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1.
Expert Opin Ther Pat ; 30(1): 27-38, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31771391

RESUMO

Introduction: The activation of free fatty acid receptor 1 (FFAR1) induces insulin secretion in a glucose-dependent manner, and thereby is considered as an attractive anti-diabetic target. The clinical studies provided a lot of evidence that FFAR1 agonists improved glucose control in T2DM without the risk of hypoglycemia. The field of FFAR1 agonists is extremely competitive with many patent applications filed in recent years identifying potent candidates.Area covered: The present review summarizes patent applications (2016-2019) filing for FFAR1 modulators, including FFAR1 partial/full agonists, atypical agonists, and multiple target agonists, along with in vitro and in vivo evaluation.Expert opinion: The clinical studies of FFAR1 agonists have proved their potential for the improvement of glucose control. However, there are a few issues still to be solved in this field since TAK-875 terminated in Phase III studies due to liver toxicity. The biggest challenge on the development of FFAR1 agonists may not be the identification of a highly potent compound, but finding out the exact mechanisms of hepatotoxicity and avoid it. Moreover, the further exploration of chemical spaces on FFAR1 full agonists and multi-targeted agonists, as well as corresponding clinical studies, will be expected and might open up new directions in this field.


Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Hipoglicemiantes/farmacologia , Receptores Acoplados a Proteínas-G/agonistas , Animais , Benzofuranos/efeitos adversos , Benzofuranos/farmacologia , Diabetes Mellitus Tipo 2/fisiopatologia , Desenvolvimento de Medicamentos , Humanos , Hipoglicemiantes/efeitos adversos , Insulina/metabolismo , Secreção de Insulina/efeitos dos fármacos , Patentes como Assunto , Receptores Acoplados a Proteínas-G/metabolismo , Sulfonas/efeitos adversos , Sulfonas/farmacologia
2.
Gut ; 69(1): 146-157, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-30723104

RESUMO

OBJECTIVE: We explored the hypothesis that TGR5, the bile acid (BA) G-protein-coupled receptor highly expressed in biliary epithelial cells, protects the liver against BA overload through the regulation of biliary epithelium permeability. DESIGN: Experiments were performed under basal and TGR5 agonist treatment. In vitro transepithelial electric resistance (TER) and FITC-dextran diffusion were measured in different cell lines. In vivo FITC-dextran was injected in the gallbladder (GB) lumen and traced in plasma. Tight junction proteins and TGR5-induced signalling were investigated in vitro and in vivo (wild-type [WT] and TGR5-KO livers and GB). WT and TGR5-KO mice were submitted to bile duct ligation or alpha-naphtylisothiocyanate intoxication under vehicle or TGR5 agonist treatment, and liver injury was studied. RESULTS: In vitro TGR5 stimulation increased TER and reduced paracellular permeability for dextran. In vivo dextran diffusion after GB injection was increased in TGR5-knock-out (KO) as compared with WT mice and decreased on TGR5 stimulation. In TGR5-KO bile ducts and GB, junctional adhesion molecule A (JAM-A) was hypophosphorylated and selectively downregulated among TJP analysed. TGR5 stimulation induced JAM-A phosphorylation and stabilisation both in vitro and in vivo, associated with protein kinase C-ζ activation. TGR5 agonist-induced TER increase as well as JAM-A protein stabilisation was dependent on JAM-A Ser285 phosphorylation. TGR5 agonist-treated mice were protected from cholestasis-induced liver injury, and this protection was significantly impaired in JAM-A-KO mice. CONCLUSION: The BA receptor TGR5 regulates biliary epithelial barrier function in vitro and in vivo through an impact on JAM-A expression and phosphorylation, thereby protecting liver parenchyma against bile leakage.


Assuntos
Sistema Biliar/fisiopatologia , Colestase Intra-Hepática/prevenção & controle , Receptores Acoplados a Proteínas-G/fisiologia , Animais , Bile/metabolismo , Ácidos e Sais Biliares/metabolismo , Moléculas de Adesão Celular/metabolismo , Células Cultivadas , Colestase Intra-Hepática/metabolismo , Impedância Elétrica , Epitélio/fisiopatologia , Ácidos Isonipecóticos/farmacologia , Ácidos Isonipecóticos/uso terapêutico , Camundongos Endogâmicos C57BL , Camundongos Knockout , Oximas/farmacologia , Oximas/uso terapêutico , Permeabilidade , Fosforilação/fisiologia , Receptores de Superfície Celular/metabolismo , Receptores Acoplados a Proteínas-G/agonistas , Transdução de Sinais/fisiologia , Proteínas de Junções Íntimas/metabolismo
3.
J Enzyme Inhib Med Chem ; 35(1): 50-58, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31656107

RESUMO

GPR119 is a promising target for discovery of anti-type 2 diabetes mellitus agents. We described the optimisation of a novel series of pyrimido[5,4-b][1,4]oxazine derivatives as GPR119 agonists. Most designed compounds exhibited good agonistic activities. Among them, compound 10 and 15 demonstrated the potent EC50 values (13 and 12 nM, respectively) and strong inherent activities. Moreover, significant hypoglycaemic effect of compound 15 was observed by reducing the blood glucose AUC0-2h at the dose of 30 mg/kg, which is stronger than Vildagliptin (23.4% reduction vs. 17.9% reduction).


