Communications Biology
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2024
·Vol. 7
·期 1
·1-13
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IF 5.2
Chen Song,Hu Zongren,Tang Jianbang,Zhu Haipeng,Zheng Yuhua,Xiao Jiedong,Xu Youhua,Wang Yao,Luo Yi,Mo Xiaoying,Wu Yalan,Guo Jianwen,Zhang Yongliang,Luo Huanhuan
High temperature and humidity in the environment are known to be associated with discomfort and disease, yet the underlying mechanisms remain unclear. We observed a decrease in plasma glucagon-like peptide-1 levels in response to high-temperature and humidity conditions. Through 16S rRNA gene sequencing, alterations in the gut microbiota composition were identified following exposure to high temperature and humidity conditions. Notably, changes in the gut microbiota have been implicated in bile acid synthesis. Further analysis revealed a decrease in lithocholic acid levels in high-temperature and humidity conditions. Subsequent in vitro experiments demonstrated that lithocholic acid increases glucagon-like peptide-1 secretion in NCI-H716 cells. Proteomic analysis indicated upregulation of farnesoid X receptor expression in the ileum. In vitro experiments revealed that the combination of lithocholic acid with farnesoid X receptor inhibitors resulted in a significant increase in GLP-1 levels compared to lithocholic acid alone. In this study, we elucidate the mechanism by which reduced lithocholic acid suppresses glucagon-like peptide 1 via farnesoid X receptor activation under high-temperature and humidity condition.
研究领域:
生理学
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微生物学
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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
EBioMedicine
·
2021
·
IF 8.143
Qi Pan,Shushan Lin,Yu Li,Liang Liu,Xiaoping Li,Xianglei Gao,Jiangyu Yan,Baohua Gu,Xiaofeng Chen,Wenjia Li,Xinfa Tang,Chao Chen,Lixin Guo
Background Fibroblast growth factor 21 (FGF21) has become a promising therapeutic target for metabolic diseases such as type 2 diabetes (T2D), obesity and non-alcoholic steatohepatitis. However, the clinical application of natural FGF21 molecule is limited because of its instability in vitro and short half-life in vivo . To improve FGF21’s therapeutic property, we screened high receptor binding FGF21 analogs and made FGF21-Fc-GLP-1 dual-targeted constructs to investigate their activity in a number of experiments . Methods Utilizing phage display high-throughput screening we identified mutations that could improve β-Klotho binding property of FGF21. IgG4 Fc was fused to FGF21 variants to extend the in vivo half-life. We further explored the potential synergistic actions of FGF21 with the incretin glucagon-like peptide-1 (GLP-1) by generating GLP-1-Fc-FGF21 dual agonists. Findings Two Fc-FGF21 variants showed enhanced β-Klotho binding affinity in vitro as well as improved glucose lowering effect in vivo . One of the dual agonists, GLP-1-Fc-FGF21 D1, provided potent and sustained glucose lowering effect in diabetic mice models. It also demonstrated superior weight loss effect to GLP-1 or FGF21 alone. Moreover, GLP-1-Fc-FGF21 D1 exhibited strong anti-NASH effect in the high-fat diet-induced ob/ob model as it improved liver function, serum and hepatic lipid profile and reduced NAFLD activity score with an efficacy superior to either FGF21 or GLP-1 analogs alone. Interpretation This novel GLP-1/FGF21 dual agonist is worth clinical development for the treatment of T2D, obesity and NASH. Funding HEC Pharm R&D Co., Ltd, National natural science fund of China.
研究领域:
药理学
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代谢性疾病
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内分泌学
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分子生物学
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PubMed
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Journal of Inflammation Research
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2022
·
IF 4.631
Jiao Peng,Xi Li,Lin Zheng,Lifang Duan,Zhengxian Gao,Die Hu,Jie Li,Xiaofeng Li,Xiangchun Shen,Haitao Xiao
Purpose GLP-1 based therapy represents a new treatment option for inflammatory bowel disease. Ban-Lan-Gen (BLG) granule, a known anti-viral TCM formulation, exhibits potential anti-inflammatory activities in treating various kinds of inflammation. However, its anti-inflammatory effect on colitis and the underlying mechanisms remain unknown.Methods Dextran sulfate sodium (DSS)-induced chronic relapsing colitis in mice was established. The disease activity index, histological sign of damage, and levels of proinflammatory cytokines were performed to assess the protective effects of BLG. Serum GLP-1 level and colonic Gcg, GPR41 and GRP43 expression, the community compositions of gut microbiota, the levels of SCFAs in the feces and GLP-1 release from primary murine colon epithelial cells were performed to characterize the effects of BLG on gut microbiota and gut SCFA derived-GLP-1 production.Results BLG treatment significantly alleviated body weight loss, DAI, colon shortening, colon tissue damage, and pro-inflammatory cytokine levels of TNF-α, IL-1β and IL-6 in the colon tissues. Moreover, BLG treatment could observably restore colonic Gcg, GPR41 and GRP43 expression and serum GLP-1 level of colitic mice, as well as correct the alteration of gut microbiota in colitic mice by increasing the abundances of SCFA-producing bacteria, eg, Akkermansia and Prevotellaceae_UCG-001, and decreasing the abundances of bacteria, eg, Eubacterium_xylanophilum_group, Ruminococcaceae_UCG-014, Intestinimonas, and Oscillibacter. Furthermore, BLG treatment could markedly increase the levels of SCFAs in feces of colitic mice. In parallel, ex vivo assay also showed that and the extract of feces from BLG-treatment mice could greatly stimulate the secretion of GLP-1 from primary murine colon epithelial cells.Conclusion These findings suggest that the anti-colitis effects of BLG are achieved at least partly by regulating gut microbiota and restoring gut SCFA derived-GLP-1 production, and BLG has the potential to be developed as a promising agent for the treatment of chronic relapsing colitis.
