Current Pharmaceutical Analysis
·
2021
·Vol. 17
·期 9
·1197-1205
·
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
✓ 已验证
DOI
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
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产品关联
DOI
PubMed
高影响因子
Fishes
·
2023
·Vol. 8
·期 3
·170
·
IF 2.3
Lei Zhang,Peng Shi,Lin Zhang,Yajun Wang,Jilin Xu,Xiaojun Yan,Kai Liao
Ghrelin, glucagon-like peptide-1 (GLP-1), and peptide YY (PYY) are potent hormones mediating food intake according to the nutritional status in fish. However, limited information is available on these genes and their expression in response to nutrition in silver pomfret (Pampus argenteus). A comparison analysis revealed thatghrelinand GLP-1 were relatively conserved in marine fish. PYYa and PYYb shared a low identity and were clustered to different PYY branches.Ghrelin,pyya, andpyybmRNAs were highly expressed in the brain, whileglp-1was highly expressed in the gills and liver. TheghrelinmRNA expression was relatively high an hour post-feeding and decreased after 3 to 72 h of fasting. Theglp-1mRNA expression was increased after 6 to 24 h of fasting. ThepyyamRNA expression was increased after 72 h of fasting, while thepyybexpression remained stable during fasting. The diet with 14% lipid promoted the expressions ofglp-1,pyya, andpyyb, but inhibited theghrelinexpression. Theghrelinexpression in the intestine was increased after palmitic acid, oleic acid (OA), linoleic acid (LA), α-linolenic acid, eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA) incubation. OA decreased the expression ofglp-1and increased the expression ofpyya. The expression ofpyybwas downregulated by LA, DHA, and EPA. These results suggest the importance ofghrelin,glp-1, andpyyin coordinating food intake in response to fasting, dietary lipid concentration, and fatty acids in silver pomfret.Keywords:ghrelin;glp-1;pyy;fasting;lipid content;fatty acids;silver pomfretKey Contribution:This study provides insight into howghrelin,glp-1, andpyyrespond to fasting, dietary lipid concentration, and fatty acids in silver pomfret.
研究领域:
海洋生物学
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分子生物学
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营养学
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产品关联
DOI
高影响因子
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
·
2023
·
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
✓ 已验证
产品关联
DOI
PubMed
高影响因子
JOURNAL OF ETHNOPHARMACOLOGY
·
2026
·
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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DOI
PubMed
高影响因子
RSC Advances
·
2023
·Vol. 13
·期 43
·30190-30201
·
IF 3.9
Huien Chen,Xinyu Liu,Meixia Xie,Xiaoting Zhong,Chunyan Yan,Minghua Xian,Shumei Wang
Rehmannia glutinosa (RG) as a Chinese herbal medicine can be used both in medicine and food. As the main component of RG, the polysaccharides have a hypoglycemic effect, however, the hypoglycemic activity of RG homopolysaccharides remains unknown. We isolated and purified two polysaccharides, RGP70-1-1 and RGP70-1-2 (4.9 kDa and 2.8 kDa) from RG. The structural characteristics, including monosaccharide composition, linkage, and configuration were analyzed by FT-IR, HPLC, GC-MS, NMR spectroscopy, Congo test, and SEM. RGP70-1-1 and RGP70-1-2 consist of four monosaccharides (glucose, mannose, arabinose, and galactose). RGP70-1-1 contains 14 connection modes, with the linkages including L-Araf-(1→, →3)-L-Araf-(1→, →5)-L-Araf-(1→, →3,5)-L-Araf-(1→, →2,5)-L-Araf-(1→, D-Manp-(1→, →2)-D-Manp-(1→, →4)-D-Manp-(1→, D-Galp-(1→, →4)-D-Galp-(1→, →4,6)-D-Galp-(1→, →6)-D-Glcp-(1→, →4,6)-D-Glcp-(1→, →3,6)-D-Glcp-(1→. The linkages of RGP70-1-2 is including →5)-L-Araf-(1→, →3,5)-L-Araf-(1→, →4)-D-Manp-(1→, →3,6)-D-Manp-(1→, D-Galp-(1→, →6)-D-Galp-(1→, D-Glcp-(1→, →6)-D-Glcp-(1→, →4,6)-D-Glcp-(1→. Furthermore, RGP70-1-1 and RGP70-1-2 can inhibit α-glucosidase and α-amylase. RGP70-1-1 stimulated GLP-1 secretion in STC-1 cells and was related to the up-regulation of PI3K and p-AKT protein expression. The findings revealed a natural product with potential hypoglycemic activity, which may be used as a GLP-1 secretagogue and a beneficial functional food ingredient for T2D.
