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1.
Eur J Pharmacol ; 843: 190-198, 2019 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-30472202

RESUMO

Interleukin (IL)-23 is thought to be critical in the pathogenesis of psoriasis, and anti-IL-23 monoclonal antibodies (mAbs) have been approved for the treatment of psoriasis. We speculated that an anti-IL-23 receptor mAb might have greater efficacy than an anti-IL-23 mAb in the treatment of local inflamed lesions with high IL-23 levels. We previously generated an anti-human IL-23 receptor mAb, AS2762900-00, which potently blocked IL-23-induced cell proliferation, regardless of the concentration of IL-23. Here, we evaluated the therapeutic potential of AS2762900-00 in the treatment of psoriasis. Compared with untreated control, AS2762900-00 significantly reduced the epidermal thickness of lesions in a clinically relevant psoriatic human skin xenograft model. The expression of inflammatory genes including genes downstream of IL-23 signaling in the lesion tended to be lower in the AS2762900-00 group than the untreated group, suggesting that the inhibitory effects of AS2762900-00 in the psoriatic human skin xenograft model might occur via blockade of IL-23 signaling pathways. Further, AS2762900-00 showed an inhibitory effect on signal transducer and activator of transcription 3 (STAT3) phosphorylation as a downstream signal of IL-23 receptor activation in whole blood from patients with psoriasis. We also confirmed that AS2762900-00 inhibited IL-23-induced STAT3 phosphorylation in a concentration-dependent manner using whole blood from healthy donors. These data suggest that AS2762900-00 is a promising drug candidate for the treatment of psoriasis. In addition, STAT3 phosphorylation in whole blood may be a useful biomarker for the evaluation of the pharmacodynamic effects of AS2762900-00 in healthy volunteers in clinical development.


Assuntos
Anticorpos Monoclonais/farmacologia , Psoríase/tratamento farmacológico , Receptores de Interleucina/imunologia , Fator de Transcrição STAT3/metabolismo , Pele/efeitos dos fármacos , Animais , Modelos Animais de Doenças , Feminino , Humanos , Hiperplasia/prevenção & controle , Imunoglobulina G/imunologia , Camundongos , Fosforilação/efeitos dos fármacos , Psoríase/imunologia , Psoríase/metabolismo , Pele/imunologia , Pele/patologia , Transplante Heterólogo
2.
Eur J Pharmacol ; 828: 89-96, 2018 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-29588152

RESUMO

Interleukin (IL)-12 and IL-23 share a common subunit (p40) and function in T-helper (Th) 1 and Th17 immunity, respectively. Anti-IL-12/23p40 and specific anti-IL-23 antibodies are currently in clinical use for psoriasis and undergoing trials for autoimmune diseases. Since expression levels of the IL-23 receptor are likely to be much lower than those of IL-23, an anti-IL-23 receptor antibody might offer greater promise in inhibiting the IL-23-IL-17 pathways involved in inflammatory disorders. To our knowledge, no anti-IL-23 receptor antibody has been trialed in clinical studies to date. This study describes the generation and characterization of AS2762900-00, a fully human monoclonal antibody against the IL-23 receptor. AS2762900-00 bound both human and cynomolgus monkey IL-23 receptors. AS2762900-00 showed potent inhibitory effects on IL-23-induced Kit-225 cell proliferation compared to the existing anti-IL-12/23p40 antibody, ustekinumab. In a single dose administration pharmacodynamics study in cynomolgus monkeys, 1 mg/kg of AS2762900-00 significantly inhibited (> 85%) IL-23-induced STAT3 phosphorylation in blood for up to 84 days. Therefore, AS2762900-00 represents a potent novel IL-23-IL-17 pathway inhibitor with the potential to be developed into a new therapy for the treatment of autoimmune diseases.