研究领域:
药理学
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免疫学
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微生物学
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胃肠病学
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DOI
PubMed
高影响因子
FOOD CHEMISTRY
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2025
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IF 9.8
Mengting Yu,Chengdeng Chi,Shuangxia Huang,Xiaoxi Li
This study presented a novel strategy to regulate postprandial glucose levels by engineering colon-targeted nanoparticles with tailored lecithin distribution for enhancing Glucagon-like peptide-1 (GLP-1) secretion. GLP-1 plays a pivotal role in regulating postprandial glucose homeostasis. Firstly, type I starch-lecithin complex (OSL) was fabricated with excellent digestion resistance (47.89 % resistant starch) and self-assembly performance (0.58 mg/mL CMC). Lecithin solutions were then incorporated into OSL to form OSL/lecithin nanoparticles (180–200 nm, negatively charged surface) with different distribution ratios of lecithin inside and outside starch helical cavity. With distribution ratio of lecithin increased from 1:1.25 to 1:10, β-lactoglobulin colon release improved by 21.67 %. Microbial fermentation led OSL/Lecithin based nanoparticles to release β-lactoglobulin, lecithin, reducing sugars, and SCFAs, which collectively boosted GLP-1 secretion by 169.48 % and 36.07 % compared with β-lactoglobulin and mixed OSL/Lecithin, respectively. This research offered a new strategy for targeted delivery of bioactive molecules to modulate GLP-1 secretion.
研究领域:
生物材料学
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纳米医学
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药剂学
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分子营养学
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胃肠内分泌学
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DOI
PubMed
高影响因子
ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY
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2025
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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
LIFE SCIENCES
·
2020
·
IF 3.647
Tian Li,Li Tu,Ran Gu,Xiu-Lin Yang,Xiu-Juan Liu,Gui-Ping Zhang,Qian Wang,Yi-Pin Ren,Bing-Jin Wang,Jin-Yong Tian
Objectives To investigate the effect of glucagon-like peptide-1 (GLP-1) receptor and glucose dependent insulinotrophic polypeptide (GIP) receptor dual agonist DA-JC4 on alleviating Parkinson's disease (PD) and unveil related cellular mechanisms. Methods Rotenone was injected to generate a rat PD model, on which the effect of DA-JC4 on motor functions was evaluated by rotational behavioral assay and open field test. The survival of dopaminergic neurons was analyzed, in addition to assays for mitochondrial stress and quantification of neurotransmitter levels using high performance liquid chromatography (HPLC). In cultured hippocampal neurons, the effect of DA-JC4 on mitochondrial stress and related cellular mechanism was analyzed by Flow cytometry, western blotting and reactive oxygen species (ROS). Results DA-JC4 significantly improved motor functions in PD rats, and elevated levels of major neurotransmitters. By histological analysis, DA-JC4 protected dopaminergic neurons from rotenone-induced cell death, which was associated with reduced mitochondrial stress. Experiments in cultured rat hippocampal neurons validated the neuroprotective role of DA-JC4 against cell apoptosis and mitochondrial stress induced by rotenone. The protective effect of DA-JC4 was later found to be dependent on AKT/JNK signal pathway, as treatment using AKT inhibitor or JNK activator abolished such effects. Conclusion Our results showed that the dual agonist of GLP-1/GIP receptor could ameliorate motor dysfunctions of PD by protecting dopaminergic neurons which was mediated by relieved mitochondrial stress and apoptosis via AKT/JNK signal pathway.
