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1.
J Psychopharmacol ; 33(1): 25-36, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30484737

RESUMO

BACKGROUND: A significant proportion of patients suffering from major depression fail to remit following treatment and develop treatment-resistant depression. Developing novel treatments requires animal models with good predictive validity. MRL/lpr mice, an established model of systemic lupus erythematosus, show depression-like behavior. AIMS: We evaluated responses to classical antidepressants, and associated immunological and biochemical changes in MRL/lpr mice. METHODS AND RESULTS: MRL/lpr mice showed increased immobility in the forced swim test, decreased wheel running and sucrose preference when compared with the controls, MRL/MpJ mice. In MRL/lpr mice, acute fluoxetine (30 mg/kg, intraperitoneally (i.p.)), imipramine (10 mg/kg, i.p.) or duloxetine (10 mg/kg, i.p.) did not decrease the immobility time in the Forced Swim Test. Interestingly, acute administration of combinations of olanzapine (0.03 mg/kg, subcutaneously)+fluoxetine (30 mg/kg, i.p.) or bupropion (10 mg/kg, i.p.)+fluoxetine (30 mg/kg, i.p.) retained efficacy. A single dose of ketamine but not three weeks of imipramine (10 mg/kg, i.p.) or escitalopram (5 mg/kg, i.p.) treatment in MRL/lpr mice restored sucrose preference. Further, we evaluated inflammatory, immune-mediated and neuronal mechanisms. In MRL/lpr mice, there was an increase in autoantibodies' titers, [3H]PK11195 binding and immune complex deposition. There was a significant infiltration of the brain by macrophages, neutrophils and T-lymphocytes. p11 mRNA expression was decreased in the prefrontal cortex. Further, there was an increase in the 5-HT2aR expression, plasma corticosterone and indoleamine 2,3-dioxygenase activity. CONCLUSION: In summary, the MRL/lpr mice could be a useful model for Treatment Resistant Depression associated with immune dysfunction with potential to expedite antidepressant drug discovery.

2.
PLoS One ; 12(7): e0181782, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28742141

RESUMO

Bruton's tyrosine kinase (BTK) regulates critical signal transduction pathways involved in the pathobiology of rheumatoid arthritis (RA) and other autoimmune disorders. BMS-986142 is a potent and highly selective reversible small molecule inhibitor of BTK currently being investigated in clinical trials for the treatment of both RA and primary Sjögren's syndrome. In the present report, we detail the in vitro and in vivo pharmacology of BMS-986142 and show this agent provides potent and selective inhibition of BTK (IC50 = 0.5 nM), blocks antigen receptor-dependent signaling and functional endpoints (cytokine production, co-stimulatory molecule expression, and proliferation) in human B cells (IC50 ≤ 5 nM), inhibits Fcγ receptor-dependent cytokine production from peripheral blood mononuclear cells, and blocks RANK-L-induced osteoclastogenesis. Through the benefits of impacting these important drivers of autoimmunity, BMS-986142 demonstrated robust efficacy in murine models of rheumatoid arthritis (RA), including collagen-induced arthritis (CIA) and collagen antibody-induced arthritis (CAIA). In both models, robust efficacy was observed without continuous, complete inhibition of BTK. When a suboptimal dose of BMS-986142 was combined with other agents representing the current standard of care for RA (e.g., methotrexate, the TNFα antagonist etanercept, or the murine form of CTLA4-Ig) in the CIA model, improved efficacy compared to either agent alone was observed. The results suggest BMS-986142 represents a potential therapeutic for clinical investigation in RA, as monotherapy or co-administered with agents with complementary mechanisms of action.


Assuntos
Artrite Experimental/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Tirosina Quinases/antagonistas & inibidores , Tirosina Quinase da Agamaglobulinemia , Animais , Formação de Anticorpos/efeitos dos fármacos , Artrite Experimental/imunologia , Artrite Experimental/patologia , Linfócitos B/efeitos dos fármacos , Linfócitos B/imunologia , Linfócitos B/patologia , Feminino , Humanos , Leucócitos Mononucleares/efeitos dos fármacos , Leucócitos Mononucleares/imunologia , Leucócitos Mononucleares/patologia , Camundongos Endogâmicos BALB C , Osteoclastos/efeitos dos fármacos , Osteoclastos/imunologia , Osteoclastos/patologia , Inibidores de Proteínas Quinases/farmacologia , Proteínas Tirosina Quinases/imunologia , Ligante RANK/imunologia
3.
J Immunol ; 198(3): 1308-1319, 2017 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-28003376

RESUMO

The serine/threonine kinase IL-1R-associated kinase (IRAK)4 is a critical regulator of innate immunity. We have identified BMS-986126, a potent, highly selective inhibitor of IRAK4 kinase activity that demonstrates equipotent activity against multiple MyD88-dependent responses both in vitro and in vivo. BMS-986126 failed to inhibit assays downstream of MyD88-independent receptors, including the TNF receptor and TLR3. Very little activity was seen downstream of TLR4, which can also activate an MyD88-independent pathway. In mice, the compound inhibited cytokine production induced by injection of several different TLR agonists, including those for TLR2, TLR7, and TLR9. The compound also significantly suppressed skin inflammation induced by topical administration of the TLR7 agonist imiquimod. BMS-986126 demonstrated robust activity in the MRL/lpr and NZB/NZW models of lupus, inhibiting multiple pathogenic responses. In the MRL/lpr model, robust activity was observed with the combination of suboptimal doses of BMS-986126 and prednisolone, suggesting the potential for steroid sparing activity. BMS-986126 also demonstrated synergy with prednisolone in assays of TLR7- and TLR9-induced IFN target gene expression using human PBMCs. Lastly, BMS-986126 inhibited TLR7- and TLR9-dependent responses using cells derived from lupus patients, suggesting that inhibition of IRAK4 has the potential for therapeutic benefit in treating lupus.