Assuntos
Anticorpos Monoclonais/imunologia , Receptores de Interleucina/imunologia , Animais , Proliferação de Células/efeitos dos fármacos , Feminino , Humanos , Interleucina-23/farmacologia , Macaca fascicularis , Masculino
3.
Eur J Pharmacol ; 824: 163-169, 2018 Apr 05.
Artigo em Inglês | MEDLINE | ID: mdl-29391156

RESUMO

Experimental colitis studies, including T cell-mediated colitis, indicate that IL-23 rather than IL-12 orchestrates intestinal inflammation in inflammatory bowel disease (IBD). Previous studies have identified the roles of IL-12 and IL-23 using mice deficient for their specific subunits, p35 and p19, respectively. However, these studies do not completely reflect the difference in roles between IL-12 and IL-23, especially since the discovery of novel IL-12 family cytokines, which also include p35 or p19 subunits. Here, to clarify the contribution of IL-12 and IL-23 in T cell-mediated colitis, we compared the efficacy of a monoclonal antibody (mAb) to an IL-23-specific receptor subunit with that of an anti-IL-12/23p40 mAb in a naive CD4+ T cell transfer model of experimental colitis, which is associated with enhanced Th1 and Th17 responses. Both antibodies almost completely prevented the development of colitis and showed reduced associated histological changes, including mucosal hyperplasia, infiltration of inflammatory cells and loss of goblet cells. The anti-IL-23 receptor mAb inhibited not only the systemic Th17-response but also the Th1-response, both of which were up-regulated in this model. These results suggest that IL-23, but not IL-12, signaling is critical for the development of colitis. Blockade of IL-23 signaling is a promising therapeutic approach for IBD.


Assuntos
Anticorpos Monoclonais/imunologia , Linfócitos T CD4-Positivos/imunologia , Colite/imunologia , Colite/prevenção & controle , Interleucina-23/imunologia , Células Th1/imunologia , Células Th17/imunologia , Animais , Anticorpos Monoclonais/sangue , Masculino , Camundongos
4.
J Antibiot (Tokyo) ; 70(1): 45-51, 2017 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-27599768

RESUMO

The novel antifungal agent ASP2397 (Vical's compound ID VL-2397) is produced by the fungal strain MF-347833 that was isolated from Malaysian leaf litter and is identified here as an Acremonium species based on its morphology, physiological properties and 28S ribosomal DNA sequence. Because of its potential importance for producing novel antifungal agents, we determined the taxonomic and biologic properties of MF-347833. We show here that ASP2397 is a cyclic hexapeptide that chelates aluminum ion and is therefore similar to ferrichrome, a hydroxamate siderophore. However, ASP2397 differs structurally from licensed antifungal agents such as amphotericin B, triazoles and echinocandins. To understand the relationship between chemical structure and biological function, we isolated certain ASP2397 derivatives from the culture broth, and we further chemically converted the metal-free form to other derivatives.


Assuntos
Acremonium/metabolismo , Antifúngicos/isolamento & purificação , Antifúngicos/farmacologia , Complexos de Coordenação/farmacologia , Peptídeos Cíclicos/farmacologia , Alumínio/química , Antifúngicos/química , Complexos de Coordenação/química , Complexos de Coordenação/isolamento & purificação , Ferricromo/farmacologia , Malásia , Peptídeos Cíclicos/química , Peptídeos Cíclicos/isolamento & purificação , RNA Ribossômico 28S/genética
5.
J Antibiot (Tokyo) ; 70(1): 41-44, 2017 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-27577982

RESUMO

Natural products are the major source of currently available drugs. However, screening natural product presents several challenges, including the time-consuming and labor-intensive steps required for the isolation of a drug from crude extracts as well as the differences between the activities of compounds in vitro and in vivo. To address these challenges, we used silkworm larvae infected with Aspergillus fumigatus to screen a natural products library for potent drugs to treat invasive aspergillosis. A rationally designed library was constructed using numerous, geographically diverse fungal species and then screened to collect extracts of microorganisms that had detectable anti-Aspergillus activity. We evaluated this library using cultures of A. fumigatus and a silkworm model system of A. fumigatus infection. With this model, we identified the novel antifungal compound ASP2397 that not only cured infected silkworm larvae but also increased the rates of survival of mice infected with A. fumigatus. These findings strongly support the utility of the silkworm screening system for the simple and rapid isolation of antibiotics from natural products libraries.