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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细胞生物学
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DOI
PubMed
高影响因子
Frontiers in Microbiology
·
2019
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IF 4.259
Cui Hong-Xin,Zhang Ling-Shuai,Luo Yang,Yuan Ke,Huang Zhi-Yong,Guo Ying
Rheum palmatum L. is widely used in traditional Chinese medicine for the treatment of constipation. Here, the therapeutic effects and underlying mechanisms of purified anthraquinone-glycoside preparation from rhubarb (RAGP) on the type 2 diabetes mellitus (T2DM) rats were investigated. After 6 weeks of metformin and RAGP treatment, the weight returned to normal. Fasting blood glucose (FBG), glycated serum protein (GSP), insulin concentration and HOMA-IR index had significantly decreased, and glucagon-like peptide-1 (GLP-1) concentrations had increased. Histological abnormalities in the pancreas and ileum had improved. These effects were associated with enhanced intestinal integrity, thereby reducing the absorption of lipopolysaccharide (LPS) and inflammation. To investigate whether RAGP ameliorated insulin resistance via effects on the gut microbiota, we performed 16s rDNA sequencing of ileal gut contents. This showed an amelioration of gut dysbiosis, with greater abundance of probiotic Lactobacillus and short-chain fatty acid-producing bacteria, and lower abundance of the Lachnospiraceae NK4A136 group and LPS-producing Desulfovibrio. The mechanism of the hypoglycemic effect of RAGP involves regulation of the gut microbiota, activation of the GLP-1/cAMP pathway to ameliorate insulin resistance. Thus, this study provides a theoretical basis for the use of RAGP to treat T2DM, and it may be a novel approach to restore the gut microbiota.
研究领域:
药理学
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微生物学
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代谢病学
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DOI
PubMed
高影响因子
Translational Psychiatry
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2026
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IF 7.5
Liu Yiran,Liu Xiao,Yin Xueyong,Li Yunluo,Yu Xiaohui,Nan Xinyu,Xue Jiping,Lu Hengtai,Li Bingyu,Zhou Fei,Liu Xiaoyu,Zhang Xiangyu,He Xiangjun,Yu Xi,Yan Shu,Li Yating,Wang Shuang,Gao Yuan,Liu Yifan,Kang Ying,Zhang Jingwen,Zhao Ye,Shi Haishui
Defensive aggression is an evolutionarily conserved instinct, and its dysregulation represents a common behavioral manifestation in multiple psychiatric disorders. Although glucagon-like peptide-1 receptor agonists (GLP-1RAs) are widely used for metabolic diseases, their role in aggressive behavior remains unclear. Here, we employed behavioral assays, chemogenetics, immunofluorescence, pharmacological manipulations, and metabolomics to investigate the regulatory effects of GLP-1RA on defensive aggression in mice. Acute intracerebroventricular administration of GLP-1RA significantly suppressed defensive aggression without affecting locomotor activity or time spent in the center of the open field. c-Fos immunofluorescence indicated that this effect was associated with reduced neuronal activity in the dorsomedial periaqueductal gray (DMPAG). Chemogenetic activation of DMPAG neurons reversed the suppressive effect of GLP-1RA on defensive aggression, supporting a key regulatory role of this region. In a social isolation (SI) induced pathological aggression model, GLP-1RA alleviated excessive defensive aggression and modulated the metabolic state of the DMPAG. Notably, GLP-1RA restored levels of L-carnosine, a dipeptide with neuroprotective and anti-excitotoxic properties whose levels were reduced in SI mice. Carnosine infusion into the DMPAG suppressed defensive aggression in SI mice, whereas administration of the carnosine degrading enzyme CNDP2 attenuated the suppressive effect of GLP-1RA, supporting carnosine signaling as a functionally relevant downstream component. These findings identify a carnosine-associated pathway by which GLP-1RA regulates defensive aggression and highlight its therapeutic potential beyond metabolic regulation.
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ACTA PHARMACOLOGICA SINICA
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2021
·Vol. 43
·期 6
·1453-1460
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IF 6.15
Wang Yu-zhe,Yang De-hua,Wang Ming-wei
Glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are regarded as ‘incretins’ working closely to regulate glucose homeostasis. Unimolecular dual and triple agonists of GLP-1R and GIPR have shown remarkable clinical benefits in treating type 2 diabetes. However, their pharmacological characterization is usually carried out in a single receptor-expressing system. In the present study we constructed a co-expression system of both GLP-1R and GIPR to study the signaling profiles elicited by mono, dual and triple agonists. We show that when the two receptors were co-expressed in HEK 293T cells with comparable receptor ratio to pancreatic cancer cells, GIP predominately induced cAMP accumulation while GLP-1 was biased towards β-arrestin 2 recruitment. The presence of GIPR negatively impacted GLP-1R-mediated cAMP and β-arrestin 2 responses. While sharing some common modulating features, dual agonists (peptide 19 and LY3298176) and a triple agonist displayed differentiated signaling profiles as well as negative impact on the heteromerization that may help interpret their superior clinical efficacies.