Assuntos
Hipoglicemiantes/farmacologia , Oxazinas/farmacologia , Pirimidinas/farmacologia , Receptores Acoplados a Proteínas-G/agonistas , Animais , Glicemia/efeitos dos fármacos , Relação Dose-Resposta a Droga , Teste de Tolerância a Glucose , Humanos , Hipoglicemiantes/síntese química , Hipoglicemiantes/química , Camundongos , Camundongos Endogâmicos C57BL , Estrutura Molecular , Oxazinas/síntese química , Oxazinas/química , Pirimidinas/síntese química , Pirimidinas/química , Relação Estrutura-Atividade
4.
Curr Top Med Chem ; 19(26): 2378-2392, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31833462

RESUMO

G protein-coupled receptors (GPCRs) represent the largest family of proteins targeted by drug design and discovery efforts. Of these efforts, the development of GPCR agonists is highly desirable, due to their therapeutic robust utility in treating diseases caused by deficient receptor signaling. One of the challenges in designing potent and selective GPCR agonists lies in the inability to achieve combined high binding affinity and subtype selectivity, due to the high homology between orthosteric sites among GPCR subtypes. To combat this difficulty, researchers have begun to explore the utility of targeting topographically distinct and less conserved binding sites, namely "allosteric" sites. Pursuing these sites offers the benefit of achieving high subtype selectivity, however, it also can result in a decreased binding affinity and potency as compared to orthosteric agonists. Therefore, bitopic ligands comprised of an orthosteric agonist and an allosteric modulator connected by a spacer and allowing binding with both the orthosteric and allosteric sites within one receptor, have been developed. It may combine the high subtype selectivity of an allosteric modulator with the high binding affinity of an orthosteric agonist and provides desired advantages over orthosteric agonists or allosteric modulators alone. Herein, we review the recent advances in the development of bitopic agonists/activators for various GPCR targets and their novel therapeutic potentials.


Assuntos
Desenvolvimento de Medicamentos/métodos , Receptores Acoplados a Proteínas-G/agonistas , Sítio Alostérico , Sequência de Aminoácidos , Animais , Sítios de Ligação , Humanos , Ligantes , Receptores Acoplados a Proteínas-G/química , Homologia de Sequência de Aminoácidos
6.
Endocrinology ; 160(12): 2959-2968, 2019 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-31613319

RESUMO

Longitudinal observation of pancreatic ß-cell mass (BCM) remains challenging because noninvasive techniques for determining BCM in vivo have not been established. Such observations would be useful for the monitoring of type 2 diabetes mellitus, a progressive disease involving loss of pancreatic BCM and function. An indium 111 (111In)-labeled exendin-4 derivative ([Lys12(111In-BnDTPA-Ahx)]exendin-4) targeting the glucagon-like peptide-1 receptor has been developed recently as a promising probe for quantifying the BCM noninvasively. In the present study, we used the 111In-exendin-4 single-photon emission CT/CT (SPECT/CT) technique to investigate the efficacy of DS-8500a, a novel G protein-coupled receptor-119 agonist currently under investigation for type 2 diabetes mellitus treatment in prediabetic db/db mice under dietary restriction. During the 8-week study, the treatment of mice with DS-8500a delayed and attenuated the progression of glucose intolerance compared with mice under dietary restriction alone. 111In-exendin-4 SPECT/CT of db/db mice revealed continuously decreasing radioactive isotope (RI) intensity in the pancreas during the 8-week intervention. DS-8500a attenuated this decrease and preserved pancreatic RI accumulation compared with dietary restriction alone at the end of the observation period. This result was corroborated not only by ex vivo pancreatic analysis using the [Lys12(111In-BnDTPA-Ahx)]exendin-4 probe but also by conventional histological BCM analysis. These results indicate that DS-8500a attenuates the progression of BCM loss beyond that of dietary restriction alone in prediabetic db/db mice. These results have shown that 111In-exendin-4 SPECT/CT will be useful for noninvasive longitudinal investigation of BCM in vivo.