Assuntos
Antifúngicos/farmacologia , Aspergilose/tratamento farmacológico , Aspergillus fumigatus/efeitos dos fármacos , Complexos de Coordenação/farmacologia , Peptídeos Cíclicos/farmacologia , Animais , Aspergilose/microbiologia , Bombyx , Modelos Animais de Doenças , Descoberta de Drogas/métodos , Feminino , Camundongos , Camundongos Endogâmicos ICR , Taxa de Sobrevida
6.
Bioorg Med Chem Lett ; 21(22): 6861-6, 2011 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-21963985

RESUMO

Oxidative stress is widely recognized as being associated with a number of disorders, including metabolic dysfunction and atherosclerosis. A series of substituted 4-quinolone derivatives were prepared and evaluated as inhibitors of reactive oxygen species (ROS) production from human umbilical vein endothelial cells (HUVECs). One compound in particular, 2-({[4-(3-hydroxy-3-methylbutoxy)pyridin-2-yl]oxy}methyl)-3-methylquinolin-4(1H)-one (25b), inhibited ROS production from HUVECs with an IC(50) of 140 nM. This compound also exhibited low CYP2D6 inhibitory activity, high aqueous solubility, and good in vitro metabolic stability. An in vivo pharmacokinetic study of this compound in SD rats revealed high oral bioavailability and a long plasma half-life.


Assuntos
4-Quinolonas/química , 4-Quinolonas/farmacologia , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Espécies Reativas de Oxigênio/antagonistas & inibidores , Espécies Reativas de Oxigênio/metabolismo , 4-Quinolonas/farmacocinética , Animais , Citocromo P-450 CYP2D6/metabolismo , Inibidores do Citocromo P-450 CYP2D6 , Células Endoteliais da Veia Umbilical Humana/metabolismo , Humanos , Ratos , Ratos Sprague-Dawley
7.
Diabetes ; 56(4): 901-11, 2007 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-17395738

RESUMO

Obesity is linked to a variety of metabolic disorders, such as insulin resistance and atherosclerosis. Dysregulated production of fat-derived secretory factors, adipocytokines, is partly responsible for obesity-linked metabolic disorders. However, the mechanistic role of obesity per se to adipocytokine dysregulation has not been fully elucidated. Here, we show that adipose tissue of obese mice is hypoxic and that local adipose tissue hypoxia dysregulates the production of adipocytokines. Tissue hypoxia was confirmed by an exogenous marker, pimonidazole, and by an elevated concentration of lactate, an endogenous marker. Moreover, local tissue hypoperfusion (measured by colored microspheres) was confirmed in adipose tissue of obese mice. Adiponectin mRNA expression was decreased, and mRNA of C/EBP homologous protein (CHOP), an endoplasmic reticulum (ER) stress-mediated protein, was significantly increased in adipose tissue of obese mice. In 3T3-L1 adipocytes, hypoxia dysregulated the expression of adipocytokines, such as adiponectin and plasminogen activator inhibitor type-1, and increased the mRNAs of ER stress marker genes, CHOP and GRP78 (glucose-regulated protein, 78 kD). Expression of CHOP attenuated adiponectin promoter activity, and RNA interference of CHOP partly reversed hypoxia-induced suppression of adiponectin mRNA expression in adipocytes. Hypoxia also increased instability of adiponectin mRNA. Our results suggest that hypoperfusion and hypoxia in adipose tissues underlie the dysregulated production of adipocytokines and metabolic syndrome in obesity.


Assuntos
Tecido Adiposo/fisiopatologia , Citocinas/genética , Hipóxia/fisiopatologia , Obesidade/fisiopatologia , Células 3T3 , Ração Animal , Animais , Primers do DNA , Proteínas de Ligação a DNA/genética , Gorduras na Dieta , Modelos Animais de Doenças , Chaperona BiP do Retículo Endoplasmático , Regulação da Expressão Gênica , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Proteínas Nucleares/genética , Obesidade/genética , Reação em Cadeia da Polimerase , Proteínas/genética , Splicing de RNA , RNA Mensageiro/genética , RNA Interferente Pequeno/genética , Fatores de Transcrição de Fator Regulador X , Fatores de Transcrição
8.
J Antibiot (Tokyo) ; 59(3): 145-8, 2006 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-16724454

RESUMO

The biological activities of the novel echinocandin-like lipopeptides, FR209602, FR209603 and FR209604, were evaluated. These compounds showed antifungal activity against Candida albicans and Aspergillus fumigatus attributed to inhibition of 1,3-beta-glucan synthesis. The minimum effective concentrations of these compounds against C. albicans and A1. fumigatus ranged from 0.02 to 0.04 microg/ml by microbroth dilution assay, and the IC50 values on C. albicans 1,3-beta-glucan synthase were 0.49, 0.64 and 0.72 microg/ml, respectively. FR209602 and FR209603 showed good efficacy by subcutaneous injection against C. albicans in a murine systemic infection model, with ED50 values of 2.0 and 1.9 mg/kg, respectively.