研究领域:
药理学
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生物化学
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药物化学
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分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
JOURNAL OF DRUG DELIVERY SCIENCE AND TECHNOLOGY
·
2024
·
IF 4.5
Zhenyu Zhao,Ruihuan Ding,Yumei Wang,Ranran Yuan,Houqian Zhang,Tianyang Li,Wei Zheng,Entao Chen,Aiping Wang,Yanan Shi
The glucagon-like peptide-1 (GLP-1) analogue used to treat diabetes is an increasingly popular polypeptide protein therapeutic, commonly marketed as an injection. However, the effective oral administration of peptide drugs remains challenging because of their extremely low bioavailability. In recent years, a number of delivery systems that have been shown to be effective in improving the therapeutic efficacy of oral drugs. Herein, liraglutide was employed as a model drug and amphoteric sulfobetaine (SB12) was selected for the surface modification of poly (D, L-lactide-co-glycolic acid) (PLGA) nanoparticles (NPs) to obtain hydrophilic and electroneutral SB12-NPs. The functional SB12-NPs were first screened to identify the optimal prescription process and obtained from the final prescription were evaluated. The particle size, zeta potential , encapsulation efficiency (EE%) and drug-loading (DL%) of SB12-NPs were 87.25 ± 0.77 nm, −3.91 ± 1.88 mV, 77.45% ± 1.62%, and 10.46% ± 0.21%, respectively. The cellular uptake of Lira-SB12 NPs was significantly better than that of free liraglutide, and verified that it was transported mainly through endocytosis mediated by clathrin- and lipid raft–mediated. The trans-mucous permeability (2.86-fold) and intestinal permeability (1.79-fold) of SB12-NPs were significantly higher than those of free liraglutide. Single and multiple doses of SB12-NPs showed that the blood sugar level of diabetic mice could be lower to about 70% of the initial value. The SB12-NPs demonstrated a higher relative bioavailability of 9.59% compared with that of oral pure liraglutide (5.13%). Thus, SB12-modified PLGA NPs with hydrophilic and electroneutral surface properties can significantly improve mucus permeability and oral bioavailability, and have the potential to be applied for oral delivery of peptides and proteins .
研究领域:
药学
·
纳米技术
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药物递送系统
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生物药剂学
✓ 已验证
产品关联
DOI
高影响因子
BIOCHEMICAL PHARMACOLOGY
·
2026
·
IF 6.5
Yijie Feng,Caili Zhang,Yinuo Wei,Enhua Liu,Hongyu Sun,Peter Flatt,Victor Gault,Nigel Irwin,Christian Hölscher,Li Hao,Zijuan Zhang
Effective disease-modifying therapies for Alzheimer’s disease (AD) remain limited. Glucagon-like peptide-1 receptor (GLP-1R) activation has shown neuroprotective potential in AD, whereas the neuropeptide Y/pancreatic polypeptide-Y4 receptor (NPY/PP-Y4R) axis has been implicated in central homeostasis and inflammatory regulation, although its role in AD remains insufficiently defined. Here, we evaluated a rationally designed bifunctional peptide predicted to target both NPY4R and GLP-1R in 5 × FAD mice and LPS-stimulated BV2 cells. In vivo , NPY4/GLP-1 improved spatial learning and memory, working memory, and exploratory behavior, and was accompanied by reduced hippocampal Aβ burden ( P < 0.05), alleviated neuronal injury ( P < 0.01), improved synaptic integrity ( P < 0.01), and attenuated mitochondrial abnormalities ( P < 0.01). These changes were associated with lower hippocampal levels of cytosolic mitochondrial DNA (mtDNA) ( P < 0.05), cGAS ( P < 0.05), STING ( P < 0.05), and phosphorylated IRF3 ( P < 0.01), together with decreased IL-1β ( P < 0.05) and increased IL-10 ( P < 0.05) expression. In LPS-stimulated BV2 cells, NPY4/GLP-1 similarly reduced STING-related signaling ( P < 0.05) and inflammatory responses ( P < 0.05). Co-treatment with the STING inhibitor C-176 provided additional support for the involvement of STING-associated inflammatory signaling under in vitro inflammatory conditions. Molecular docking suggested that NPY4/GLP-1 may interact with both NPY4R and GLP-1R, providing a structural rationale for its bifunctional design. Collectively, these findings indicate that NPY4/GLP-1 exerts beneficial effects in AD-related models and that these effects are associated with attenuation of mtDNA-cGAS-STING-related neuroinflammatory signaling. This study provides initial evidence supporting further evaluation of this novel bifunctional peptide as a candidate therapeutic strategy for AD.
