BIOORGANIC & MEDICINAL CHEMISTRY
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2024
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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
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内分泌学
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糖尿病研究
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药物开发
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产品关联
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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产品关联
DOI
PubMed
高影响因子
ACTA PHARMACOLOGICA SINICA
·
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
✓ 已验证
DOI
PubMed
高影响因子
npj Science of Food
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2025
·Vol. 9
·期 1
·1-13
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IF 7.8
Liao Yingyi,Xie Xingyu,Lin Zixin,Huang Ning,Wei Guilan,Wu Jiazhen,Li Yucui,Chen Jiannan,Su Ziren,Yu Xiuting,Chen Liping,Liu Yuhong
Visceral adiposity is an important characteristic of metabolic dysfunction-associated steatohepatitis (MASH) that affects its development. Curcumin (Cur) attenuates MASH through microbial biotransformation. However, antibiotics (Abx) do not weaken but rather enhance the resistance to weight gain of Cur on MASH rats. The resistance to weight gain mechanism of Cur is different from its anti-MASH effect, which may relate to alleviate visceral adiposity. Here we investigated the mechanism of Cur against visceral adiposity in high-fat diet-induced MASH rats. The results demonstrated that Cur and Abx reduced body, liver and visceral fat weights of MASH rats. Unlike Abx, which induces resistance to weight gain by reducing appetite, Cur mainly reduced the weight of visceral fat, especially that of perirenal fat. Intriguingly, the reduction in perirenal fat caused by Cur was attributed to its specific inhibition of gastric inhibitory polypeptide (GIP) release. The Cur-induced decrease in intestinal GIP release inhibited the activation of GIP receptors to alleviate adipogenesis and inflammation in perirenal adipose tissue. Moreover, Cur alleviated intestinal epithelium and vascular barrier disruption-mediated hypoxia to inhibit GIP release. In summary, the pharmacological effects of Cur on visceral adiposity were mainly contributed by inhibiting gut barrier disruption-mediated hypoxia to attenuate GIP release.
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产品关联
DOI
PubMed
高影响因子
INTERNATIONAL IMMUNOPHARMACOLOGY
·
2025
·
IF 4.7
Weiting Hu,Wenyu Gong,Fan Yang,Rui Cheng,Gerong Zhang,Lu Gan,Yikun Zhu,Weiwei Qin,Ying Gao,Xing Li,Jing Liu
Tirzepatide is a dual agonist of glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) receptors and is a promising therapeutic option for type 2 diabetes mellitus (T2DM). Nevertheless, its effect and underlying mechanism on hepatic steatosis remain ambiguous. Herein, we explored the impact of tirzepatide on improving hepatic steatosis in diabetic mice, with a particular focus on the gut microbiota and bile acids (BAs) using animal models. The tirzepatide effectively reduced body weight, improved insulin resistance, decreased serum and hepatic lipid levels, and mitigated liver injury. Compared to semaglutide, tirzepatide exhibited superior efficacy in reducing hepatic lipid accumulation. 16S rRNA gene sequencing and targeted metabolomics of BAs revealed that tirzepatide ameliorated gut microbiota dysbiosis and BAs metabolism in diabetic mice. Notably, tirzepatide observably increased the abundance of beneficial genera such as Akkermansia , elevated the ratio of farnesoid X receptor (FXR) antagonists (glycoursodeoxycholic acid: GUDCA, β-muricholic acid: β-MCA, hyodeoxycholic acid: HDCA, ursodeoxycholic acid: UDCA) to natural agonists (cholic acid: CA, lithocholic acid: LCA, chenodeoxycholic acid: CDCA, glycocholic acid: GCA, taurodeoxycholic acid: TDCA), and reduced FXR expression in intestinal tissues. In conclusion, tirzepatide attenuated hepatic steatosis in diabetic mice and regulated the gut microbiota and BAs metabolism, which may help to provide a novel therapeutic approach and therapeutic target for metabolic dysfunction-associated steatotic liver disease (MASLD).
研究领域:
药理学
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代谢组学
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微生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
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