Cell Death & Disease
·
2017
·Vol. 8
·期 2
·e2609
·
IF 5.965
Yang Mengliu,Wang Jinzhi,Wu Shaobo,Yuan Lei,Zhao Xiaodong,Liu Chaohong,Xie Jing,Jia Yanjun,Lai Yerui,Zhao Allan Zijian,Boden Guenther,Li Ling,Yang Gangyi
Intestinal glucagon-like peptide-1 (GLP-1) is a hormone that stimulates insulin secretion and acts as a neuropeptide to control glucose homeostasis, but little is known whether intestinal GLP-1 has any effect in the control of hepatic glucose production (HGP). Here we found that intraduodenal infusion of GLP-1 activated duodenal PKC- δ , lowered HGP and was accompanied by a decrease in hepatic expression of gluconeogenic enzymes and an increase in hepatic insulin signaling in rats. However, gut co-infusion of either the GLP-1 receptor antagonist Ex-9, or the PKC- δ inhibitor rottlerin with GLP-1, negated the ability of gut GLP-1 to lower HGP and to increase hepatic insulin signaling during clamps. The metabolic and molecular signal effects of duodenal GLP-1 were also negated by co-infusion with tetracaine, pharmacologic inhibition of N -methyl- d -aspartate receptors within the dorsalvagal complex, or hepatic vagotomy in rats. In summary, we identified a neural glucoregulatory function of gut GLP-1 signaling.
研究领域:
内分泌学
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代谢生物学
·
神经生物学
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DOI
PubMed
高影响因子
MOLECULAR PHARMACEUTICS
·
2018
·
IF 4.556
Sida Ruan,Yuanyuan Gu,Bo Liu,Huashan Gao,Xiongwei Hu,Haiping Hao,Liang Jin,Ting Cai
Glucagon-like peptide 1 (GLP-1) has recently received significant attention as an efficacious way to treat diabetes mellitus. However, the short half-life of the peptide limits its clinical application in diabetes. In our previous study, a novel GLP-1 analog (PGLP-1) with a longer half-life was synthesized and evaluated. Herein, we prepared the PGLP-1-loaded poly(d,l-lactide-co-glycolide) microspheres to achieve long-term effects on blood glucose control. The incorporation of zinc ion into the formulation can effectively decrease the initial burst release, and a uniform drug distribution was obtained, in contrast to native PGLP-1 encapsulated microspheres. We demonstrated that the solubility of the drug encapsulated in microspheres played an important role in in vitro release behavior and drug distribution inside the microspheres. The Zn-PGLP-1 microspheres had a prominent acute glucose reduction effect in the healthy mice. A hypoglycemic effect was observed in the streptozotocin (STZ) induced diabetic mice through a 6-week treatment of Zn-PGLP-1-loaded microspheres. Meanwhile, the administration of Zn-PGLP-1 microspheres led to the β-cell protection and stimulation of insulin secretion. The novel GLP-1 analog-loaded sustained microspheres may greatly improve patient compliance along with a desirable safety feature.
