evidence, including the pharmacokinetic clinical similarity of ABP 980, further supports that ABP 980 is highly similar to trastuzumab. CONCLUSION: Based on the comprehensive analytical similarity assessment, ABP 980 is analytically highly similar to the reference product, trastuzumab.


Assuntos
Medicamentos Biossimilares/química , Medicamentos Biossimilares/farmacologia , Trastuzumab/química , Trastuzumab/farmacologia , Sequência de Aminoácidos , Linhagem Celular , Europa (Continente) , Humanos , Leucócitos Mononucleares/efeitos dos fármacos , Processamento de Proteína Pós-Traducional/efeitos dos fármacos , Estados Unidos
15.
Carbohydr Polym ; 215: 160-169, 2019 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-30981341

RESUMO

Inulin has interesting physicochemical and functional properties, and therefore a wide range of applications in the food and medical industries. It has gained great traction due to its ability to form nanoparticles and its possible application as nanovehicle for drug delivery. In this work, we demonstrated that the enzymatically-synthesized high molecular weight (HMW) inulin forms stable spherical nanoparticles with an average diameter of 112 ± 5 nm. The self-assemblage of HMW inulin nanoparticles is carried out during enzymatic synthesis of the polymer, and become detectable after a certain critical aggregation concentration (CAC) is reached. Both, the CAC and nanoparticle size are influenced by the reaction temperature. These nanoparticles are not toxic for peripheral blood mononuclear cells, at concentrations below 200 µg/mL; no significant prebiotic potential was detected in cultures of 13 probiotic strains. This work contributes to a better understanding of the formation of HMW inulin nanoparticles and their biological properties.


Assuntos
Portadores de Fármacos/síntese química , Portadores de Fármacos/toxicidade , Hexosiltransferases/química , Inulina/síntese química , Inulina/toxicidade , Leuconostoc/enzimologia , Nanopartículas/química , Nanopartículas/toxicidade , Portadores de Fármacos/química , Liberação Controlada de Fármacos , Feminino , Humanos , Inulina/química , Leucócitos Mononucleares/efeitos dos fármacos , Peso Molecular , Prebióticos , Probióticos
16.
Molecules ; 24(8)2019 Apr 19.
Artigo em Inglês | MEDLINE | ID: mdl-31010141

RESUMO

The incidence of inflammatory bowel disease (IBD) increases gradually in Western countries with high need for novel therapeutic interventions. Mannich curcuminoids, C142 or C150 synthetized in our laboratory, have been tested for anti-inflammatory activity in a rat model of TNBS (2,4,6-trinitrobenzenesulphonic acid) induced colitis. Treatment with C142 or C150 reduced leukocyte infiltration to the submucosa and muscular propria of the inflamed gut. C142 or C150 rescued the loss of body weight and C150 decreased the weight of standard colon preparations proportional with 20% less tissue oedema. Both C142 and C150 curcumin analogues caused 25% decrease in the severity of colonic inflammation and haemorrhagic lesion size. Colonic MPO (myeloperoxidase) enzyme activity as an indicator of intense neutrophil infiltration was 50% decreased either by C142 or C150 Mannich curcuminoids. Lipopolysaccharide (LPS) co-treatment with Mannich curcuminoids inhibited NF-κB (nuclear factor kappa B) activity on a concentration-dependent manner in an NF-κB-driven luciferase expressing reporter cell line. Co-treatment with LPS and curcuminoids, C142 or C150, resulted in NF-κB inhibition with 3.57 µM or 1.6 µM half maximal effective concentration (EC50) values, respectively. C150 exerted a profound inhibition of the expression of inflammatory cytokines, tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and interleukin-4 (IL-4) in human PBMCs (peripheral blood mononuclear cells) upon LPS stimulus. Mannich curcuminoids reported herein possess a powerful anti-inflammatory activity.


Assuntos
Anti-Inflamatórios/uso terapêutico , Colite/tratamento farmacológico , Colite/metabolismo , Curcumina/uso terapêutico , Doenças Inflamatórias Intestinais/tratamento farmacológico , Doenças Inflamatórias Intestinais/metabolismo , Animais , Curcumina/análogos & derivados , Humanos , Interleucina-4/metabolismo , Interleucina-6/metabolismo , Leucócitos Mononucleares/efeitos dos fármacos , Leucócitos Mononucleares/metabolismo , Masculino , NF-kappa B/metabolismo , Ratos , Ratos Wistar , Fator de Necrose Tumoral alfa/metabolismo
17.
Pharmacol Rep ; 71(3): 485-490, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31005034