Assuntos
Quinases Associadas a Receptores de Interleucina-1/antagonistas & inibidores , Lúpus Eritematoso Sistêmico/tratamento farmacológico , Prednisolona/uso terapêutico , Animais , Modelos Animais de Doenças , Feminino , Humanos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Fator 88 de Diferenciação Mieloide/fisiologia , Receptor 7 Toll-Like/fisiologia , Receptor Toll-Like 9/fisiologia
4.
Int Immunopharmacol ; 21(2): 328-35, 2014 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-24859061

RESUMO

Inflammatory bowel disease (IBD) is an idiopathic chronic inflammation of the gastrointestinal tract which is mainly caused by dysregulated gut immune response to commensal flora. Very limited treatment options with marginal efficacy are available along with surgery which has high risk of reoccurrence. As both innate and adaptive immune responses have been found altered in IBD, a good therapeutic strategy could be to restrict both of them under chronic inflammatory conditions. Effect of chloroquine on TLR9 signaling is well reported, while there are limited studies on non-endosomal TLRs as well as T cell responses. Hence, we studied its effect on other TLRs as well as T cell response along with testing it as a potential therapeutics in IBD using murine preclinical colitis model. Chloroquine significantly suppressed the TLR2 as well as TLR9 signaling in both in vitro as well as in vivo experimental settings, while it had no effect on TLR4 pathway. It also suppressed the T cell cytokine and proliferative responses. In, DSS-induced murine colitis model, chloroquine administration, significantly improved body weight loss, colon length shortening, tissue damage and inflammatory cell infiltration. Based on our findings in preclinical murine model of IBD, chloroquine has the potential to be considered as a therapeutic option in clinics through inhibition of diverse TLR and T cell responses.


Assuntos
Cloroquina/farmacologia , Doenças Inflamatórias Intestinais/tratamento farmacológico , Animais , Peso Corporal/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Colite/tratamento farmacológico , Colite/metabolismo , Colo/efeitos dos fármacos , Colo/metabolismo , Citocinas/metabolismo , Modelos Animais de Doenças , Feminino , Doenças Inflamatórias Intestinais/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Transdução de Sinais/efeitos dos fármacos , Linfócitos T/efeitos dos fármacos , Linfócitos T/metabolismo , Receptor 2 Toll-Like/metabolismo , Receptor Toll-Like 9/metabolismo
5.
PLoS One ; 7(10): e47873, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-23118901

RESUMO

BACKGROUND: Epidemiological studies suggest that mushroom intake is inversely correlated with gastric, gastrointestinal and breast cancers. We have recently demonstrated anticancer and anti-inflammatory activity of triterpene extract isolated from mushroom Ganoderma lucidum (GLT). The aim of the present study was to evaluate whether GLT prevents colitis-associated carcinogenesis in mice. METHODS/PRINCIPAL FINDINGS: Colon carcinogenesis was induced by the food-borne carcinogen (2-Amino-1-methyl-6-phenylimidazol[4,5-b]pyridine [PhIP]) and inflammation (dextran sodium sulfate [DSS]) in mice. Mice were treated with 0, 100, 300 and 500 mg GLT/kg of body weight 3 times per week for 4 months. Cell proliferation, expression of cyclin D1 and COX-2 and macrophage infiltration was assessed by immunohistochemistry. The effect of GLT on XRE/AhR, PXR and rPXR was evaluated by the reporter gene assays. Expression of metabolizing enzymes CYP1A2, CYP3A1 and CYP3A4 in colon tissue was determined by immunohistochemistry. GLT treatment significantly suppressed focal hyperplasia, aberrant crypt foci (ACF) formation and tumor formation in mice exposed to PhIP/DSS. The anti-proliferative effects of GLT were further confirmed by the decreased staining with Ki-67 in colon tissues. PhIP/DSS-induced colon inflammation was demonstrated by the significant shortening of the large intestine and macrophage infiltrations, whereas GLT treatment prevented the shortening of colon lengths, and reduced infiltration of macrophages in colon tissue. GLT treatment also significantly down-regulated PhIP/DSS-dependent expression of cyclin D1, COX-2, CYP1A2 and CYP3A4 in colon tissue. CONCLUSIONS: Our data suggest that GLT could be considered as an alternative dietary approach for the prevention of colitis-associated cancer.