研究领域:
药学
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生物医学工程
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内分泌学
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产品关联
DOI
PubMed
高影响因子
NEUROENDOCRINOLOGY
·
2023
·
IF 4.1
Zhu Ye,Tian Jun,Wei Xiali,Jia Shaohui,Shu Qing
Introduction: We investigated the effects of electroacupuncture (EA) on improving obesity and insulin resistance (IR) in high-fat diet-induced (HFDI) obese rats by modulating the nucleus tractus solitarius (NTS) glucagon-like peptide-1 (GLP-1)-ventral tegmental area (VTA) dopamine (DA) neural reward circuit, thereby uncovering a possible central mechanism underlying EA’s actions in improving obesity and IR. Methods: We randomly allocated 45 Wistar male rats to five groups (normal, model, EA, chemogenetic activation, chemogenetic suppression + EA), with 9 rats in each group. All interventions were conducted within 8 weeks after the model was established. We tested rats for obesity phenotypes included body mass, Lee’s index, 24-h food intake, and glucose-metabolism parameters. We observed protein and gene expression for GLP-1 in the NTS and tyrosine hydroxylase in the VTA by Western blotting and real-time polymerase chain reaction, as well as their localization by immunofluorescence. We also determined the DA content in the VTA using high-performance liquid chromatography. Results: Obese rats exhibited marked hyperphagia, accompanied by increased excitability of DA neurons in the VTA region and reduced insulin sensitivity. After EA treatment, obese rats showed augmented excitability of NTS GLP-1 and suppression of VTADA neurons with a diminution in food intake, showing results similar to those in the chemogenetic activation group. After EA treatment and while inhibiting GLP-1 neurons by chemogenetics, the effect of EA on activating GLP-1 neurons and inhibiting VTADA was partially abrogated. The effects of improving obesity and insulin sensitivity were likewise also suppressed. Conclusion: EA effectively activated GLP-1 neurons in the NTS, thereby inhibited the expression of DA in the VTA and improved obesity and insulin sensitivity in HFDI-obese rats
研究领域:
神经科学
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内分泌学
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代谢学
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针灸
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DOI
PubMed
高影响因子
BRITISH JOURNAL OF PHARMACOLOGY
·
2014
·Vol. 171
·期 23
·5252-5264
·
IF 4.99
Jing Han,Lidan Sun,Xun Huang,Zheng Li,Chenyu Zhang,Hai Qian,Wenlong Huang
Background and Purpose The short biological half-life limits the therapeutic use of glucagon-like peptide-1 (GLP-1) and chemical modification to improve the interaction of peptides with serum albumin represents an effective strategy to develop long-acting peptide analogues. Coumarin, a natural product, is known to bind tightly to plasma proteins and possesses many biological activities. Therefore, we designed and synthesized a series of coumarin-modified GLP-1 derivatives, hypothesizing that conjugation with coumarin would retain the therapeutic effects and prolong the biological half-life of the conjugates. Experimental Approach Four cysteine-modified GLP-1 analogues (1–4) were prepared using Gly 8 -GLP-1(7–36)-NH 2 peptide as a starting point. These analogues were conjugated with two coumarin maleimides to yield eight compounds (conjugates 6–13) for testing. Activation of human GLP-1 receptors, stability to enzymic inactivation in plasma and binding to human albumin were assessed in vitro . In vivo , effects on oral glucose tolerance tests (OGTT) in rats and on blood glucose levels in db/db mice were studied. Key Results Most conjugates showed well preserved receptor activation efficacy, enhanced albumin-binding properties and improved in vitro plasma stability and conjugate 7 was selected to undergo further assessment. In rats, conjugate 7 had a longer circulating t 1/2 than exendin-4 or liraglutide. A prolonged antidiabetic effect of conjugate 7 was observed after OGTT in rats and a prolonged hypoglycaemic effect in db/db mice. Conclusions and Implications Cysteine-specific coumarin conjugation with GLP-1 offers a useful approach to the development of long-acting incretin-based antidiabetic agents. Conjugate 7 is a promising long-lasting GLP-1 derivative deserving further investigation.
研究领域:
药理学
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糖尿病研究
·
药物化学
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DOI
PubMed
高影响因子
INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES
·
2024
·
IF 7.7
Wang Liu,Ya-Min Qin,Jin-Yang Shi,De-Ling Wu,Chun-Yang Liu,Juan Liang,Song-Zi Xie
This study aimed to evaluate the influence of ultrasonic degradation on the physicochemical and biological characteristics of Polygonatum cyrtonema polysaccharide (PCP, 8.59 kDa). PCP was subjected to ultrasonic treatment for 8, 16, and 24 h and yielded the degraded fractions PCP-8, PCP-16, and PCP-24 (5.06, 4.13, and 3.69 kDa), respectively. Compared with the intact PCP, PCP-8, PCP-16 and PCP-24 had a reduced particle size (decrements of 28.03 %, 46.15 % and 62.54 %, respectively). Although ultrasonic degradation did not alter the primary structure of PCP, its triple helical and superficial structures were disrupted, with degraded fractions demonstrating reduced thermal stability and apparent viscosities compared with those of the intact PCP. Furthermore, the functional properties of the degraded fractions were different. PCP-16 most favourably affected GLP-1 secretion, while PCP-8 and PCP-24 exhibited the strongest antioxidant and enzyme inhibitory activities, respectively. Hence, controlled ultrasound irradiation is an appealing approach for partially degrading PCP and enhancing its bioactivity as a functional agent.