RESUMO

BACKGROUND: The role of monocyte/macrophage-derived microparticles (MPs) in the pathophysiology of cancer and chronic inflammatory diseases has been reported; nevertheless, the mechanism underlying microparticles release is currently unclear. The aim of the current study was to investigate whether matrix metalloproteinase (MMP) inhibitors could prevent MP shedding from stimulated human monocyte/macrophage. METHODS: Microparticles were obtained by isolated peripheral blood mononuclear cells after stimulation with the calcium ionophore, A23187. MP shedding, intracellular calcium concentration, analysis of RhoA expression, and proteolytic activities of isolated MPs were assessed in the absence or presence of MMP inhibitors. RESULTS: We demonstrated that MMP inhibitors remarkably prevented MP shedding in a concentration-dependent manner with IC50 values in the nano- to micromolar range. Such an effect was related to their ability to reduce the intracellular Ca2+ levels induced by the calcium ionophore and the consequent translocation of RhoA from cytosol to membrane. Furthermore, MMP inhibitors could inhibit the proteolytic activity of cell-derived MPs. CONCLUSIONS: The current study provide evidence that MMP inhibitors can prevent MPs shedding from stimulated human monocyte/macrophage and the proteolytic activity of released MPs. Finally, the most active compound tested might represent the lead compound of a new class of molecules with therapeutic potential in cancer and chronic inflammatory diseases.


Assuntos
Micropartículas Derivadas de Células/efeitos dos fármacos , Leucócitos Mononucleares/efeitos dos fármacos , Macrófagos/efeitos dos fármacos , Inibidores de Metaloproteinases de Matriz/farmacologia , Monócitos/efeitos dos fármacos , Proteólise/efeitos dos fármacos , Cálcio/metabolismo , Membrana Celular/efeitos dos fármacos , Membrana Celular/metabolismo , Micropartículas Derivadas de Células/metabolismo , Células Cultivadas , Citosol/efeitos dos fármacos , Citosol/metabolismo , Humanos , Leucócitos Mononucleares/metabolismo , Macrófagos/metabolismo , Monócitos/metabolismo
18.
Inflamm Res ; 68(6): 493-509, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30972425

RESUMO

OBJECTIVE AND DESIGN: To evaluate the potency of RORγt blockade for treatment of Inflammatory Bowel Disease (IBD), the efficacy of TAK-828F, a novel RORγt inverse agonist, in anti-TNF-α mAb non-responsive mouse colitis model and effect of TAK-828F on IL-17 production in peripheral mononuclear blood cells (PBMCs) of anti-TNF-α naive and treatment-failure patients of IBD was investigated. METHODS AND RESULTS: The colitis model showed Th17-dependent pathogenicity and response to anti-IL-12/23p40 monoclonal antibody (mAb), but no response to anti-TNF-α mAb. In the model, TAK-828F, at oral dosages of 1 and 3 mg/kg, inhibited progression of colitis and reduced the immune reaction that characterize Th17 cells. Anti-IL-17A mAb showed neither efficacy nor change in the T cell population and colonic gene expression in the model. In the normal mouse, a 4-week treatment of TAK-828F at 30 mg/kg did not severely reduce lymphocyte cell counts in peripheral and intestinal mucosa, which was observed in RORγ-/- mice. TAK-828F strongly inhibited IL-17 gene expression with IC50 values from 21.4 to 34.4 nmol/L in PBMCs from anti-TNF mAb naive and treatment-failure patients of IBD. CONCLUSIONS: These results indicate that RORγt blockade would provide an effective approach for treating refractory patients with IBD by blocking IL-23/Th17 pathway.


Assuntos
Acetatos/farmacologia , Acetatos/uso terapêutico , Doenças Inflamatórias Intestinais/tratamento farmacológico , Leucócitos Mononucleares/efeitos dos fármacos , Naftiridinas/farmacologia , Naftiridinas/uso terapêutico , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/imunologia , Adolescente , Adulto , Animais , Anticorpos Monoclonais/farmacologia , Anticorpos Monoclonais/uso terapêutico , Células Cultivadas , Colo/efeitos dos fármacos , Colo/imunologia , Colo/patologia , Modelos Animais de Doenças , Feminino , Humanos , Doenças Inflamatórias Intestinais/genética , Doenças Inflamatórias Intestinais/imunologia , Interleucina-17/antagonistas & inibidores , Interleucina-17/genética , Interleucina-17/imunologia , Mucosa Intestinal/efeitos dos fármacos , Mucosa Intestinal/imunologia , Mucosa Intestinal/patologia , Leucócitos Mononucleares/imunologia , Masculino , Camundongos Endogâmicos BALB C , Camundongos Knockout , Camundongos SCID , Pessoa de Meia-Idade , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Adulto Jovem
19.
Phytomedicine ; 58: 152868, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30831466