Assuntos
Antifúngicos/farmacologia , Lipoproteínas/farmacologia , Peptídeos Cíclicos/farmacologia , Animais , Candida albicans/efeitos dos fármacos , Candidíase/tratamento farmacológico , Feminino , Lipopeptídeos , Camundongos , Camundongos Endogâmicos ICR , Testes de Sensibilidade Microbiana
9.
J Antibiot (Tokyo) ; 58(8): 503-6, 2005 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-16266121

RESUMO

A novel glycogen phosphorylase inhibitor FR258900 was isolated from the cultured broth of a fungal strain No. 138354. We examined the hypoglycemic effects of FR258900 in diabetic animal models. FR258900 treatment significantly reduced the plasma glucose concentrations during oral glucose tolerance tests in diabetic mice models, including db/db mice and STZ-induced diabetic mice. Furthermore, FR258900 treatment resulted in rapid decrease in the plasma glucose levels in db/db mice. These improvements in glucose disposal were accompanied by increased liver glycogen contents, suggesting that the glucose lowering effects of FR258900 were attributed to suppressed hepatic glycogen breakdown and increased hepatic glycogen synthesis. Taken together, our results suggest that glycogen phosphorylase is a potentially useful target in new therapies against diabetes.


Assuntos
Fungos/química , Glicogênio Fosforilase/antagonistas & inibidores , Hipoglicemiantes/isolamento & purificação , Glicogênio Hepático/metabolismo , Animais , Glicemia/metabolismo , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Experimental/metabolismo , Modelos Animais de Doenças , Glicogênio/metabolismo , Hipoglicemiantes/uso terapêutico , Insulina/sangue , Fígado/enzimologia , Camundongos , Camundongos Endogâmicos C57BL
10.
J Antibiot (Tokyo) ; 58(8): 497-502, 2005 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-16266120

RESUMO

FR258900 is a novel glycogen synthesis activator produced by Fungus No. 138354. This compound was isolated from the culture broth by solvent extraction and reverse-phase column chromatography. FR258900 stimulated glycogen synthesis and glycogen synthase activity in primary rat hepatocytes. FR258900 exhibited a potent inhibitory effect on the activity of liver glycogen phosphorylase, suggesting that this compound may activate hepatic glycogen synthesis via glycogen phosphorylase inhibition. Thus, this glycogen phosphorylase inhibitor may be useful in the treatment of postprandial hyperglycemia in type 2 diabetes.


Assuntos
Cinamatos/isolamento & purificação , Inibidores Enzimáticos/isolamento & purificação , Fungos/classificação , Glutaratos/isolamento & purificação , Glicogênio Fosforilase/antagonistas & inibidores , Cromatografia Líquida de Alta Pressão , Cinamatos/farmacologia , Inibidores Enzimáticos/farmacologia , Fermentação , Fungos/química , Fungos/metabolismo , Glutaratos/farmacologia , Glicogênio/metabolismo
11.
Biochem Biophys Res Commun ; 328(2): 369-74, 2005 Mar 11.
Artigo em Inglês | MEDLINE | ID: mdl-15694357

RESUMO

Hyperglycemia-induced activation of hexosamine biosynthesis pathway (HBP) has been implicated in the development of insulin resistance in skeletal muscles. In the present study, the content of uridine-5'-diphospho-N-acetylglucosamine, the end product of the HBP, was elevated in skeletal muscle of obese diabetic KKA(y) mice, compared with control mice. To elucidate the effect of elevated HBP in the skeletal muscle, we treated C2C12 myoblasts with glucosamine, an intermediate metabolite of the HBP. Glucosamine induced lipid accumulation and significantly increased the mRNA expression levels of peroxisome proliferator-activated receptor gamma, adiponectin, and aP2 in C2C12 myoblasts. Similar mRNA changes were observed in skeletal muscles of Sprague-Dawley rats treated with glucosamine infusion. Our results provide a possible explanation of hyperglycemia-induced insulin resistance in skeletal muscle.