研究领域:
生物化学
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药理学
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食品科学
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产品关联
DOI
PubMed
高影响因子
Journal of Pharmaceutical Analysis
·
2023
·
IF 8.8
Zhang Mao,Haochen Hui,Xuerong Zhao,Lina Xu,Yan Qi,Lianhong Yin,Liping Qu,Lan Han,Jinyong Peng
It is necessary to explore potent therapeutic agents via regulating gut microbiota and metabolism to combat Parkinson's disease (PD). Dioscin, a bioactive steroidal saponin, shows various activities. However, its effects and mechanisms against PD are limited. In this study, dioscin dramatically alleviated neuroinflammation and oxidative stress, and restored the disorders of mice induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). 16S rDNA sequencing assay demonstrated that dioscin reversed MPTP-induced gut dysbiosis to decrease Firmicutes -to- Bacteroidetes ratio and the abundances of Enterococcus , Streptococcus , Bacteroides and Lactobacillus genera , which further inhibited bile salt hydrolase (BSH) activity and blocked bile acid (BA) deconjugation. Fecal microbiome transplantation test showed that the anti-PD effect of dioscin was gut microbiota-dependent. In addition, non-targeted fecal metabolomics assays revealed many differential metabolites in adjusting steroid biosynthesis and primary bile acid biosynthesis. Moreover, targeted bile acid metabolomics assay indicated that dioscin increased the levels of ursodeoxycholic acid, tauroursodeoxycholic acid, taurodeoxycholic acid and β-muricholic acid in feces and serum. In addition, ursodeoxycholic acid administration markedly improved the protective effects of dioscin against PD in mice. Mechanistic test indicated that dioscin significantly up-regulated the levels of takeda G protein-coupled receptor 5 (TGR5), glucagon-like peptide-1 receptor (GLP-1R), GLP-1, superoxide dismutase (SOD), and down-regulated NADPH oxidases 2 (NOX2) and nuclear factor-kappaB (NF-κB) levels. Our data indicated that dioscin ameliorated PD phenotype by restoring gut dysbiosis and regulating bile acid-mediated oxidative stress and neuroinflammation via targeting GLP-1 signal in MPTP-induced PD mice, suggesting that the compound should be considered as a prebiotic agent to treat PD in the future.
研究领域:
神经科学
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药理学
·
微生物学
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产品关联
DOI
PubMed
高影响因子
JOURNAL OF COLLOID AND INTERFACE SCIENCE
·
2025
·
IF 9.7
Yiran Qian,Xiaoxi Chang,Mingyang Sun,Yunqi Chen,Jiachen Zang,Chenyan Lv,Guanghua Zhao,Tuo Zhang
Bioactive peptides have attracted significant attention for their potential health benefits; however, their oral administration is challenged by degradation from digestive proteases and limited intestinal absorption. In this study, we demonstrated the exceptional gastrointestinal stability of ferritin nanocages, which remained largely intact after 30 min of simulated gastric digestion and were highly resistant to intestinal proteolysis. Consistent with in vitro findings, orally administered ferritin successfully reached the intestinal tract without significant degradation in mice. We engineered a fusion protein by linking a glucagon-like peptide-1 (GLP-1) motif to the C-terminus of heteropolymer ferritin, generating HLG. Through Caco-2 monolayer assays, we confirmed that HLG absorption occurs primarily via TfR1-mediated endocytosis, followed by lysosomal trafficking and subsequent release of bioactive GLP-1. Oral administration of HLG significantly reduced blood glucose levels and food intake in type 2 diabetic mice, whereas the GLP-1 analog exenatide alone showed no such effects. These findings highlight the potential of ferritin-based nanocages as an effective oral delivery platform for bioactive peptides.
