NUTRITIONAL NEUROSCIENCE
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2022
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IF 4.062
Yumin Liu,Ziqi Hu,Jing Wang,Yanjun Liao,Luan Shu
Objective Depression is one of the most common complications in patients with diabetes. Our previous study demonstrated puerarin, a dietary isoflavone, improved glucose homeostasis and β-cell regeneration in high-fat diet (HFD)-induced diabetic mice. Here, we aim to evaluate the potential effect of puerarin on diabetes-induced depression.Methods The co-occurrence of diabetes and depression with related biochemical alterations were confirmed in HFD mice and db/db mice, respectively using behavioral analysis, ELISA and western blotting assay. Furthermore, impacts of puerarin on depression-related symptoms and pathological changes were investigated in HFD mice.Results The results showed that puerarin effectively alleviated the depression-like behaviors of HFD mice, down-regulated serum levels of corticosterone and IL-1β, while up-regulated the content of 5-hydroxytryptamine. Simultaneously, puerarin increased the number of hippocampal neurons in HFD mice, and suppressed the apoptosis of neurons to protect the hippocampal neuroplasticity. GLP-1R expression in hippocampus of HFD mice was enhanced by puerarin, which subsequently activated AMPK, CREB and BDNF/TrkB signaling to improve neuroplasticity. Importantly, our data indicated that puerarin had an advantage over fluoxetine or metformin in treating diabetes-induced depression.Conclusion Taken together, puerarin exerts anti-depressant-like effects on HFD diabetic mice, specifically by improving hippocampal neuroplasticity via GLP-1R/BDNF/TrkB signaling. Puerarin as a dietary supplement might be a potential candidate in intervention of diabetes with comorbid depression.
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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DOI
PubMed
高影响因子
PHYTOMEDICINE
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2020
·
IF 4.268
Chunjun Wang,Jihong Yao,Linjie Ju,Xiaohua Wen,Luan Shu
Background Diabetes is characterized by β-cell loss and dysfunction. A strategy for diabetes treatment is to promote new β-cell formation. Puerarin is an isoflavone from the root of Pueraria lobata (Willd.) Ohwi . Our previous study demonstrated puerarin could ameliorate hyperglycemia in diabetic mice. However, related mechanisms and potential roles of puerarin in β-cell neogenesis have not been elucidated. Purpose The present study aims to investigate whether anti-diabetic effect of puerarin is dependent on promoting β-cell neogenesis via GLP-1R signaling activation. Methods A high-fat diet (HFD) induced diabetic mouse model was applied to investigate effects of puerarin in vivo , exendin-4 (GLP-1R agonist) and metformin were used as positive controls. Moreover, related mechanisms and GLP-1R downstream signal transduction were explored in isolated cultured mouse pancreatic ductal cells. Results Puerarin improved glucose homeostasis in HFD diabetic mice significantly. Markers of new β-cell formation (insulin, PDX1 and Ngn3) were observed in pancreatic ducts of HFD mice treated by puerarin. Of note, efficacy of puerarin in vivo was suppressed by GLP-1R antagonist exendin9-39, but enhanced by exendin-4 respectively. In cultured mouse pancreatic ductal cells, puerarin induced expressions of insulin and PDX1, upregulated GLP-1R expression and activated β-catenin and STAT3 subsequently. Expressions of insulin and PDX1 in ductal cells could be blocked by exendin9-39, or β-catenin inhibitor ICG001, or JAK2 inhibitor AG490 . Conclusion These data clarified puerarin ameliorated hyperglycemia of HFD mice via a novel mechanism involved promoting β-cell neogenesis. Our finding highlights the potential value of puerarin developing as an anti-diabetic agent.
