Nutrients
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2025
·Vol. 17
·期 10
·1693
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IF 5
Binsong Han,Yuhui Ye,Cunzheng Zhang,Lina Zhang,Peng Zhou
Background: Camel milk is considered to be an important source of bioactive peptides with potential anti-diabetic effects. However, the mechanism by which these active peptides exert their anti-diabetic effects is not clear. The aim of this study was to systematically evaluate the in vivo anti-diabetic effects of Leucine-Leucine-Proline-Lysine (LLPK), a novel dipeptidyl peptidase-4 (DPP-4) inhibitory peptide identified from the in vitro gastrointestinal digestion product of camel milk.Methods: Adb/dbdiabetic mouse model was used, and LLPK was administered to mice at doses of 50 mg/kg BW and 100 mg/kg BW as a daily oral gavage for 30 days. The effects of LLPK on fasting blood glucose (FBG), oral glucose tolerance test (OGTT), insulin tolerance test (ITT), and serum lipid levels were monitored, and possible mechanisms of action were elucidated using proteomics.Results: The results demonstrated that LLPK significantly improved diabetic symptoms, including FBG, OGTT, ITT, and serum lipid levels indb/dbdiabetic mice. Furthermore, significantly increased levels of serum glucagon-like peptide 1 (GLP-1) and reduced serum DPP-4 activity were observed in the LLPK-treated group compared to the control group. Hepatic proteomics indicated that LLPK improved glucose and lipid metabolism via the PPAR signaling pathway, where the key targets were Scd1, Acox1, Acaa1b, Slc27a1, Acsl1, and Ehhadh.Conclusions: In summary, this study provided new insights into the anti-diabetic mechanisms of camel milk and supported the development of camel milk-based anti-diabetic functional foods or nutraceuticals.
研究领域:
营养学
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分子生物学
·
代谢研究
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DOI
PubMed
高影响因子
BMC Pharmacology & Toxicology
·
2024
·Vol. 25
·期 1
·1-15
·
IF 2.8
Wang Tianyan,Tao Ting,Liu Yi,Dong Jie,Ni Shanhong,Liu Yun,Li Yanli,Xu Ning,Sun Zengxian
Background and purposes It is unclear whether the parent Saxagliptin (SAX) in vivo is the same as that in vitro, which is twice that of 5-hydroxy Saxagliptin (5-OH SAX). This study is to construct a Pharmacokinetic-Pharmacodynamic (PK-PD) link model to evaluate the genuine relationship between the concentration of parent SAX in vivo and the effect. Methods First, we established a reliable Ultra Performance Liquid Chromatography-Mass Spectrometry (UPLC-MS/MS) method and DPP-4 inhibition ratio determination method. Then, the T2DM rats were randomly divided into four groups, intravenous injection of 5-OH SAX (0.5 mg/kg) and saline group, intragastric administration of SAX (10 mg/kg) and Sodium carboxymethyl cellulose (CMC-Na) group. Plasma samples were collected at different time points for subsequent testing. Finally, we used the measured concentrations and inhibition ratios to construct a PK-PD link model for 5-OH SAX and parent SAX. Results A two-compartment with additive model showed the pharmacokinetic process of SAX and 5-OH SAX, the concentration-effect relationship was represented by a sigmoidal E max model and sigmoidal E max with E 0 model for SAX and 5-OH SAX, respectively. Fitting parameters showed SAX was rapidly absorbed after administration ( T max =0.11 h, t 1/2, ka =0.07 h), widely distributed in the body (V ≈ 20 L/kg), plasma exposure reached 3282.06 ng*h/mL, and the elimination half-life was 6.13 h. The maximum plasma dipeptidyl peptidase IV (DPP-4) inhibition ratio of parent SAX was 71.47%. According to the final fitting parameter EC 50 , EC 50, 5−OH SAX =0.46EC 50, SAX(parent) , it was believed that the inhibitory effect of 5-OH SAX was about half of the parent SAX, which is consistent with the literature. Conclusions The PK-PD link model of the parent SAX established in this study can predict its pharmacokinetic process in T2DM rats and the strength of the inhibitory effect of DPP-4 based on non-clinical data.
研究领域:
药理学
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药代动力学
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药效学
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糖尿病研究
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分析化学
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产品关联
DOI
PubMed
高影响因子
EUROPEAN JOURNAL OF PHARMACOLOGY
·
2020
·
IF 3.263
Shumin Jiang,Xueli Wu,Yi Wang,Jingtao Zou,Xiaoping Zhao
Dipeptidyl Peptidase-4 (DPP-4) is a specific enzyme hydrolyzing the incretin hormone glucagon like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) to reduce insulin secretion, meanwhile DPP-4 inhibitors play an important role in diabetic therapy. In present study, 14 potential inhibitors were screened with an inhibition over 50% on DPP-4 activity from Xiao-Ke-An formula (XKA) and 12 of them exhibited a dose-dependently inhibitory effect at concentrations of 5–50 μmol/l. We found 10 DPP-4 inhibitors restrained differentiation of 3T3-L1 pre-adipocytes as well as reducing the triglycerides and total cholesterol content in 3T3-L1 adipocytes. Furthermore, 7 DPP-4 inhibitors promoted the glucose consumption in insulin-resistance BNL CL.2 cells. Thereinto, ginsenoside Rk 1 up-regulated the protein kinase B (AKT) and glycogen synthase kinase-3 (GSK-3β) phosphorylation expression, while kukoamine B and coptisine hydrochloride obviously increased the phosphorylation of AKT protein and columbamine , panaxadiol , ginsenoside Ro , timosaponin AI significantly promoted the phosphorylation of GSK-3β protein. It's our first effort to confirm those seven compounds could serve as DPP-4 inhibitors to attenuate DPP-4 activities, accompanied with the ability to adjust glucolipid metabolism. Moreover, activating the AKT/GSK-3β signaling pathway to ameliorate insulin resistant may be the anti-diabetic mechanism of XKA.
研究领域:
药理学
·
糖尿病研究
·
分子生物学
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DOI
PubMed
高影响因子
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