Assuntos
Neoplasias do Colo , Inflamação , Extratos Vegetais/administração & dosagem , Reishi , Aminopiridinas/toxicidade , Animais , Anti-Inflamatórios/administração & dosagem , Apoptose/efeitos dos fármacos , Carcinógenos/toxicidade , Proliferação de Células/efeitos dos fármacos , Transformação Celular Neoplásica/efeitos dos fármacos , Colite/complicações , Colite/tratamento farmacológico , Colite/patologia , Neoplasias do Colo/induzido quimicamente , Neoplasias do Colo/dietoterapia , Neoplasias do Colo/metabolismo , Sulfato de Dextrana/toxicidade , Neoplasias Gastrointestinais/complicações , Neoplasias Gastrointestinais/dietoterapia , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Hiperplasia/induzido quimicamente , Hiperplasia/dietoterapia , Hiperplasia/metabolismo , Imidazóis/toxicidade , Inflamação/induzido quimicamente , Inflamação/dietoterapia , Macrófagos/efeitos dos fármacos , Camundongos , Neoplasias Experimentais/induzido quimicamente , Neoplasias Experimentais/dietoterapia , Neoplasias Experimentais/metabolismo , Extratos Vegetais/química , Reishi/química
6.
Nutr J ; 10: 52, 2011 May 16.
Artigo em Inglês | MEDLINE | ID: mdl-21575254

RESUMO

BACKGROUND: Mushrooms are well recognized for their culinary properties as well as for their potency to enhance immune response. In the present study, we evaluated anti-inflammatory properties of an edible oyster mushroom (Pleurotus ostreatus) in vitro and in vivo. METHODS: RAW264.7 murine macrophage cell line and murine splenocytes were incubated with the oyster mushroom concentrate (OMC, 0-100 µg/ml) in the absence or presence of lipopolysacharide (LPS) or concanavalin A (ConA), respectively. Cell proliferation was determined by MTT assay. Expression of cytokines and proteins was measured by ELISA assay and Western blot analysis, respectively. DNA-binding activity was assayed by the gel-shift analysis. Inflammation in mice was induced by intraperitoneal injection of LPS. RESULTS: OMC suppressed LPS-induced secretion of tumor necrosis factor-α (TNF-α, interleukin-6 (IL-6), and IL-12p40 from RAW264.7 macrophages. OMC inhibited LPS-induced production of prostaglandin E2 (PGE2) and nitric oxide (NO) through the down-regulation of expression of COX-2 and iNOS, respectively. OMC also inhibited LPS-dependent DNA-binding activity of AP-1 and NF-κB in RAW264.7 cells. Oral administration of OMC markedly suppressed secretion of TNF-α and IL-6 in mice challenged with LPS in vivo. Anti-inflammatory activity of OMC was confirmed by the inhibition of proliferation and secretion of interferon-γ (IFN-γ), IL-2, and IL-6 from concanavalin A (ConA)-stimulated mouse splenocytes. CONCLUSIONS: Our study suggests that oyster mushroom possesses anti-inflammatory activities and could be considered a dietary agent against inflammation. The health benefits of the oyster mushroom warrant further clinical studies.


Assuntos
Agaricales/química , Anti-Inflamatórios/farmacologia , Inflamação/tratamento farmacológico , NF-kappa B/metabolismo , Pleurotus/química , Fator de Transcrição AP-1/metabolismo , Administração Oral , Animais , Western Blotting , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Concanavalina A/administração & dosagem , Ciclo-Oxigenase 2/genética , Ciclo-Oxigenase 2/metabolismo , Dinoprostona/metabolismo , Regulação para Baixo/efeitos dos fármacos , Feminino , Glucanos/análise , Inflamação/induzido quimicamente , Interferon gama/metabolismo , Subunidade p40 da Interleucina-12/metabolismo , Interleucina-2/metabolismo , Interleucina-6/metabolismo , Lipopolissacarídeos/administração & dosagem , Macrófagos/citologia , Macrófagos/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Óxido Nítrico Sintase Tipo II/antagonistas & inibidores , Óxido Nítrico Sintase Tipo II/genética , Transdução de Sinais , Fator de Necrose Tumoral alfa/metabolismo
7.
Anticancer Res ; 31(2): 379-85, 2011 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-21378315

RESUMO

The multi-functional apyrimidinic endonuclease 1/redox factor-1 (APE1/Ref-1) DNA repair and redox signaling protein has been shown to have a role in cancer growth and survival, however, little has been investigated concerning its role in inflammation. In this study, an APE1 redox-specific inhibitor (E3330) was used in lypopolysaccharide (LPS)-stimulated macrophages (RAW264.7). E3330 clearly suppressed secretion of inflammatory cytokines including tumor necrosis factor-α (TNF-α), interleukin (IL-6) and IL-12 and inflammatory mediators nitric oxide (NO) as well as prostaglandin E(2) (PGE(2)) from the LPS-stimulated RAW264.7 cells. These data were supported by the down-regulation of the LPS-dependent expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) genes in the RAW264.7 cells. The effects of E3330 were mediated by the inhibition of transcription factors nuclear factor-κB (NF-κB) and activator protein 1 (AP-1) in the LPS-stimulated macrophages, both known targets of APE1. In conclusion, pharmacological inhibition of APE1 by E3330 suppresses inflammatory response in activated macrophages and can be considered as a novel therapeutic strategy for the inhibition of tumor-associated macrophages.