研究领域:
药理学
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内分泌学
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糖尿病研究
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分子生物学
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DOI
PubMed
高影响因子
ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY
·
2025
·
IF 6.1
Yinan Zhang,Qilei Chen,Yaning Xu,Yanming Lv,Yini Wang,Xin-yu Shi,Jiaqi Liu,Jie Wen,Xueting Li,Baixiang Li
Atrazine (ATR), a widely used herbicide, is linked to dopaminergic neurotoxicity and persistent gut microbiota dysbiosis after early life exposure. However, whether the gut microbiota mediates ATR-induced loss of dopaminergic neurons remains unclear. Mice were exposed to ATR from juvenility (4 th week) until adulthood (12 th week), after which exposure ceased until the 20 th week. The role of gut microbiota was confirmed through fecal microbiota transplantation (FMT), which was classified into different groups based on the donor's ATR treatment status. 16S rRNA sequencing revealed that Akkermansia , which exhibited significant differences across FMT groups, is a classic short-chain fatty acid (SCFA)-producing bacteria. FMT recipients receiving ATR-donor microbiota exhibited reduced colonic G Protein-Coupled Receptor 43 (GPR43), serum Glucagon-like Peptide-1 (GLP-1), and substantia nigra Glucagon-like Peptide-1 receptor (GLP-1R)/Tyrosine hydroxylase (TH) levels. Soy isoflavones (SIF), selected for their dual prebiotic and neuroprotective effects, attenuated ATR-induced dopaminergic neurotoxicity by enriching SCFA-producing gut microbiota and the level of SCFAs, thereby activating the GPR43/GLP-1/GLP-1R axis and reducing neuronal loss. These findings demonstrate the critical role of gut microbiota in ATR-induced dopaminergic neurodegeneration, positioning SIF-mediated microbiota modulation as a promising therapeutic approach within the "food-medicine homology" framework.
研究领域:
神经毒理学
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环境健康
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微生物组研究
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神经药理学
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营养科学
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DOI
PubMed
高影响因子
DIABETES OBESITY & METABOLISM
·
2026
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IF 6.1
Yunxiao Zhang,Bo Zhu,Binhui Peng,Peng Wu,Guyu Zhong,Yongchen Wang,Zhaofeng Wang,Xinyu Feng,Dongfang Tang,Dezheng Peng,Yu Liu
Background The GLP-1 receptor (GLP-1R) and GIP receptor (GIPR) are key targets for diabetes and obesity therapies. Pharmacological agents including GLP-1R agonists (e.g., Semaglutide), dual GLP-1R/GIPR agonists (e.g., Tirzepatide) and a GLP-1R agonist/GIPR antagonist (AMG133) have demonstrated considerable promise in anti-diabetic and weight management applications. However, a systematic comparison of the specific contributions of GIPR activation versus GIPR inhibition to weight loss within the context of GLP-1/GIP dual-targeting therapies remains unexplored. Research Design and Methods To address this, we designed three IgG4 Fc-fusion proteins: a GLP-1R agonist/GIPR agonist, (i) GLP-1(A8G)/GIP(A2G)-Fc; a GLP-1R agonist/GIPR inhibitor, (ii) GLP-1(A8G)/GIP(3–30)-Fc; and a sequential molecule that hypothesised to transition from dual GLP-1R/GIPR agonism to GLP-1R agonism/GIPR inhibition, (iii) GLP-1(A8G)/GIP(1–30)-Fc. Mono-agonist GLP-1(A8G)-Fc and dual-agonist GLP-1(A8G)/GIP(A2G)-Fc were used as controls to investigate the weight loss effects of GIPR activation and inhibition in DIO mice. Results Our findings revealed that the sequential molecule GLP-1(A8G)/GIP(1–30)-Fc produced the greatest body weight reduction (21.59%), significantly outperforming GLP-1(A8G)/GIP(3–30)-Fc (14.5%; p < 0.001). Furthermore, both GIPR activation and inhibition, when combined with GLP-1R agonism, markedly improved serum and hepatic lipid metabolism, as evidenced by reduced triglycerides and total cholesterol. Conclusion Together, these findings validate a peptide-based inhibitory strategy for synergistic weight loss and provide insights into the differential metabolic roles of GIPR activation versus inhibition, guiding the development of novel anti-obesity therapeutics.