Assuntos
Benzamidas/farmacologia , Ciclopropanos/farmacologia , Diabetes Mellitus Experimental/diagnóstico por imagem , Hipoglicemiantes/farmacologia , Células Secretoras de Insulina/efeitos dos fármacos , Oxidiazóis/farmacologia , Receptores Acoplados a Proteínas-G/agonistas , Animais , Benzamidas/uso terapêutico , Ciclopropanos/uso terapêutico , Diabetes Mellitus Experimental/tratamento farmacológico , Exenatida , Hipoglicemiantes/uso terapêutico , Radioisótopos de Índio , Estudos Longitudinais , Masculino , Camundongos Endogâmicos C57BL , Oxidiazóis/uso terapêutico , Tomografia Computadorizada com Tomografia Computadorizada de Emissão de Fóton Único
8.
Artif Cells Nanomed Biotechnol ; 47(1): 3569-3576, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31448639

RESUMO

Osteoporosis-related bone fracture and falls have a severe impact on patients' daily lives. Osteoblasts are bone-building cells that play a vital role in bone formation and remodeling. Imbalanced osteoblast differentiation could lead to osteoporosis. GPR39 is an orphan G protein-coupled receptor that mediates metabolic pathways. In this study, we show that GPR39 is expressed in MC3T3-E1 cells. Osteoblast differentiation culture media induces GPR39, suggesting that GPR39 is a differentiation-responsive factor. Activation of GPR39 using its selective agonist TC-G 1008 induces alkaline phosphatase (ALP), osteocalcin (OCN), and type I collagen (Col-I) expression, and increases cellular ALP activity and calcium deposition, implying that GPR activation promotes cells toward osteoblast differentiation. Treatment with TC-G 1008 also increases Runx-2 expression and AMPK activation. However, the inhibition of AMPK by Compound C abolished TC-G 1008-mediated ALP, OCN, and Col-I induction, and reduces ALP activity and cellular calcium deposition as well as Runx-2 induction. These data indicate that TC-G 1008-mediated GPR39 activation involves AMPK-mediated Runx-2 induction. In summary, our study uncovers a new role of GPR39 activation in osteoblast differentiation, implying that GPR39 could be a promising therapeutic target for osteoporosis.


Assuntos
Diferenciação Celular/efeitos dos fármacos , Minerais/metabolismo , Osteoblastos/citologia , Osteoblastos/efeitos dos fármacos , Pirimidinas/farmacologia , Receptores Acoplados a Proteínas-G/agonistas , Sulfonamidas/farmacologia , Células 3T3 , Proteínas Quinases Ativadas por AMP/metabolismo , Animais , Linhagem Celular , Subunidade alfa 1 de Fator de Ligação ao Core/genética , Subunidade alfa 1 de Fator de Ligação ao Core/metabolismo , Ativação Enzimática/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Camundongos , Óxido Nítrico/biossíntese , Óxido Nítrico Sintase Tipo III/metabolismo , Osteoblastos/metabolismo , Osteogênese/efeitos dos fármacos , Fosforilação/efeitos dos fármacos
9.
Sheng Li Xue Bao ; 71(4): 527-536, 2019 Aug 25.
Artigo em Chinês | MEDLINE | ID: mdl-31440749

RESUMO

The aim of this study was to investigate whether G protein-coupled estrogen receptor (GPER) could alleviate hippocampal neuron injury under cerebral ischemia-reperfusion injury (CIRI) by acting on endoplasmic reticulum stress (ERS). The CIRI animal model was established by middle cerebral artery occlusion (MCAO). Female ovariectomized (OVX) Sprague-Dawley (SD) female rats were randomly divided into 4 groups: control, ischemia-reperfusion injury (MCAO), vehicle (MCAO+DMSO), and GPER-specific agonist G1 (MCAO+G1) groups. The neurobehavioral score was assessed by the Longa score method, the morphological changes of the neurons were observed by the Nissl staining, the cerebral infarction was detected by the TTC staining, and the neural apoptosis in the hippocampal CA1 region was detected by TUNEL staining. The distribution and expression of GRP78 (78 kDa glucose-regulated protein 78) in the hippocampal CA1 region were observed by immunofluorescent staining. The protein expression levels of GRP78, Caspase-12, CHOP and Caspase-3 were detected by Western blot, and the mRNA expression levels of GRP78, Caspase-12, and CHOP were detected by the real-time PCR. The results showed that the neurobehavioral score, cerebral infarct volume, cellular apoptosis index, as well as GRP78, Caspase-12 and CHOP protein and mRNA expression levels in the MCAO group were significantly higher than those of control group. And G1 reversed the above-mentioned changes in the MCAO+G1 group. These results suggest that the activation of GPER can decrease the apoptosis of hippocampal neurons and relieve CIRI, and its mechanism may involve the inhibition of ERS.