Assuntos
DNA Liase (Sítios Apurínicos ou Apirimidínicos)/imunologia , Macrófagos/enzimologia , Macrófagos/imunologia , Animais , Anti-Inflamatórios não Esteroides , Benzoquinonas/farmacologia , Células Cultivadas , Ciclo-Oxigenase 2/biossíntese , DNA Liase (Sítios Apurínicos ou Apirimidínicos)/antagonistas & inibidores , DNA Liase (Sítios Apurínicos ou Apirimidínicos)/metabolismo , Dinoprostona/imunologia , Dinoprostona/metabolismo , Lipopolissacarídeos/farmacologia , Macrófagos/efeitos dos fármacos , Camundongos , NF-kappa B/imunologia , NF-kappa B/metabolismo , Óxido Nítrico/imunologia , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase Tipo II/biossíntese , Oxirredução , Propionatos/farmacologia , Transdução de Sinais , Fator de Transcrição AP-1/imunologia , Fator de Transcrição AP-1/metabolismo , Fator de Necrose Tumoral alfa/biossíntese
8.
Int J Mol Med ; 26(5): 643-50, 2010 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-20878085

RESUMO

Colorectal cancer is one of the leading causes of cancer deaths in both men and women in the world. However, colon cancer can be prevented to some extent by consumption of edible natural products with chemopreventive properties. Therefore, we investigated, whether edible mushroom Pleurotus ostreatus (PO) has chemopreventive effect on inflammation-associated colon carcinogenesis induced by 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) and promoted by dextran sodium sulfate (DSS). PO treatment, at both doses (100 and 500 mg/kg), significantly reduced by 50 and 78% the number of aberrant crypt foci and the multiplicity of colon neoplasms by 43 and 89%, respectively. However, incidence of colon tumors and high grade dysplasia was reduced by 50 and 63% only in the dose 500 mg/kg of PO, respectively. Colon shortening and dysplastic index was significantly reduced by PO treatment in dose-dependent manner. The immunohistochemistry of colons revealed that treatment with PO suppressed expression of cyclin D1, Ki-67, COX-2 and F4/80. In summary, our data suggest that PO may prevent inflammation-associated colon carcinogenesis with exposure to PhIP through combined modulatory mechanisms of inflammation and tumor growth via suppression of COX-2, F4/80, Ki-67 and cyclin D1 expression in mice.


Assuntos
Transformação Celular Neoplásica/patologia , Colite/complicações , Colo/patologia , Neoplasias do Colo/patologia , Neoplasias do Colo/prevenção & controle , Pleurotus , Animais , Antígenos de Diferenciação/genética , Antígenos de Diferenciação/metabolismo , Testes de Carcinogenicidade , Carcinógenos/farmacologia , Colite/induzido quimicamente , Colite/patologia , Colo/metabolismo , Neoplasias do Colo/metabolismo , Ciclina D1/genética , Ciclina D1/metabolismo , Ciclo-Oxigenase 2/genética , Ciclo-Oxigenase 2/metabolismo , Sulfato de Dextrana/efeitos adversos , Imuno-Histoquímica , Antígeno Ki-67/genética , Antígeno Ki-67/metabolismo , Camundongos , Camundongos Endogâmicos ICR
9.
Immunobiology ; 215(3): 242-9, 2010 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-19457576

RESUMO

Tumor-associated macrophages were linked to the growth, angiogenesis, and metastasis of variety of cancers. However, the role of macrophages in colon cancer is elusive. In the present study, we demonstrate that activated macrophage-conditioned medium (AMCM), containing tumor necrosis factor-alpha (TNF-alpha), interleukin-1beta (IL-1beta), and IL-6, markedly induced proliferation and migration of human colon cancer cells HCT116. Furthermore, AMCM significantly increased activation of transcription factor NF-kappaB and secretion of vascular endothelial growth factor (VEGF) from colon cancer cells, which subsequently induced capillary morphogenesis of human aortic endothelial cells. In conclusion, the interruption of signaling between activated macrophages and colon cancer cells could be considered as a new therapeutic strategy.


Assuntos
Neoplasias do Colo/imunologia , Ativação de Macrófagos/imunologia , Macrófagos/imunologia , Transdução de Sinais/imunologia , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Movimento Celular/imunologia , Proliferação de Células/efeitos dos fármacos , Meios de Cultivo Condicionados/farmacologia , Ensaio de Desvio de Mobilidade Eletroforética , Ensaio de Imunoadsorção Enzimática , Humanos , Interleucina-1beta/biossíntese , Interleucina-1beta/imunologia , Interleucina-6/biossíntese , Interleucina-6/imunologia , NF-kappa B , Transdução de Sinais/efeitos dos fármacos , Fator de Necrose Tumoral alfa/biossíntese , Fator de Necrose Tumoral alfa/imunologia
10.
J Immunol ; 183(11): 7505-13, 2009 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-19917693

RESUMO

Designing mimetic of the interface functional groups of known receptor-ligand complexes is an attractive strategy for developing potential therapeutic agents that interfere with target protein-protein interactions. The CD80/CD86-CD28/CD152 costimulatory interactions transmit signals for CD4(+) T cell activation and suppression and are critically involved in the initiation, progression, and reactivation of the immunopathology in multiple sclerosis. Differences in the pattern, levels, and kinetics of expression of CD80/CD86 molecules in conjunction with differences in the strength of the signals delivered upon binding CD28 or CD152 determine the outcome of the immune response. A temporal up-regulation of surface expression of CD80 relative to CD86 on APCs and CNS-infiltrating cells has been shown to correlate with disease progression in experimental autoimmune encephalomyelitis an animal model for multiple sclerosis. Hence blockade of the CD80 costimulatory axis has therapeutic potential in multiple sclerosis. In this study, we report the efficacy of a novel CD80-blocking agent CD80-competitive antagonist peptide (CD80-CAP) in suppressing clinical disease and relapse in experimental autoimmune encephalomyelitis. The CD80-CAP mediates protection by inhibiting proinflammatory cytokines and skewing toward anti-inflammatory response presumably by enhancing the expression of glucocorticoid-induced leucine zipper in activated CD4(+) T cells.