Assuntos
Adipócitos/metabolismo , Adipócitos/patologia , Metabolismo dos Lipídeos , Músculo Esquelético/metabolismo , Músculo Esquelético/patologia , Mioblastos/metabolismo , Mioblastos/patologia , Adipócitos/efeitos dos fármacos , Animais , Diferenciação Celular/efeitos dos fármacos , Linhagem Celular , Diabetes Mellitus Experimental/patologia , Diabetes Mellitus Experimental/fisiopatologia , Hexosaminas/metabolismo , Resistência à Insulina , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Músculo Esquelético/efeitos dos fármacos , Mioblastos/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Uridina Difosfato N-Acetilglicosamina/metabolismo
12.
J Clin Invest ; 114(12): 1752-61, 2004 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-15599400

RESUMO

Obesity is a principal causative factor in the development of metabolic syndrome. Here we report that increased oxidative stress in accumulated fat is an important pathogenic mechanism of obesity-associated metabolic syndrome. Fat accumulation correlated with systemic oxidative stress in humans and mice. Production of ROS increased selectively in adipose tissue of obese mice, accompanied by augmented expression of NADPH oxidase and decreased expression of antioxidative enzymes. In cultured adipocytes, elevated levels of fatty acids increased oxidative stress via NADPH oxidase activation, and oxidative stress caused dysregulated production of adipocytokines (fat-derived hormones), including adiponectin, plasminogen activator inhibitor-1, IL-6, and monocyte chemotactic protein-1. Finally, in obese mice, treatment with NADPH oxidase inhibitor reduced ROS production in adipose tissue, attenuated the dysregulation of adipocytokines, and improved diabetes, hyperlipidemia, and hepatic steatosis. Collectively, our results suggest that increased oxidative stress in accumulated fat is an early instigator of metabolic syndrome and that the redox state in adipose tissue is a potentially useful therapeutic target for obesity-associated metabolic syndrome.


Assuntos
Síndrome Metabólica/metabolismo , Obesidade/metabolismo , Estresse Oxidativo , Células 3T3-L1 , Adipócitos/metabolismo , Tecido Adiposo/metabolismo , Idoso , Animais , Antioxidantes/química , Antioxidantes/metabolismo , Peso Corporal , Diferenciação Celular , Citocinas/metabolismo , Relação Dose-Resposta a Droga , Feminino , Humanos , Peróxido de Hidrogênio/química , Peróxido de Hidrogênio/metabolismo , Immunoblotting/métodos , Peroxidação de Lipídeos , Masculino , Síndrome Metabólica/patologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Obesos , Pessoa de Meia-Idade , Modelos Biológicos , NADPH Oxidases/antagonistas & inibidores , NADPH Oxidases/metabolismo , Obesidade/patologia , Oxirredução , RNA Mensageiro/metabolismo , Espécies Reativas de Oxigênio , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Substâncias Reativas com Ácido Tiobarbitúrico/metabolismo , Fatores de Tempo
13.
J Antibiot (Tokyo) ; 56(2): 72-9, 2003 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-12715864
14.
J Antibiot (Tokyo) ; 56(2): 80-6, 2003 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-12715865

RESUMO

FR235222, a novel immunosuppressant which possesses potent inhibitory effects on the activity of mammalian histone deacetylases (HDACs), has been isolated from the fermentation broth of a fungus, Acremonium sp. No. 27082. FR235222 exhibited marked immunosuppressive effects on mouse ex vivo splenic T-lymphocyte proliferation, mouse delayed type hypersensitivity (DTH) response, rat adjuvant-induced arthritis (AA) and rat heterotopic cardiac transplantation. These results showed potential clinical use of this compound as a new type immunosuppressant in the fields of autoimmune diseases and organ transplantations.


Assuntos
Acremonium/metabolismo , Inibidores Enzimáticos/farmacologia , Inibidores de Histona Desacetilases , Imunossupressores/farmacologia , Peptídeos Cíclicos/farmacologia , Animais , Artrite Experimental/tratamento farmacológico , Artrite Experimental/imunologia , Células da Medula Óssea/citologia , Células da Medula Óssea/efeitos dos fármacos , Células da Medula Óssea/imunologia , Feminino , Sobrevivência de Enxerto/efeitos dos fármacos , Sobrevivência de Enxerto/imunologia , Transplante de Coração/imunologia , Hipersensibilidade Tardia/imunologia , Ativação Linfocitária/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Distribuição Aleatória , Ratos , Ratos Endogâmicos Lew , Linfócitos T/citologia , Linfócitos T/efeitos dos fármacos , Linfócitos T/imunologia
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