Assuntos
Isquemia Encefálica , Estresse do Retículo Endoplasmático , Neurônios/citologia , Receptores Estrogênicos/fisiologia , Receptores Acoplados a Proteínas-G/agonistas , Traumatismo por Reperfusão , Animais , Apoptose , Região CA1 Hipocampal/citologia , Caspase 12/metabolismo , Caspase 3/metabolismo , Feminino , Proteínas de Choque Térmico/metabolismo , Distribuição Aleatória , Ratos , Ratos Sprague-Dawley , Fator de Transcrição CHOP/metabolismo
10.
Cell Host Microbe ; 26(2): 273-282.e7, 2019 08 14.
Artigo em Inglês | MEDLINE | ID: mdl-31378678

RESUMO

Despite evidence linking the human microbiome to health and disease, how the microbiota affects human physiology remains largely unknown. Microbiota-encoded metabolites are expected to play an integral role in human health. Therefore, assigning function to these metabolites is critical to understanding these complex interactions and developing microbiota-inspired therapies. Here, we use large-scale functional screening of molecules produced by individual members of a simplified human microbiota to identify bacterial metabolites that agonize G-protein-coupled receptors (GPCRs). Multiple metabolites, including phenylpropanoic acid, cadaverine, 9-10-methylenehexadecanoic acid, and 12-methyltetradecanoic acid, were found to interact with GPCRs associated with diverse functions within the nervous and immune systems, among others. Collectively, these metabolite-receptor pairs indicate that diverse aspects of human health are potentially modulated by structurally simple metabolites arising from primary bacterial metabolism.


Assuntos
Bactérias/metabolismo , Interações entre Hospedeiro e Microrganismos/imunologia , Interações entre Hospedeiro e Microrganismos/fisiologia , Microbiota/imunologia , Microbiota/fisiologia , Receptores Acoplados a Proteínas-G/agonistas , Proteínas Angiogênicas/agonistas , Animais , Cadaverina/metabolismo , Cadaverina/farmacologia , Ácidos Graxos/metabolismo , Ácidos Graxos/farmacologia , Fermentação , Vida Livre de Germes , Agonistas dos Receptores Histamínicos , Humanos , Sistema Imunitário , Ligantes , Camundongos , Camundongos Endogâmicos C57BL , Modelos Animais , Propionatos/metabolismo , Propionatos/farmacologia , Receptores Acoplados a Proteínas-G/metabolismo , Receptores Histamínicos/efeitos dos fármacos , Receptores de Neurotransmissores/agonistas
11.
Int J Mol Sci ; 20(14)2019 Jul 10.
Artigo em Inglês | MEDLINE | ID: mdl-31295865

RESUMO

G-protein-coupled receptor 40 (GPR40) has an anti-apoptotic effect in pancreatic ß-cells. However, its role in renal tubular cell apoptosis remains unclear. To explore the role of GPR40 in renal tubular apoptosis, a two-week unilateral ureteral obstruction (UUO) mouse model was used. The protein expression of GPR40 was decreased, while the Bax/Bcl-2 protein expression ratio, the expression of tumor necrosis factor (TNF)-α mRNA, and angiotensin II type 1 receptor (AT1R) protein were increased in mice with UUO. In vitro, pretreatment of rat proximal tubular (NRK52E) cells with GW9508, a GPR40 agonist, attenuated the decreased cell viability, increased the Bax/Bcl-2 protein expression ratio, increased protein expression of cleaved caspase-3 and activated the nuclear translocation of nuclear factor-κB (NF-κB) p65 subunit induced by TNF-α treatment. TNF-α treatment significantly increased the expression of AT1R protein and the generation of reactive oxygen species (ROS), whereas GW9508 treatment markedly reversed these effects. Pretreatment with GW1100, a GPR40 antagonist, or silencing of GPR40 in NRK52E cells promoted the increased expression of the cleaved caspase-3 protein by TNF-α treatment. Our results demonstrate that decreased expression of GPR40 is associated with apoptosis via TNF-α and AT1R in the ureteral obstructed kidney. The activation of GPR40 attenuates TNF-α-induced apoptosis by inhibiting AT1R expression and ROS generation through regulation of the NF-κB signaling pathway.


Assuntos
Lesão Renal Aguda/metabolismo , Apoptose/efeitos dos fármacos , Túbulos Renais Proximais/efeitos dos fármacos , Túbulos Renais Proximais/metabolismo , Receptores Acoplados a Proteínas-G/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Lesão Renal Aguda/tratamento farmacológico , Lesão Renal Aguda/etiologia , Lesão Renal Aguda/patologia , Animais , Apoptose/genética , Biomarcadores , Modelos Animais de Doenças , Imunofluorescência , Expressão Gênica , Imuno-Histoquímica , Túbulos Renais Proximais/patologia , Masculino , Ratos , Receptores Acoplados a Proteínas-G/agonistas , Receptores Acoplados a Proteínas-G/genética , Transdução de Sinais/efeitos dos fármacos , Fator de Necrose Tumoral alfa/farmacologia , Obstrução Ureteral/complicações , Obstrução Ureteral/genética , Obstrução Ureteral/metabolismo
12.
Clin Drug Investig ; 39(10): 967-978, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31321631

