EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
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2018
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IF 4.816
Xing-Wu Jiang,Bei-Er Jiang,Hao Liu,Zhi-Tao Liu,Long-Long Hu,Mingyao Liu,Weiqiang Lu,Han-Kun Zhang
GPR40 , also known as free fatty acid receptor 1 (FFAR1), is a member of G protein-coupled receptors (GPCR) family and has emerged as an attractive target for the treatment of type 2 diabetes mellitus . So far, most of the synthetic GPR40 agonists, including several drug candidates discontinued in clinical trials , were derived from the phenylpropionic acid scaffold. For discovering novel GPR40 agonists with diverse chemical structures, a series of phenylpropiolic acid derivatives were designed, synthesized, and evaluated under a battery of bioassays. Compound 9 , the most potent compound in this series, exhibited submicromolar agonist activity and similar agonistic efficacy compared to that of TAK-875. In addition, compound 9 was able to dose-dependently amplify glucose-stimulated insulin secretion (GSIS) in pancreatic β -cell line MIN6, which could be reversed by a selective GPR40 antagonist GW1100. In addition, compound 9 was found to have potent glucose-lowering effects during an oral glucose tolerance test in normal C57BL/6 mice.
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PubMed
高影响因子
EUROPEAN JOURNAL OF PHARMACOLOGY
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2021
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IF 4.432
Yuhang Gong,Yanfeng Li,Xin Liu,Ling He
The functions and mechanisms of GPR40 receptor to ameliorating the Alzheimer's disease (AD) by external treatment of encephalopathy remain unknown. In present study, the typical Aβ 1-42 induced mice model was applied to explore the functions and mechanisms of GPR40 receptor by external treatment of encephalopathy in AD. GPR40 agonist GW9508 and antagonist GW1100 were given by i.g injection to activate/inhibit the GPR40 receptor respectively in the gut of AD mouse which illustrated the function and mechanism of GPR40 receptor in ameliorating AD symptoms by external treatment of encephalopathy. A series of behavioral experiments were used to investigate the cognitive function and memory ability of mice, while molecular biology experiments such as Western blot , ELISA , flow cytometry were used to detect the corresponding changes of signaling pathways. The results revealed that intragastric administrated GW9508 could significantly ameliorate cognitive deficits of AD mouse, up-regulate the expression levels of gut-brain peptides both in blood circulation and hypothalamus thus up-regulate the expression levels of α-MSH in hypothalamus, while the negative autophagy-related proteins and inflammation-related proteins were down-regulated correspondingly. Meanwhile, GW9508 could also inhibit the pathological process of neuroinflammation in microglia . GW1100 reversed the effects of GW9508 significantly. These results suggested that GPR40 was an underlying therapeutic target for the external treatment of encephalopathy related to AD and GPR40 agonist could be explored as the emerging AD therapeutic drug.
研究领域:
神经科学
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药理学
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分子生物学
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行为科学
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PubMed
高影响因子
INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES
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2024
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IF 7.7
Jian Yang,Dongyu Wang,Haojie Yu,Li Wang,Yun Wang,Xiaowei Liu,Yudi Huang,Chenguang Ouyang,Yichuan Hong,Shuning Ren,Yu Wang,Yang Jin,Jian Hu,Jingyi Feng
The infected diabetic wound healing is an increasingly severe healthcare problem worldwide. Bacterial infection and the inflammatory microenvironment hinder diabetic wound healing. Meanwhile, the combination of inhibiting bacterial growth and promoting macrophage polarization in the wound microenvironment is beneficial for treating diabetic wounds. Nowadays, hydrogels, as an emerging wound dressing, have great potential to replace or supplement traditional bandages or gauze. Here, glycyl methacrylate gelatin (Gel-Gym), oxidized hyaluronic acid (HA-CHO) and lauric acid (LA) were used to prepare the composite hydrogel (GH/LA) in addressing the clinical dilemma. The hydrogel could withstand 50 % compression deformation, its swelling rate was as low as 18 %, and its adhesion to pig skin reached 14 kPa. Moreover, a diabetic infected wound model was used to evaluate the feasibility of GH/LA hydrogel in vivo . The hydrogels' antimicrobial, anti-inflammatory and prorestitutive potentials were further investigated, and GH/LA showed a therapeutic effect on diabetic wounds. Interestingly, macrophage polarization into the M2 phenotype was significantly enhanced in the presence of GH/LA via GPR40/NF-κB pathway. This study provided a new avenue for treating methicillin-resistant staphylococcus aureus ( MRSA ) infected diabetic wounds.
研究领域:
生物医学工程
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材料科学
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药剂学
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伤口愈合
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感染性疾病
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免疫学
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PubMed
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ACTA PHARMACOLOGICA SINICA
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2023
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IF 8.2
Xu Jia-wen,Xu Xu,Ling Yun,Wang Yan-chun,Huang Yu-jie,Yang Juan-zhen,Wang Jia-ying,Shen Xu
Diabetic peripheral neuropathy (DPN) is a common complication of diabetes, which has yet no curable medication. Neuroinflammation and mitochondrial dysfunction are tightly linked to DPN pathology. G-protein-coupled receptor 40 (GPR40) is predominantly expressed in pancreatic β-cells, but also in spinal dorsal horn and dorsal root ganglion (DRG) neurons, regulating neuropathic pain. We previously have reported that vincamine (Vin), a monoterpenoid indole alkaloid extracted from Madagascar periwinkle , is a GPR40 agonist. In this study, we evaluated the therapeutic potential of Vin in ameliorating the DPN-like pathology in diabetic mice. Both STZ-induced type 1 (T1DM) and db/db type 2 diabetic (T2DM) mice were used to establish late-stage DPN model (DPN mice), which were administered Vin (30 mg·kg -1 ·d -1 , i.p.) for 4 weeks. We showed that Vin administration did not lower blood glucose levels, but significantly ameliorated neurological dysfunctions in DPN mice. Vin administration improved the blood flow velocities and blood perfusion areas of foot pads and sciatic nerve tissues in DPN mice. We demonstrated that Vin administration protected against sciatic nerve myelin sheath injury and ameliorated foot skin intraepidermal nerve fiber (IENF) density impairment in DPN mice. Moreover, Vin suppressed NLRP3 inflammasome activation through either β-Arrestin2 or β-Arrestin2/IκBα/NF-κB signaling, improved mitochondrial dysfunction through CaMKKβ/AMPK/SIRT1/PGC-1α signaling and alleviated oxidative stress through Nrf2 signaling in the sciatic nerve tissues of DPN mice and LPS/ATP-treated RSC96 cells. All the above-mentioned beneficial effects of Vin were abolished by GPR40-specific knockdown in dorsal root ganglia and sciatic nerve tissues. Together, these results support that pharmacological activation of GPR40 as a promising therapeutic strategy for DPN and highlight the potential of Vin in the treatment of this disease.
研究领域:
药理学
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神经科学
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内分泌学
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分子生物学
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PubMed
高影响因子
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