Assuntos
Antígeno B7-1/imunologia , Linfócitos T CD4-Positivos/imunologia , Encefalomielite Autoimune Experimental/imunologia , Zíper de Leucina/imunologia , Oligopeptídeos/farmacologia , Animais , Antígeno B7-1/efeitos dos fármacos , Antígeno B7-1/metabolismo , Antígeno B7-2/imunologia , Antígeno B7-2/metabolismo , Antígenos CD28/imunologia , Antígenos CD28/metabolismo , Linfócitos T CD4-Positivos/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Citocinas/biossíntese , Citocinas/efeitos dos fármacos , Encefalomielite Autoimune Experimental/patologia , Feminino , Citometria de Fluxo , Glucocorticoides/imunologia , Glucocorticoides/farmacologia , Zíper de Leucina/efeitos dos fármacos , Camundongos , Reação em Cadeia da Polimerase Via Transcriptase Reversa
11.
J Sep Sci ; 32(23-24): 4052-8, 2009 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-19937965

RESUMO

Ganoderma lucidum is a mushroom with a long history of medical applications. Research has demonstrated chemotherapeutic effects of G. lucidum in tissue culture, and bioactive fractions of the mushroom have been shown to contain high levels of triterpenoids and polysaccharides. In this study, we developed a new method for the detection of ganoderic acids and other triterpenes in Ganoderma mushroom extracts based on a post-biosynthetic stable isotope encoding technique. Overall, 57 doublets were identified as potential ganoderic acids and 11 of those matched with the database. Ganoderic acid A, F and H were confirmed by standards and their absolute concentrations were measured in GLT (GA A: 3.88 mg/g; GA F: 0.95 mg/g and GA H: 1.74 mg/g) and ReishiMax (GA A: 2.32 mg/g; GA F: 0.43 mg/g and GA H: 0.85 mg/g) extracts. The method was also used for the evaluation of bioavailability of triterpenes after an oral application and demonstrated the presence of G. lucidum triterpenes in plasma.


Assuntos
Reishi/metabolismo , Triterpenos/análise , Triterpenos/metabolismo , Animais , Disponibilidade Biológica , Cromatografia Líquida de Alta Pressão , Deutério , Feminino , Ácidos Heptanoicos/análise , Lanosterol/análogos & derivados , Lanosterol/análise , Ratos , Ratos Sprague-Dawley , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por Matriz
12.
Int Immunopharmacol ; 9(11): 1272-80, 2009 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-19651243

RESUMO

Ganoderma lucidum is a popular medicinal mushroom, which has been used in the Traditional Chinese medicine for the prevention or treatment of a variety of diseases. In the present study we evaluated the anti-inflammatory effects of the triterpene extract from G. lucidum (GLT) in LPS-stimulated macrophages. Here we show that GLT markedly suppressed the secretion of inflammatory cytokine tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6), and inflammatory mediator nitric oxide (NO) and prostaglandin E(2) (PGE(2)) from lipopolysaccharide (LPS)-stimulated murine RAW264.7 cells. GLT also down-regulated LPS-dependent expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase 2 (COX-2) in RAW264.7 cells. The anti-inflammatory effects of GLT were mediated by the inhibition of transcription factor NF-kappaB as demonstrated by decreased NF-kappaB-DNA binding activity, and the suppression of p65 phosphorylation in LPS-stimulated macrophages treated with GLT. Moreover, GLT inhibited LPS-dependent AP-1-DNA binding activity and down-regulated expression of AP-1 subunit c-Jun. In addition, GLT suppressed the activity of MAP kinases as observed by the down-regulation of LPS-induced phosphorylation of ERK1/2 and JNK but not p38. In vivo experiments clearly demonstrated that GLT also inhibited the production of TNF-alpha and IL-6 in LPS-induced endotoxemic mice. Apart from its anti-inflammatory activity, GLT suppressed cell proliferation of RAW264.7 cells through cell cycle arrest at G0/G1-G2M, which was mediated by the down-regulation of expression of cell cycle regulatory proteins cyclin D1, CDK4 and cyclin B1, respectively. In conclusion, the anti-inflammatory and anti-proliferative effects of GLT on macrophages are mediated through the inhibition of NF-kappaB and AP-1 signaling pathways.


Assuntos
Anti-Inflamatórios/farmacologia , Medicamentos de Ervas Chinesas/farmacologia , Macrófagos/efeitos dos fármacos , Triterpenos/farmacologia , Animais , Ciclo Celular/efeitos dos fármacos , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Feminino , Mediadores da Inflamação/metabolismo , Lipopolissacarídeos/farmacologia , Camundongos , Camundongos Endogâmicos BALB C , Modelos Biológicos , Reishi/química
13.
Eur J Pain ; 12(3): 321-8, 2008 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-17703974