RESUMO

BACKGROUND: Non-clinical study data suggest that DS-8500a, a G protein-coupled receptor 119 agonist, exhibits antidiabetic activity, inhibition of some transporters and induction of cytochrome P450 (CYP) 3A. Statins are substrates for some transporters and CYP3A that may be coadministered with DS-8500a in clinical practice. OBJECTIVE: To determine the potential effects of DS-8500a on the pharmacokinetics of statins, we evaluated the effects of repeated oral administration of DS-8500a 75 mg on the pharmacokinetics of rosuvastatin and atorvastatin in healthy adults. METHODS: We performed two single-center, open-label, single-sequence studies. In Study I, subjects received single-dose rosuvastatin 10 mg (Period A) and DS-8500a 75 mg once daily + single-dose rosuvastatin 10 mg (Period B). In Study II, subjects received single-dose atorvastatin 10 mg (Period A) and DS-8500a 75 mg once daily + single-dose atorvastatin 10 mg (Period B). Primary pharmacokinetic endpoints were maximum plasma concentration (Cmax) and area under the plasma concentration-time curve (AUC) of rosuvastatin and atorvastatin. Safety was evaluated. RESULTS: In Study I, the Cmax and AUC of rosuvastatin increased by 66% and 33%, respectively, when coadministered with DS-8500a, versus rosuvastatin alone. In Study II, the Cmax of atorvastatin increased by 28%, but AUC remained unchanged following coadministration with DS-8500a, versus atorvastatin alone. Treatment-emergent adverse events were mild to moderate and mostly unrelated to the study drugs. CONCLUSIONS: Multiple doses of DS-8500a increased exposure to rosuvastatin and atorvastatin. This short-term study suggests that the impact of DS-8500a coadministration on atorvastatin exposure is limited and may not be clinically relevant. Nevertheless, caution may be necessary when patients are coadministered rosuvastatin with DS-8500a. CLINICALTRIALS. GOV IDENTIFIER: NCT03699774. JAPAN PHARMACEUTICAL INFORMATION CENTER IDENTIFIER: JapicCTI-152878.


Assuntos
Atorvastatina/farmacocinética , Benzamidas/farmacocinética , Ciclopropanos/farmacocinética , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacocinética , Hipoglicemiantes/farmacocinética , Oxidiazóis/farmacocinética , Receptores Acoplados a Proteínas-G/agonistas , Rosuvastatina Cálcica/farmacocinética , Adulto , Atorvastatina/administração & dosagem , Benzamidas/administração & dosagem , Estudos Cross-Over , Ciclopropanos/administração & dosagem , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/epidemiologia , Interações de Medicamentos/fisiologia , Feminino , Voluntários Saudáveis , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/administração & dosagem , Hipoglicemiantes/administração & dosagem , Japão/epidemiologia , Masculino , Pessoa de Meia-Idade , Oxidiazóis/administração & dosagem , Rosuvastatina Cálcica/administração & dosagem
13.
Eur J Med Chem ; 179: 608-622, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31279294

RESUMO

Based on an old phenoxyacetic acid scaffold, CPU014 (compound 14) has been identified as a superior agonist by comprehensive exploration of structure-activity relationship. In vitro toxicity study suggested that CPU014 has lower risk of hepatotoxicity than TAK-875. During acute toxicity study (5-500 mg/kg), a favorable therapeutic window of CPU014 was observed by evaluation of plasma profiles and liver slices. Moreover, CPU014 promotes insulin secretion in a glucose-dependent manner, while no GLP-1 secretion has been enhanced. Other than good pharmacokinetic properties, CPU014 significantly improved glucose tolerance both in normal and diabetic models without the risk of hypoglycemia. These subversive findings provided a safer candidate CPU014, which is currently in preclinical study to assess its potential for the treatment of diabetes.


Assuntos
Acetatos/farmacologia , Diabetes Mellitus Tipo 2/tratamento farmacológico , Desenho de Drogas , Hipoglicemiantes/farmacologia , Receptores Acoplados a Proteínas-G/agonistas , Acetatos/síntese química , Acetatos/química , Animais , Diabetes Mellitus Tipo 2/metabolismo , Relação Dose-Resposta a Droga , Teste de Tolerância a Glucose , Hipoglicemiantes/síntese química , Hipoglicemiantes/química , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos ICR , Estrutura Molecular , Ratos , Ratos Sprague-Dawley , Receptores Acoplados a Proteínas-G/metabolismo , Relação Estrutura-Atividade
14.
Chem Commun (Camb) ; 55(61): 8975-8978, 2019 Aug 07.
Artigo em Inglês | MEDLINE | ID: mdl-31290492
15.
Biomed Pharmacother ; 117: 109172, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31261028