研究领域:
药理学
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内分泌学
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细胞生物学
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分子生物学
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DOI
PubMed
高影响因子
Cell Host & Microbe
·
2026
·Vol. 34
·期 6
·1000-1017
·
IF 23.2
Liang Bian,Yang Cai,Yuan Zhang,Ling Shen,Huijuan Wang,Feng Gao,Ningbo Cai,Wenbo Chen,Conghui You,Yurui Yang,Fang Wang,Yonggui Yuan,Bing Han,Honghong Yao
Despite widespread clinical use of glucagon-like peptide-1 receptor (GLP-1R) agonists for metabolic disease, their neuropsychiatric effects remain poorly understood and controversial. Here, we demonstrate that liraglutide alleviates depression through a gut-brain pathway that operates independently of GLP-1R. Using both pharmacological and genetic approaches, we demonstrated that liraglutide retained antidepressant efficacy in GLP-1R antagonist-Exn9-treated mice or in Glp1r −/− mice, whereas gut microbiota depletion abolished its effects. Multi-omics analyses revealed that liraglutide increased the abundance of Lactobacillus delbrueckii , which in turn restored the levels of the endocannabinoid 2-arachidonoylglycerol (2-AG). The elevation of 2-AG mediated the antidepressant effects by normalizing excessive neuronal activity in emotional processing brain regions. Importantly, fecal microbiota transplantation from liraglutide-treated mice or Lactobacillus delbrueckii colonization replicated the antidepressant effects. These findings uncover a non-canonical mechanism of action for GLP-1 analogs, highlighting a specific microbiota-endocannabinoid metabolic pathway as a potential therapeutic target for depression.
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PubMed
高影响因子
CARBOHYDRATE POLYMERS
·
2026
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IF 13.2
Sandeep Karki,Sahil Malhotra,Muhammad Ijaz,Nicolas Rollet,Eoin D. O'Cearbhaill,Estela Bini,David J. Brayden
The buccal route has re-emerged as an alternative non-injectable route for peptide delivery. However, buccal peptide bioavailability is low, necessitating new formulation strategies. Pullulan, a water-soluble carbohydrate polymer, offers potential as a film-forming agent for buccal peptide delivery. Our aim was to co-administer a glucagon-like peptide-1 receptor agonist (GLP-1 RA) model analogue with an epithelial permeation enhancer, sodium glycodeoxycholate (GDC) in a bilayer film using a pullulan-based mucoadhesive layer. A pullulan–carboxymethyl cellulose mucoadhesive layer was selected, along with a backing layer made from an ammonio-methacrylate copolymer (Eudragit® RLPO). Physicochemical characterization confirmed the suitability of the pullulan-based film for buccal application. A Hilltop Chamber comprising an adhesive-backed cotton pad identified an optimal GLP-1 RA:GDC ratio for peptide permeation across ex vivo porcine buccal mucosae. 200 mM GDC (94.4 mg/mL) enabled ∼6% flux at 3 h using a donor concentration of 50 mg/mL GLP-1 RA (∼1:2). When these concentrations were incorporated into the prototype pullulan films, GLP-1 RA fluxes across mucosae reached ∼4.5% and ∼2% at 3 h for single mucoadhesive-layer and bilayer films, respectively, without overt tissue damage. Integrating GLP-1 RA and GDC into a pullulan–based bilayer film offers a promising carbohydrate polymer platform for enhancing buccal peptide delivery.
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BIOCHEMICAL PHARMACOLOGY
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2013
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IF 4.576
Jing Han,Xun Huang,Lidan Sun,Zheng Li,Hai Qian,Wenlong Huang
A series of fatty chain conjugates of glucagon-like peptide-1(GLP-1) were designed and synthesized. First, eleven cysteine modified peptides ( 1 – 11 ) were prepared using Gly 8 -GLP-1(7-36)-NH 2 peptide as a starting point. Peptides 1 , 6 , 9 , and 11 which showed comparable GLP-1 receptor activate potency and glucose-lowering effect in vivo with Gly 8 -GLP-1(7-36)-NH 2 were selected for second step modifications to yield conjugates 12 – 23 . All conjugates retained significant GLP-1 receptor activate potency and more importantly exerted enhanced albumin-binding properties and in vitro plasma stability. The protracted antidiabetic effects of the most stable compound 14 were further confirmed by both multiple intraperitoneal glucose tolerance test and hypoglycemic efficacies test in vivo. Furthermore, once daily injection of compound 14 to db/db mice achieved long-term beneficial effects on HbA1c lowering and glucose tolerance. Our results suggest that compound 14 is a promising type 2 antidiabetic agent deserving further investigation.
研究领域:
药理学
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药物化学
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内分泌学
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PubMed
高影响因子
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