研究领域:
纳米医学
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药剂学
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分子药理学
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生物材料
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消化系统疾病
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药物递送
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代谢性疾病
✓ 已验证
产品关联
DOI
PubMed
高影响因子
EMBO JOURNAL
·
2024
·
IF 9.4
GengShan,YangShan,TangXuejiao,XueShiyao,LiKe,LiuDongfang,ChenChen,ZhuZhiming,ZhengHongting,WangYuanqiang,YangGangyi,LiLing,YangMengliu
Communication of gut hormones with the central nervous system is important to regulate systemic glucose homeostasis, but the precise underlying mechanism involved remain little understood. Nesfatin-1, encoded by nucleobindin-2 (NUCB2), a potent anorexigenic peptide hormone, was found to be released from the gastrointestinal tract, but its specific function in this context remains unclear. Herein, we found that gut nesfatin-1 can sense nutrients such as glucose and lipids and subsequently decreases hepatic glucose production. Nesfatin-1 infusion in the small intestine of NUCB2-knockout rats reduced hepatic glucose production via a gut – brain – liver circuit. Mechanistically, NUCB2/nesfatin-1 interacted directly with melanocortin 4 receptor (MC4R) through its H-F-R domain and increased cyclic adenosine monophosphate (cAMP) levels and glucagon-like peptide 1 (GLP-1) secretion in the intestinal epithelium, thus inhibiting hepatic glucose production. The intestinal nesfatin-1 -MC4R-cAMP-GLP-1 pathway and systemic gut-brain communication are required for nesfatin-1 - mediated regulation of liver energy metabolism. These findings reveal a novel mechanism of hepatic glucose production control by gut hormones through the central nervous system.
研究领域:
内分泌学
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代谢学
·
胃肠病学
·
神经科学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Food Bioscience
·
2025
·
IF 5.9
Xing Chen,Menglin Jiang,Jie Liu,Genyi Zhang
Whole grain food is a type of healthy food with many beneficial effects, but the fundamental mechanism is still illusive. In the current study, a whole grain component (WGC), as a whole grain model, was prepared by mimicking the endosperm cellular structure through encapsulating glucomannan (dietary fiber) and starch in a matrix formed by polysaccharide gelation. A high level of slowly digestible starch (SDS) (>50 %) in WGC was observed from an in vitro digestion experiment. When the in vivo test of WGC was conducted, a reduced postprandial glycemia and an increased GLP-1 response were observed, which confirmed the stimulation effect of WGC on the secretion GLP-1, an incretin hormone with numerous health benefits. Further study showed that the blood glucose level (from 29.2 to 9.5 mmol/L) and the biomarker HbA1c (from 10.5 to 6.4 %) in diabetic mice were significantly reduced under the condition of WGC-containing diet (WGC-diet). The β-cell function and insulin sensitivity were also significantly improved. Furthermore, the WGC-diet reversed the dysbiosis with increased production of healthy short-chain fatty acids, which are likely the basis to the secretion of GLP-1. Gene expression revealed that WGC-diet activated the GLP-1 signaling pathway, leading to an increased secretion of insulin and improved β-cell function, which all contribute to the glycemic control in diabetic mice. Thus, GLP-1, as pleotropic incretin hormone, could be an important mechanism to the various health benefits of whole grain foods.