RESUMO

Macrophages in the kidney play different roles in renal interstitial fibrosis (RIF) depending on their phenotypes. M2 phenotype macrophages are believed to protect the kidney against RIF. Free fatty acid receptor GPR120 is expressed in macrophages, and its activation induces macrophage transition to M2 phenotype. In this study, the effects of GPR120 agonist-programmed macrophages on RIF were investigated. The peritoneal macrophages collected from rats were incubated with GPR120 agonist TUG891 in vitro for 24 h, and then they were transplanted autologously to the kidney with ureteral obstruction by intrarenal injection for 7 days on the same day following unilateral ureteral obstruction (UUO) operation. RIF was identified by Masson trichrome histological staining, and the expression of RIF-related proteins was analyzed by immunohistochemistry and western blot. It was observed that TUG891-programmed macrophages up-regulated the expression of CD206 and arginase-1 while the expression of interleukin-6 and tumor necrosis factor-α were down-regulated. RIF in rats was significantly increased following UUO, which was markedly alleviated by TUG891-programmed macrophages but not untreated macrophages. TUG891-programmed macrophages inhibited the abnormal expression of TGF-ß1 and SMAD2. The abnormal expression of epithelial-mesenchymal transition (EMT)-related proteins including vimentin, α-SMA and ß-catenin was also significantly decreased in rats with transplantation of TUG891-programmed macrophages as compared to UUO rats. This study suggests that autologous administration of peritoneal macrophages programmed in vitro by GPR120 agonist to kidney has a protective effect against RIF following UUO.


Assuntos
Nefropatias/patologia , Macrófagos Peritoneais/metabolismo , Substâncias Protetoras/farmacologia , Receptores Acoplados a Proteínas-G/agonistas , Obstrução Ureteral/complicações , Animais , Compostos de Bifenilo/farmacologia , Citocinas/metabolismo , Fibrose , Regulação da Expressão Gênica/efeitos dos fármacos , Nefropatias/genética , Macrófagos Peritoneais/efeitos dos fármacos , Macrófagos Peritoneais/transplante , Masculino , Modelos Biológicos , Fenótipo , Fenilpropionatos/farmacologia , Ratos Sprague-Dawley , Receptores Acoplados a Proteínas-G/metabolismo , Transdução de Sinais/efeitos dos fármacos , Fator de Crescimento Transformador beta1/metabolismo , Obstrução Ureteral/genética , Vimentina/metabolismo , beta Catenina/metabolismo
16.
Int J Mol Sci ; 20(14)2019 Jul 12.
Artigo em Inglês | MEDLINE | ID: mdl-31336833

RESUMO

Leukocyte infiltration is a hallmark of inflammatory responses. This process depends on the bacterial and host tissue-derived chemotactic factors interacting with G-protein-coupled seven-transmembrane receptors (GPCRs) expressed on the cell surface. Formylpeptide receptors (FPRs in human and Fprs in mice) belong to the family of chemoattractant GPCRs that are critical mediators of myeloid cell trafficking in microbial infection, inflammation, immune responses and cancer progression. Both murine Fprs and human FPRs participate in many patho-physiological processes due to their expression on a variety of cell types in addition to myeloid cells. FPR contribution to numerous pathologies is in part due to its capacity to interact with a plethora of structurally diverse chemotactic ligands. One of the murine Fpr members, Fpr2, and its endogenous agonist peptide, Cathelicidin-related antimicrobial peptide (CRAMP), control normal mouse colon epithelial growth, repair and protection against inflammation-associated tumorigenesis. Recent developments in FPR (Fpr) and ligand studies have greatly expanded the scope of these receptors and ligands in host homeostasis and disease conditions, therefore helping to establish these molecules as potential targets for therapeutic intervention.


Assuntos
Fatores Quimiotáticos/metabolismo , Receptores de Formil Peptídeo/metabolismo , Sequência de Aminoácidos , Animais , Proteínas de Bactérias/química , Proteínas de Bactérias/metabolismo , Quimiotaxia , Quimiotaxia de Leucócito/imunologia , Descoberta de Drogas , Interações Hospedeiro-Patógeno/genética , Interações Hospedeiro-Patógeno/imunologia , Humanos , Leucócitos/imunologia , Leucócitos/metabolismo , Ligantes , Peptídeos/química , Peptídeos/metabolismo , Receptores de Formil Peptídeo/agonistas , Receptores Acoplados a Proteínas-G/agonistas , Receptores Acoplados a Proteínas-G/metabolismo , Transdução de Sinais , Proteínas Virais/química , Proteínas Virais/metabolismo
17.
Biol Pharm Bull ; 42(8): 1415-1418, 2019 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-31167986