RESUMO

OBJECTIVES: The objective of this study was to examine the nature of interaction between cyclooxygenase-2 inhibitor meloxicam and inducible nitric oxide synthase inhibitor aminoguanidine in formalin-induced nociception in mice and the possible therapeutic advantage. METHODS: Antinociceptive effect of meloxicam (1, 3, 10 and 30 mg/kg, oral) and aminoguanidine (10, 30, 100 and 300 mg/kg, oral) and their combinations was examined in formalin-induced paw licking model in mice. Analysis of variance and isobolographic method were employed to identify the nature of antinociceptive interaction. RESULTS: Higher doses of meloxicam (10 and 30 mg/kg) and aminoguanidine (100 and 300 mg/kg) produced significant reduction in paw licking time (antinociceptive) in late phase of formalin-induced nociception. Combination of sub-threshold dose of meloxicam (3 mg/kg) with increasing doses of aminoguanidine (10, 30, 100 and 300 mg/kg) resulted in synergistic antinociceptive effect. Similarly, co-administration of sub-threshold dose of aminoguanidine (30 mg/kg) with increasing doses of meloxicam (1, 3, 10 and 30 mg/kg) produced significant reduction in formalin-induced paw licking behaviour. The experimental ED(50) for combination with their confidence limits are below the confidence interval of theoretical line of additive interaction, suggesting synergistic nature of interaction between meloxicam and aminoguanidine in isobolographic analysis. CONCLUSION: Co-administration of meloxicam and aminoguanidine showed synergistic antinociceptive effect which might possibly reduce gastrointestinal toxicity associated with the use of meloxicam.


Assuntos
Anti-Inflamatórios não Esteroides/uso terapêutico , Inibidores de Ciclo-Oxigenase 2/uso terapêutico , Formaldeído/toxicidade , Guanidinas/uso terapêutico , Óxido Nítrico Sintase Tipo II/antagonistas & inibidores , Nociceptores/efeitos dos fármacos , Dor/prevenção & controle , Tiazinas/uso terapêutico , Tiazóis/uso terapêutico , Animais , Anti-Inflamatórios não Esteroides/administração & dosagem , Inibidores de Ciclo-Oxigenase 2/administração & dosagem , Avaliação Pré-Clínica de Medicamentos , Sinergismo Farmacológico , Quimioterapia Combinada , Guanidinas/administração & dosagem , Masculino , Meloxicam , Camundongos , Dor/induzido quimicamente , Medição da Dor , Tiazinas/administração & dosagem , Tiazóis/administração & dosagem
14.
Eur J Pain ; 11(5): 528-34, 2007 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-16920373

RESUMO

OBJECTIVES: The objective of this study was to examine the effects of rofecoxib, meloxicam, both cyclooxygenase-2 (COX-2) inhibitors and aminoguanidine hydrochloride, an inducible nitric oxide synthase (iNOS) inhibitor and their combinations in neuropathic pain in rats. METHODS: Neuropathy was induced by chronic constriction injury (CCI) of right sciatic nerve under ketamine anesthesia in rats. Effect of ED(50) of aminoguanidine hydrochloride, rofecoxib and meloxicam administered orally was investigated using behavioral tests. Effect of combinations of aminoguanidine hydrochloride with rofecoxib and meloxicam was also investigated in neuropathic pain employing behavioral tests. RESULTS: Behavioral tests, mechanical, thermal and cold stimuli confirmed the development of neuropathic pain after CCI. Aminoguanidine hydrochloride, rofecoxib and meloxicam when administered alone, produced significant increase in paw withdrawal threshold to mechanical stimuli at 6 h in ipsilateral hind paw after CCI. Co-administration of aminoguanidine hydrochloride (30 mg/kg) with rofecoxib (1.31 mg/kg) and meloxicam (1.34 mg/kg) was also found to produce significant increase in paw withdrawal latencies to mechanical stimuli at 6 h. Combined administration of aminoguanidine hydrochloride with meloxicam and rofecoxib produced significant rise in pain threshold for mechanical hyperalgesia in ipsilateral hind paw when compared with the groups treated with aminoguanidine hydrochloride, meloxicam and rofecoxib alone. CONCLUSION: Co-administration of meloxicam and rofecoxib with aminoguanidine hydrochloride may be an alternative approach for the treatment of neuropathic pain.


Assuntos
Inibidores de Ciclo-Oxigenase 2/farmacologia , Neurônios Aferentes/efeitos dos fármacos , Óxido Nítrico Sintase Tipo II/antagonistas & inibidores , Nociceptores/efeitos dos fármacos , Doenças do Sistema Nervoso Periférico/tratamento farmacológico , Animais , Inibidores de Ciclo-Oxigenase 2/uso terapêutico , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Combinação de Medicamentos , Sinergismo Farmacológico , Guanidinas/farmacologia , Guanidinas/uso terapêutico , Hiperalgesia/tratamento farmacológico , Hiperalgesia/enzimologia , Hiperalgesia/fisiopatologia , Lactonas/farmacologia , Lactonas/uso terapêutico , Masculino , Meloxicam , Neuralgia/tratamento farmacológico , Neuralgia/enzimologia , Neuralgia/fisiopatologia , Neurônios Aferentes/enzimologia , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase Tipo II/metabolismo , Nociceptores/enzimologia , Nociceptores/fisiopatologia , Limiar da Dor/efeitos dos fármacos , Limiar da Dor/fisiologia , Doenças do Sistema Nervoso Periférico/enzimologia , Doenças do Sistema Nervoso Periférico/fisiopatologia , Estimulação Física/efeitos adversos , Ratos , Tempo de Reação/efeitos dos fármacos , Tempo de Reação/fisiologia , Neuropatia Ciática/tratamento farmacológico , Neuropatia Ciática/enzimologia , Neuropatia Ciática/fisiopatologia , Sulfonas/farmacologia , Sulfonas/uso terapêutico , Tiazinas/farmacologia , Tiazinas/uso terapêutico , Tiazóis/farmacologia , Tiazóis/uso terapêutico , Resultado do Tratamento
15.
Life Sci ; 78(10): 1044-8, 2006 Feb 02.
Artigo em Inglês | MEDLINE | ID: mdl-16109432