研究领域:
营养学
·
分子生物学
·
医学
✓ 已验证
DOI
高影响因子
npj Science of Food
·
2025
·Vol. 9
·期 1
·1-9
·
IF 7.8
Ye Xiang,Chen Wen,Yan Fujie,Zheng Xiaodong,Tu Pengcheng
In late-stage type 2 diabetes mellitus (T2DM), impaired islet β cell function leads to absolute insulin deficiency, thereby disrupting blood glucose homeostasis. GLP-1, an incretin hormone, stimulates insulin secretion from islet β cells post-meals. This study investigated the effects of anthocyanin cyanidin-3-O-glucoside (C3G) on GLP-1 secretion using STC-1 (intestinal endocrine L cells) and NIT-1 (islet β cells). In a co-culture system, C3G treatment increased GLP-1 secretion in STC-1 cells, promoting insulin release in NIT-1 cells under high glucose. Mechanistically, C3G activated the PPARβ/δ-β-catenin-TCF-4 pathway in STC-1 cells, enhancing PG precursor transcription and GLP-1 synthesis.Inhibiting PPARβ/δ with GSK0660 blocked this C3G-induced upregulation. Overall, C3G stimulates GLP-1 secretion from intestinal L cells via this pathway, indirectly boosting insulin release from β cells. These findings enhance T2DM mechanism understanding and suggest the potential of C3G in GLP-1-based T2DM therapy.
研究领域:
分子生物学
·
代谢疾病研究
·
药理学
✓ 已验证
DOI
PubMed
高影响因子
BIOORGANIC & MEDICINAL CHEMISTRY
·
2024
·
IF 3.3
Yuanzhen Dong,Jinhua Zhang,Hongjiang Xu,Hengqiao Shen,Qin Lu,Jun Feng,Zhengyan Cai
Tirzepatide , the first approved dual GLP-1/GIP receptor agonist (RA), has achieved better clinical outcomes than other GLP-1RAs. However, it is an imbalanced dual GIP/GLP-1 RA, and it remains unclear whether the degree of imbalance is optimal. Here, we present a novel long-acting dual GLP-1/GIP RA that exhibits better activity than tirzepatide toward GLP-1R. A candidate conjugate, D314, identified via peptide design, synthesis, conjugation, and experimentation, was evaluated using chronic studies in db/db and diet induced obese (DIO) mice. D314 achieved favorable blood glucose and body weight-lowering effects, equal to those of tirzepatide. Its half-life in dogs (T 1/2 : 78.3 ± 14.01 h) reveals its suitability for once-weekly administration in humans . This preclinical study suggests the potential role of D314 as an effective agent for treating T2DM and obesity.
研究领域:
药理学
·
内分泌学
·
糖尿病研究
·
药物开发
✓ 已验证
产品关联
DOI
PubMed
高影响因子
INTERNATIONAL IMMUNOPHARMACOLOGY
·
2025
·
IF 4.7
Rihong Luo,Yuhan Kang,He Ma,Zhenqiang Zhang,Christian Hölscher,Li Hao,Zijuan Zhang
To date, no therapeutic drugs available on the market can effectively reverse the progression of Alzheimer's disease (AD). Although Glucagon-like peptide-1 (GLP-1) receptor agonists (RAs) and Cholecystokinin (CCK) RAs have shown some promise in AD research, little is known about the neuroprotective effects of a novel dual CCK/GLP-1 RA in AD. This study sought to examine the effects of the novel dual CCK/GLP-1 RA on cognitive performance in an AD mouse model and to explore the associated mechanisms. Our findings indicate that dual CCK/GLP-1 RA improved cognitive deficits, reduced amyloid-beta (Aβ) accumulation, and alleviated mitochondrial damage in 5 × FAD mice by inducing mitophagy. In an in vitro model of AD cells induced by Aβ, CCK/GLP-1 RA could exert neuroprotective effects by regulating PINK1/Parkin-mediated mitophagy. These data reveal for the first time that the new CCK/GLP-1 RA modulates mitophagy via PINK1/Parkin pathway and enhances cognitive function in the 5 × FAD animal model. Moreover, the performance of the CCK/GLP-1 RA in certain indicators was superior to that of GLP-1 analogue liraglutide, suggesting that it may represent a more promising therapeutic option for AD.
研究领域:
神经科学
·
药理学
·
分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）