RESUMO

The protective effects of G protein-coupled receptor 39 (GPR39) on concanavalin A (Con A)-induced hepatitis in mice was examined. In a dose dependent manner and at 24 h after the elicitation by Con A, oral administration of TC-G 1008, a GPR39 agonist, reduced both, the glutamic-pyruvic transaminase levels (a marker for liver injury) and the necrosis area, as revealed by the histological analysis of tissues from mice with Con A-induced hepatitis. TC-G 1008 also suppressed serum interleukin (IL)-6 and tumor necrosis factor (TNF)-α significantly at 6 h after the elicitation, suggesting that the cells producing IL-6 and/or TNF-α are the targets of TC-G 1008. One potential target cell appears to be a monocyte-derived macrophages because TC-G 1008 treatment suppressed lipopolysaccharide-induced IL-6 production from U937 macrophages in vitro. Taken together, GPR39 agonist TC-G 1008 ameliorates liver injury in the Con A model by blocking pro-inflammatory cytokine production. Use of GPR39 agonists for monotherapy or in combination with immunosuppressants might prove to be beneficial in the treatment of autoimmune hepatitis.


Assuntos
Doença Hepática Induzida por Substâncias e Drogas/tratamento farmacológico , Hepatite/tratamento farmacológico , Pirimidinas/farmacologia , Receptores Acoplados a Proteínas-G/agonistas , Receptores Acoplados a Proteínas-G/metabolismo , Sulfonamidas/farmacologia , Animais , Técnicas de Cultura de Células , Doença Hepática Induzida por Substâncias e Drogas/patologia , Concanavalina A/farmacologia , Humanos , Imidazóis/farmacologia , Interleucina-10/sangue , Interleucina-10/metabolismo , Interleucina-6/sangue , Interleucina-6/metabolismo , Fígado/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Modelos Animais , Pirazóis/farmacologia , Piridazinas/farmacologia , Fator de Necrose Tumoral alfa/sangue , Fator de Necrose Tumoral alfa/metabolismo , Células U937
18.
Artif Cells Nanomed Biotechnol ; 47(1): 2612-2617, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31237151

RESUMO

Aging-related osteoarthritis (OA) is the most common type of arthritis. Chondrocyte senescence has been linked with the pathogenesis of OA. Here, we examined the expression of GPR39 in chondrocytes and its modulatory effect on IL-1ß-induced cellular senescence. We show that GPR39 is moderately expressed in human chondrocytes and its expression is repressed by the pro-inflammatory cytokine IL-1ß. The GPR39 agonist TC-G 1008 mitigates IL-1ß-induced chondrocyte senescence. Mechanistically, we show that TC-G 1008 mitigates IL-1ß-induced cell cycle arrest at G1 phase by suppressing the expression of p53, p21, PAI-1, and K382 acetylation of p53. Moreover, we show that TC-G 1008 treatment restores IL-1ß-induced inhibition of SIRT1 and the silencing of SIRT1 abolishes the function of TC-G 1008 on p53 acetylation and senescence, suggesting that the function of GPR39 signaling is mediated by SIRT1 in chondrocytes. Altogether, our findings implicate that the activation of GPR39 signaling ameliorates IL-1ß-induced chondrocyte senescence and the GPR39 agonist TC-G 1008 could have the potential to modulate aging-associated OA.


Assuntos
Senescência Celular/efeitos dos fármacos , Condrócitos/citologia , Condrócitos/efeitos dos fármacos , Interleucina-1beta/farmacologia , Pirimidinas/farmacologia , Receptores Acoplados a Proteínas-G/agonistas , Sulfonamidas/farmacologia , Acetilação/efeitos dos fármacos , Linhagem Celular , Condrócitos/metabolismo , Inibidor de Quinase Dependente de Ciclina p21/metabolismo , Pontos de Checagem da Fase G1 do Ciclo Celular/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Inibidor 1 de Ativador de Plasminogênio/química , Inibidor 1 de Ativador de Plasminogênio/metabolismo , Receptores Acoplados a Proteínas-G/genética , Receptores Acoplados a Proteínas-G/metabolismo , Transdução de Sinais/efeitos dos fármacos , Sirtuína 1/antagonistas & inibidores , Proteína Supressora de Tumor p53/metabolismo
19.
J Pharmacol Sci ; 140(2): 144-152, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31242961

RESUMO

G protein-coupled receptor (GPR) 40 is a receptor for long-chain free fatty acids that enhances glucagon-like peptide (GLP)-2 production in intestinal L-cells. GLP-2 and its analogs have reported to increase remission rates in patients with Crohn's disease and improve experimental colitis in rodents. In the present study, we investigated the ameliorative effect of GPR40 activation in a dextran sulfate sodium (DSS)-induced murine colitis model using a specific GPR40 agonist, AS2034178. The daily administration of AS2034178 attenuated DSS-induced increases in the disease activity index, the shortening of the colon length, and the histological colonic injury, and increased the myeloperoxidase (MPO) activity and expression of inflammatory cytokines, in a dose-dependent manner. These effects were abolished by treatment with DC260126, a GPR40 antagonist, or GLP-2 (3-33), a GLP-2 antagonist. GPR40 was expressed in the colonic mucosa, which was colocalized with proglucagon, a precursor of GLP-2. AS2034178 significantly increased the amount of GLP-2 in the colonic tissue, which was abolished by DC260126 but not GLP-2 (3-33). Furthermore, AS2034178 significantly promoted the healing of DSS-induced colitis. These findings suggest that GPR40 activation ameliorates DSS-induced colitis in mice by enhancing GLP-2 production. Thus, GPR40 is a potential target for the treatment of IBD.