RESUMO

Interaction studies with inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) inhibitor have been conducted to assess the nature of interaction and the possible therapeutic advantage. The interaction between meloxicam--a selective COX-2 inhibitor--and aminoguanidine hydrochloride--a selective iNOS inhibitor-- was examined in carrageenan-induced paw edema in rats. Appropriate statistical method was applied to detect the nature of anti-inflammatory interaction. Different doses of meloxicam (1, 3, 10 and 30 mg/kg) or aminoguanidine hydrochloride (10, 30, 100 and 300 mg/kg) were administered orally to adult male albino rats. Higher doses of meloxicam (3, 10 and 30 mg/kg) showed statistically significant anti-inflammatory effect. However, aminoguanidine hydrochloride did not show any anti-inflammatory activity. Combination of sub-threshold dose of meloxicam (1 mg/kg) with increasing doses of aminoguanidine hydrochloride (30, 100 and 300 mg/kg) resulted in synergistic anti-inflammatory effect. Combined therapy with sub-threshold dose of aminoguanidine hydrochloride (30 mg/kg) with increasing doses of meloxicam (1, 3, 10 and 30 mg/kg) also resulted in synergistic anti-inflammatory effect. The possible mechanism of interaction could be the stimulation of COX-2 activity by nitric oxide (NO) by combining with heme component. These results suggest that co-administration of meloxicam and aminoguanidine hydrochloride may be an alternative in clinical control of inflammation.


Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Inibidores de Ciclo-Oxigenase 2/farmacologia , Inibidores Enzimáticos/farmacologia , Guanidinas/farmacologia , Inflamação/tratamento farmacológico , Óxido Nítrico Sintase Tipo II/antagonistas & inibidores , Tiazinas/farmacologia , Tiazóis/farmacologia , Animais , Carragenina , Relação Dose-Resposta a Droga , Sinergismo Farmacológico , Pé/patologia , Inflamação/induzido quimicamente , Inflamação/patologia , Masculino , Meloxicam , Ratos
16.
Eur J Pain ; 10(7): 573-9, 2006 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-16214382

RESUMO

OBJECTIVES: The objectives of this study were to examine the role of reactive oxygen species and oxidative stress in peripheral neuropathy and behavioural pain responses in experimentally induced chronic constriction injury (CCI) of sciatic nerve of rat. Effect of N-acetyl-L-cysteine (NAC) administered intraperitoneally, was also investigated on CCI-induced neuropathic pain in rats. METHODS: Neuropathy was induced by CCI of the right sciatic nerve in ketamine anaesthetized rats. Effect of intraperitoneally administered NAC in rats was also investigated using nociceptive behavioural tests. Malondialdehyde, an index of oxidative stress and antioxidant enzymes was also estimated in ligated sciatic nerve. RESULTS: Behavioural tests, mechanical, thermal and cold stimuli confirmed the development of neuropathic pain after the CCI. The malondialdehyde levels of ligated sciatic nerves were significantly increased compared to non-ligated sciatic nerves (sham operated). The antioxidant enzyme reduced, glutathione was inhibited, while superoxide dismutase increased. However, catalase remained unaffected in the injured sciatic nerves. Intraperitoneal administration of NAC resulted in significant reduction of hyperalgesia in CCI-induced neuropathic rats. CONCLUSIONS: This study identifies antioxidants superoxide dismutase and reduced glutathione, and oxidative stress as important determinants of neuropathological and behavioural consequences of CCI-induced neuropathy, and NAC may be a potential candidate for alleviation of neuropathic pain.


Assuntos
Acetilcisteína/farmacologia , Neuralgia/tratamento farmacológico , Neuralgia/fisiopatologia , Estresse Oxidativo/fisiologia , Doenças do Sistema Nervoso Periférico/tratamento farmacológico , Doenças do Sistema Nervoso Periférico/fisiopatologia , Acetilcisteína/uso terapêutico , Animais , Comportamento Animal/efeitos dos fármacos , Comportamento Animal/fisiologia , Biomarcadores/metabolismo , Modelos Animais de Doenças , Depuradores de Radicais Livres/farmacologia , Depuradores de Radicais Livres/uso terapêutico , Glutationa/metabolismo , Ligadura , Masculino , Malondialdeído/metabolismo , Neuralgia/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Medição da Dor/efeitos dos fármacos , Doenças do Sistema Nervoso Periférico/metabolismo , Ratos , Ratos Wistar , Espécies Reativas de Oxigênio/metabolismo , Neuropatia Ciática/tratamento farmacológico , Neuropatia Ciática/metabolismo , Neuropatia Ciática/fisiopatologia , Superóxido Dismutase/metabolismo , Resultado do Tratamento
17.
Eur J Pharmacol ; 530(1-2): 59-69, 2006 Jan 13.
Artigo em Inglês | MEDLINE | ID: mdl-16364289