RESUMO

BACKGROUND: Populus tremula L. (Poplar), Fraxinus excelsior L. (ash) and Solidago virgaurea L. (goldenrod) have been used for medicinal purposes through centuries, to treat pain, fever and inflammation, but their mechanisms of action are still not fully understood. The present study was performed to investigate, whether the herbal medicinal product Phytodolor® (STW 1) and its components have anti-inflammatory effects on activated human monocytes and differentiated human macrophages to elucidate their modes of action in comparison with well-known analgesic, non-steroidal anti-inflammatory drug (NSAIDs) as diclofenac. METHODS: Adherent human monocytes obtained from peripheral blood mononuclear cells (PBMCs) were cultured in serum-free medium and pre-treated with 50-100 µg/ml of diclofenac, STW 1, their components, poplar, ash or goldenrod or its combination (0.05% to 2%). Thereafter, monocytes were activated with 0.1 or 1 µg/ml LPS for 24 h. The intracellular expressions of TNF-α or PTGS2 were determined by cell-based ELISA. Apoptotic cells were identified by YO-PRO-1 staining. Protein or total RNA were isolated to perform SDS-PAGE/Western blot and qRT-PCR analyses. PMA-differentiated human THP-1 macrophages were pre-treated with diclofenac (50 µg/ml) or STW1 (0.1%) and afterwards with LPS (1 µg/ml) and the translocation of the intracellular p62 NF-κB subunit was detected by immunofluorescence. RESULTS: STW 1 inhibited the intracellular content of TNF-α and PTGS2 protein, as well as of TNF-α and PTGS2 gene expression and induced apoptosis in LPS-activated human monocytes under serum free conditions. Furthermore, STW 1 inhibited the translocation of the p65 subunit of the redox-regulated NF-κB into the nucleus in LPS-activated human macrophages. CONCLUSION: The present in vitro investigations suggest a significant anti-inflammatory activity of STW 1 and its components by inhibiting pro-inflammatory cytokine as TNF-α and the key enzyme PTGS2 in LPS-activated human monocytes, which is, at least partly mediated through the suppression of NF-κB activation. Our results provide evidence for distinctive anti-inflammatory effects of STW 1 and its components on LPS-activated human monocytes/macrophages and, thus, for the therapeutic use of STW 1 in inflammation and pain related disorders.


Assuntos
Fraxinus/química , Inflamação/tratamento farmacológico , Fitoterapia , Extratos Vegetais/administração & dosagem , Populus/química , Solidago/química , Anti-Inflamatórios não Esteroides/administração & dosagem , Apoptose/efeitos dos fármacos , Ciclo-Oxigenase 2/metabolismo , Diclofenaco/administração & dosagem , Humanos , Inflamação/induzido quimicamente , Leucócitos Mononucleares/efeitos dos fármacos , Lipopolissacarídeos/efeitos adversos , Macrófagos/efeitos dos fármacos , Monócitos/efeitos dos fármacos , NF-kappa B/metabolismo , Plantas Medicinais , Células THP-1 , Fator de Necrose Tumoral alfa/metabolismo
20.
BMC Complement Altern Med ; 19(1): 54, 2019 Mar 04.
Artigo em Inglês | MEDLINE | ID: mdl-30832648

RESUMO

BACKGROUND: We previously reported that tacrolimus (Tac) does not decrease T helper 17 cells (Th17) response in kidney transplantation. In this study, we evaluated whether Resveratrol (Resv) has immunosuppressive effects by decreasing Th17 responses in Tac-based immunosuppression. METHODS: We investigated the effects of Resv under Tac-treatment conditions, on CD4+ T cell differentiation to Th17 cells in peripheral blood mononuclear cells (PBMCs), and proliferation of CD4+ T cells co-cultured with human renal proximal tubular epithelial cells (HRPTEpiCs). The effects of Resv on Th17 cells were tested in the murine skin transplant model. RESULTS: In PBMCs, Tac did not but combination of Tac and Resv further suppressed Th17 immune response. In the co-culture study, combination of Resv to Tac significantly decreased HRPTEpiC-induced T cell proliferation compared to Tac alone. Resv treatment in the Jurkat cell induced the expression of AMP-activated protein kinase and suppressed the expression of mammalian target of rapamycin (mTOR), suggesting blocking Th17 pathway by Resv. In the murine skin transplant model, combination of Resv to Tac significantly prolonged skin graft survival accompanied by the suppression of Th17 cells, compared to either the Tac-alone or control groups. CONCLUSION: The results of our study suggest that Resv provides additional immunosuppressive effects to Tac by suppressing effector CD4+ T cells, especially Th17 cells, in the transplantation setting.


Assuntos
Imunossupressores/farmacologia , Resveratrol/farmacologia , Tacrolimo/farmacologia , Células Th17/efeitos dos fármacos , Proteínas Quinases Ativadas por AMP/metabolismo , Adulto , Animais , Diferenciação Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Sobrevivência de Enxerto/efeitos dos fármacos , Humanos , Leucócitos Mononucleares/efeitos dos fármacos , Leucócitos Mononucleares/metabolismo , Masculino , Camundongos , Transplante de Pele , Serina-Treonina Quinases TOR/metabolismo , Células Th17/imunologia , Células Th17/metabolismo
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