Assuntos
Compostos de Bifenilo/farmacologia , Compostos de Bifenilo/uso terapêutico , Colite/tratamento farmacológico , Colite/genética , Sulfato de Dextrana/efeitos adversos , Peptídeo 2 Semelhante ao Glucagon/metabolismo , Oxidiazóis/farmacologia , Oxidiazóis/uso terapêutico , Receptores Acoplados a Proteínas-G/agonistas , Receptores Acoplados a Proteínas-G/metabolismo , Regulação para Cima/genética , Animais , Compostos de Bifenilo/administração & dosagem , Colite/induzido quimicamente , Colite/metabolismo , Citocinas/metabolismo , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Células Enteroendócrinas/metabolismo , Mediadores da Inflamação/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Terapia de Alvo Molecular , Oxidiazóis/administração & dosagem , Receptores Acoplados a Proteínas-G/fisiologia
20.
J Pharmacol Exp Ther ; 370(2): 172-181, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31182471

RESUMO

The GPR40/FFA1 receptor is a G-protein-coupled receptor expressed in the pancreatic islets and enteroendocrine cells. Here, we report the pharmacological profiles of (3S)-3-cyclopropyl-3-{2-[(1-{2-[(2,2-dimethylpropyl)(6-methylpyridin-2-yl)carbamoyl]-5-methoxyphenyl}piperidin-4-yl)methoxy]pyridin-4-yl}propanoic acid (SCO-267), a novel full agonist of GPR40. Ca2+ signaling and insulin and glucagon-like peptide-1 (GLP-1) secretion were evaluated in GPR40-expressing CHO, MIN6, and GLUTag cells. Hormone secretions and effects on fasting glucose were tested in rats. Single or repeated dosing effects were evaluated in neonatally streptozotocin-induced diabetic rats (N-STZ-1.5 rats), diet-induced obese (DIO) rats, and GPR40-knockout (Ffar1-/- ) mice. Treatment with SCO-267 activated Gq signaling in both high- and low-FFAR1-expressing CHO cells, stimulated insulin secretion in MIN6 cells, and induced GLP-1 release in GLUTag cells. When administered to normal rats, SCO-267 increased insulin, glucagon, GLP-1, glucose-dependent insulinotropic peptide, and peptide YY (PYY) secretions under nonfasting conditions. These results show the full agonistic property of SCO-267 against GPR40. Hypoglycemia was not induced in SCO-267-treated rats during the fasting condition. In diabetic N-STZ-1.5 rats, SCO-267 was highly effective in improving glucose tolerance in single and 2-week dosing studies. DIO rats treated with SCO-267 for 2 weeks showed elevated plasma GLP-1 and PYY levels, reduced food intake, and decreased body weight. In wild-type mice, SCO-267 induced GLP-1 secretion, food intake inhibition, and body weight reduction; however, these effects were abolished in Ffar1-/- mice, indicating a GPR40-dependent mechanism. In conclusion, SCO-267 stimulated islet and gut hormone secretion, improved glycemic control in diabetic rats, and decreased body weight in obese rats. These data suggest the therapeutic potential of SCO-267 for the treatment of diabetes and obesity.


Assuntos
Glicemia/metabolismo , Peso Corporal/efeitos dos fármacos , Ciclopropanos/farmacologia , Diabetes Mellitus Experimental/sangue , Diabetes Mellitus Experimental/tratamento farmacológico , Obesidade/complicações , Piperidinas/farmacologia , Propionatos/farmacologia , Receptores Acoplados a Proteínas-G/agonistas , Animais , Células CHO , Cricetulus , Ciclopropanos/uso terapêutico , Diabetes Mellitus Experimental/complicações , Modelos Animais de Doenças , Cães , Ingestão de Alimentos/efeitos dos fármacos , Peptídeo 1 Semelhante ao Glucagon/metabolismo , Humanos , Secreção de Insulina/efeitos dos fármacos , Ilhotas Pancreáticas/efeitos dos fármacos , Ilhotas Pancreáticas/metabolismo , Masculino , Camundongos , Piperidinas/uso terapêutico , Propionatos/uso terapêutico , Ratos
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