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PubMed
高影响因子
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
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2023
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IF 3.1
Qiuxia Zhu,Yong Luo,Yuetao Wen,Ding Wang,Jing Li,Zhongcai Fan
Apoptosis is a major pathophysiological change following myocardial ischemia/reperfusion (I/R) injury. Glucagon-like peptide 1 (GLP-1) and its receptor GLP-1R are widely expressed in the cardiovascular system and GLP-1/GLP-1R activates the protein kinase G (PKG)-related signaling pathway. Therefore, this study tested whether semaglutide, a new GLP-1 analog, inhibits I/R injury-induced cardiomyocyte apoptosis by activating the PKG/PKCε/ERK1/2 pathway. We induced myocardial I/R injury in rats and hypoxia/reoxygenation (H/R) injury in H9C2 cells and detected the effects of semaglutide, a PKG analog (8-Br-cGMP), and a PKG inhibitor (KT-5823) on the PKG/PKCε/ERK1/2 pathway and cardiomyocyte apoptosis. We found that semaglutide upregulated GLP-1R levels, and both semaglutide and 8-Br-cGMP activated the PKG/PKCε/ERK1/2 pathway, inhibited myocardial infarction (MI), decreased hs-cTNT levels, increased NT-proBNP levels, and suppressed cardiomyocyte apoptosis in I/R rats and H/R H9C2 cells. However, KT-5823 exerted contrasting effects with semaglutide and 8-Br-cGMP, and KT-5823 weakened the cardioprotective effects of semaglutide. In conclusion, semaglutide inhibits I/R injury-induced cardiomyocyte apoptosis by activating the PKG/PKCε/ERK1/2 pathway. The beneficial effect of GLP-1/GLP-1R, involved in the activation of the PKG/PKCε/ERK1/2 pathway, may provide a novel treatment method for myocardial I/R injury.
研究领域:
心脏病学
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药理学
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分子生物学
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DOI
PubMed
高影响因子
iScience
·
2023
·Vol. 26
·期 6
·106918-106918
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IF 5.8
Huixia Wang,Wanhui Hu,Tiandan Xu,Ya Yuan,Dongsheng Liu,Kurt Wüthrich
Crystal and cryo-EM structures of the glucagon-like peptide-1 receptor (GLP-1R) and glucagon receptor (GCGR) bound with their peptide ligands have been obtained with full-length constructs, indicating that the extracellular domain (ECD) is indispensable for specific ligand binding. This article complements these data with studies of ligand recognition of the two receptors in solution. Paramagnetic NMR relaxation enhancement measurements using dual labeling with fluorine-19 probes on the receptor and nitroxide spin labels on the peptide ligands provided new insights. The glucagon-like peptide-1 (GLP-1) was found to interact with GLP-1R by selective binding to the extracellular surface. The ligand selectivity toward the extracellular surface of the receptor was preserved in the transmembrane domain (TMD) devoid of the ECD. The dual labeling approach further provided evidence of cross-reactivity of GLP-1R and GCGR with glucagon and GLP-1, respectively, which is of interest in the context of medical treatments using combinations of the two polypeptides.
研究领域:
结构生物学
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分子生物学
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药理学
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DOI
PubMed
高影响因子
Current Pharmaceutical Analysis
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2021
·Vol. 17
·期 9
·1197-1205
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IF 0.89
Wang Jie,Lu Ping,Zhang Shengting,Li Wanwan,Ji Xiuling,Li Jing,Zhang Hui,Wei Yunlin,Liang Chenggang
Background: Current methods for assaying bioactivity of GLP-1 analogues are costly and time consuming, mainly dependent on AlphaScreen luminous beads, based on fluorescent resonance energy transfer technology, and cAMP-GloTM Max assay kit, and on ATP to generate a negative- association
curve. Objective: To establish a sensitive, stable, and low-cost method for the determination of biological activity of therapeutic glucagon-like peptide-1(GLP-1) and their analogous drugs in vitro in quality control. Methods: An applicable fluorescent high-content system (fHCS)
method was developed in U2OS cell, which was stably transfected with green fluorescent protein (GFP) labeled at the C-terminal of glucagon-like peptide-1 receptor (GLP-1R). HCS was firstly used to measure per unit area of fluorescent intensity changes as a result of drug-stimulated receptor
endocytosis. Results: The detection sensitivity improved at least 30 folds than the other reported methods. This method showed a wide detection range with a good linear regression of R2>0.98. In five scgs from 50~150% SCG, the accuracy achieved the standard of the 41st United States
Pharmacopoeia with all biases being less than 7.5%. The precision attained the 9.0th European Pharmacopoeia standard with all relative standard deviations (RSDs) below 10%. This assay result can be kept stable over 100 h at room temperature. Furthermore, the U2OS/GLP-1R cells showed a sharp
specificity towards GLP-1 analogues during detecting activities in a mixture of different ligands. Conclusion: These results suggested that the GLP-1R/fHCS method can be employed broadly in the bioactivity determination of GLP-1 analogous drugs and as a platform for screening GLP-1 similar
active ingredients in natural products.