RESUMO

This study was conducted to examine the role of nitric oxide (NO) in peripheral neuropathy induced by chronic constriction injury of sciatic nerve of rats by using NO precursor, NO donors and nitric oxide synthase (NOS) inhibitors. Chronic constriction injury of sciatic nerve of rats resulted in peripheral neuropathy as confirmed by nociceptive behavioural tests using mechanical, thermal and cold allodynia. NO precursor, L-arginine and NO donors sodium nitroprusside, S-nitroso-N-acetylpenicillamine potentiated the hyperalgesia and allodynia significantly suggesting proalgesic effect in neuropathic rats. Intracerebroventricular (i.c.v.) administration of rats with NOS inhibitors such as L-N(G)-nitroarginine methyl ester, N-iminoethyl lysine and 7-nitroindazole did not show any effect but i.p. administration of NOS inhibitors aminoguanidine, L-N(G)-nitroarginine methyl ester and 7-nitroindazole caused alleviation of pain. The study confirms the involvement of endogenously synthesized and exogenously administered NO in chronic constriction injury-induced neuropathy in rats. Significant increase in the levels of nitrate and nitrite in ligated sciatic nerve suggest that local up regulation of NO in the production and maintenance of neuropathic pain. In conclusion, initial attempt to manipulate L-arginine: NO pathway is indicative of therapeutic potential of these interventions in the management of neuropathic pain.


Assuntos
Neuralgia/fisiopatologia , Óxido Nítrico/fisiologia , Animais , Arginina/farmacologia , Comportamento Animal/efeitos dos fármacos , Temperatura Baixa/efeitos adversos , Constrição Patológica/complicações , Modelos Animais de Doenças , Membro Posterior/inervação , Temperatura Alta/efeitos adversos , Hiperalgesia/etiologia , Hiperalgesia/fisiopatologia , Injeções Intraperitoneais , Injeções Intraventriculares , Masculino , Neuralgia/etiologia , Nitratos/sangue , Óxido Nítrico/metabolismo , Doadores de Óxido Nítrico/administração & dosagem , Óxido Nítrico Sintase/antagonistas & inibidores , Óxido Nítrico Sintase/metabolismo , Nitritos/sangue , Nitroprussiato/administração & dosagem , Limiar da Dor/efeitos dos fármacos , Ratos , Ratos Wistar , S-Nitroso-N-Acetilpenicilamina/administração & dosagem , Nervo Isquiático/lesões , Nervo Isquiático/fisiopatologia , Estresse Mecânico
18.
Eur J Pharmacol ; 492(2-3): 117-22, 2004 May 25.
Artigo em Inglês | MEDLINE | ID: mdl-15178354

RESUMO

Studies with inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 inhibitor were conducted to assess their synergistic antinociceptive effect and possible therapeutic advantage. The antinociceptive interaction of rofecoxib, a selective cyclooxygenase-2 inhibitor, with aminoguanidine hydrochloride, a selective iNOS inhibitor, was examined in the formalin-induced paw-licking model in mice. Analysis of variance (ANOVA) and the isobolographic method were used to identify the nature of the antinociceptive interaction. Different doses of rofecoxib (1, 3, 10 and 30 mg/kg) and aminoguanidine hydrochloride (10, 30, 100 and 300 mg/kg) alone were administered orally to adult male albino mice (20-30 g). Only high doses of rofecoxib (10 and 30 mg/kg) and aminoguanidine hydrochloride (100 and 300 mg/kg) showed a statistically significant antinociceptive effect. Combination of a subthreshold dose of rofecoxib (1 mg/kg) with increasing doses of aminoguanidine hydrochloride (30, 100 and 300 mg/kg) resulted in potentiated antinociception (P<0.05). Combined therapy with a subthreshold dose of aminoguanidine hydrochloride (30 mg/kg) with increasing doses of rofecoxib (1, 3, 10 and 30 mg/kg) also resulted in significant antinociception (P<0.05). These results suggest that rofecoxib and aminoguanidine hydrochloride act synergistically in their antinociceptive action in mice. A possible mechanism of interaction is that nitric oxide (NO) stimulates the activity of cyclooxygenase-2 by combining with its heme component. Furthermore, the present results suggest that combination therapy with rofecoxib and aminoguanidine hydrochloride may provide an alternative for the clinical control of pain.


Assuntos
Inibidores de Ciclo-Oxigenase/farmacologia , Guanidinas/farmacologia , Lactonas/farmacologia , Óxido Nítrico Sintase/antagonistas & inibidores , Dor/tratamento farmacológico , Prostaglandina-Endoperóxido Sintases/metabolismo , Sulfonas/farmacologia , Animais , Ciclo-Oxigenase 2 , Inibidores de Ciclo-Oxigenase 2 , Inibidores de Ciclo-Oxigenase/administração & dosagem , Inibidores de Ciclo-Oxigenase/uso terapêutico , Relação Dose-Resposta a Droga , Sinergismo Farmacológico , Quimioterapia Combinada , Formaldeído , Guanidinas/administração & dosagem , Guanidinas/uso terapêutico , Lactonas/administração & dosagem , Lactonas/uso terapêutico , Masculino , Camundongos , Óxido Nítrico Sintase Tipo II , Dor/induzido quimicamente , Medição da Dor , Sulfonas/administração & dosagem , Sulfonas/uso terapêutico
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