研究领域:
药理学
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药物开发
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生物技术
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细胞生物学
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DOI
高影响因子
Frontiers in Pharmacology
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2021
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IF 5.811
Yang Xiaohua,Zhang Min,Lu Zhihong,Zhi Linping,Xue Huan,Liu Tao,Liu Mengmeng,Cui Lijuan,Liu Zhihong,He Peifeng,Liu Yunfeng,Zhang Yi
Glucagon-like peptide-1 receptor (GLP-1R) agonist-based therapeutics for type 2 diabetes mellitus have attracted worldwide attention. However, there are challenges in the development of small molecule GLP-1R agonists owing to the complexity of ligand recognition and signal induction mechanisms. Here, we attained S6 using virtual screening and fluorescent imaging plate reader (FLIPR)-based calcium assays. The purpose of this study was to identify and characterize S6, a novel small molecule GLP-1R agonist. Data from cellular thermal shift assay (CETSA) and Bio-Layer Interferometry (BLI) indicated that S6 could bind potently with GLP-1R. Radioimmunoassay data showed that S6 potentiated insulin secretion in a glucose-dependent manner and the insulinotropic effect was mediated by GLP-1R. Calcium imaging techniques suggested that S6 elevated the intracellular calcium concentration [(Ca2+)i] by activating GLP-1R. In patch-clamp experiments, we demonstrated that S6 inhibited voltage-dependent K+ (Kv) channels in a GLP-1R-dependent fashion. Besides, S6 significantly prolonged action potential duration but had no effect on voltage-dependent Ca2+ channels. In summary, these findings indicate that S6 stimulates glucose-dependent insulin secretion mainly by acting on GLP-1R, inhibiting Kv channels, increasing (Ca2+)i. This study will provide direction for the screening and development of novel small-molecule agents targeting GLP-1R in the future.
研究领域:
药理学
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内分泌学
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糖尿病
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分子生物学
✓ 已验证
DOI
PubMed
高影响因子
JOURNAL OF ETHNOPHARMACOLOGY
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2026
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IF 6.8
Xin Gao,Zhen-Zi Shang,Qiang-Ming Li,Feng-Yun Zhang,Xue-Qiang Zha,Jian-Ping Luo
Ethnopharmacological relevance Dendrobium huoshanense has been long used to treat gastrointestinal disorders including ulcerative colitis (UC) in traditional Chinese medicine. Polysaccharides as its main active components can alleviate UC by reducing inflammation, and promote the secretion of glucagon-like peptide-1 (GLP-1), which possesses anti-inflammatory effects via GLP-1 receptor (GLP-1R). However, it remains unclear whether polysaccharides from different parts of this herb are equally effective in alleviating UC and whether polysaccharides function via GLP-1/GLP-1R axis. Aim of the study To identify the part in which the polysaccharide is most effective in alleviating UC and to explore its mechanism of action through GLP-1/GLP-1R axis. Materials and methods The physicochemical properties of polysaccharides were analyzed. A dextran sulfate sodium (DSS)-induced UC mouse model was used to assess colitis-associated damage via morphological scoring, histopathological evaluation and inflammatory examination with multi-cytokine array and western blotting. Gut microbiota compositions, short-chain fatty acid contents and GLP-1 levels were measured, and their roles were checked using antibiotic mixture and GLP-1R antagonist Exendin (9-39). Results Stem, leaf and flower polysaccharides, with different molecular weight, monosaccharide composition and spatial conformation, differentially alleviated UC symptoms, and stem polysaccharide (DHPS) showed the strongest efficacy, as evidenced by improved epithelial integrity, mucus barrier and inflammatory disorder. DHPS-alleviated UC was independent of DHPS-altered gut microbiota and positively correlated with DHPS-elevated GLP-1 levels, which could be abolished by Exendin (9-39), suggesting that GLP-1-activated GLP-1R signaling mediated the effects of DHPS against UC. Conclusions DHPS is the most effective polysaccharide for alleviating DSS-induced UC through GLP-1/GLP-1R axis, proposing DHPS is a valid candidate for UC treatment using D. huoshanense .
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PubMed
高影响因子
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