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Frontiers in Microbiology
·
2025
·
IF 4.5
Zhang Yue,Wang Xiang,Deng Duping,Gong Yuanyuan,Chen Xuanyi,Li Juan,Hong Xiaojuan
Objective: This study aimed to investigate the impact of electroacupuncture (EA) on blood glucose levels, gut microbiota, short-chain fatty acids (SCFAs), and glucagon-like peptide-1 (GLP-1) in a rat model of type 2 diabetes mellitus (T2DM).Methods: Forty Sprague–Dawley (SD) rats were randomly assigned to five groups (n = 8/group) using a random number table: normal control, T2DM model, electroacupuncture (EA), EA + antibiotics (EA + A), and antibiotics (A). The normal rats received a standard diet and saline gavage, while the other groups were fed a high-fat diet and emulsion. The EA + A and A groups received additional antibiotic solution gavage. The normal, model, and A groups were immobilized and restrained for 30 min, six times per week, for 4 weeks. The EA and EA + A groups received EA treatment at specific acupoints for 30 min, six times per week, for 4 weeks. EA parameters were continuous waves at 10 Hz and 1–2 mA. During the intervention, water and food consumption, body weight, fasting blood glucose (FBG), and oral glucose tolerance test (OGTT) were monitored. Pancreatic tissue was examined using hematoxylin and eosin (H&E) staining. Fecal microbial communities were analyzed by 16S rDNA sequencing, and short-chain fatty acids (SCFAs) were measured using gas chromatography–mass spectrometry (GC–MS). Serum levels of fasting insulin (FINS), glycated hemoglobin (HbA1c), and glucagon-like peptide-1 (GLP-1) were determined using enzyme-linked immunosorbent assay (ELISA).Results: EA significantly improved daily water intake, food consumption, and body weight in T2DM rats (p < 0.01). EA also reduced FBG, the area under the curve of the OGTT, FINS, and homeostasis model assessment of insulin resistance (HOMA-IR) in T2DM rats (p < 0.05). The ELISA results showed a lower concentration of HbA1c in the EA group (p < 0.05). EA improved the overall morphology and area of pancreatic islets, increased the number of β-cell nuclei, and alleviated β-cell hypertrophy. The abundance of operational taxonomic units (OTUs) in the EA group increased than the model group (p < 0.05), and EA upregulated the Shannon, Chao1, and Ace indices (p < 0.05). EA increased the concentrations of acetic acid, butyric acid, and GLP-1 (p < 0.05). Correlation analysis revealed negative associations between Lactobacillaceae (R = −0.81, p = 0.015) and Lactobacillus (R = −0.759, p = 0.029) with FBG. Peptostreptococcaceae and Romboutsia were negatively correlated with HbA1c (R = −0.81, p = 0.015), while Enterobacteriaceae was positively correlated with OGTT (R = 0.762, p = 0.028). GLP-1 was positively correlated with acetic acid (R = 0.487, p = 0.001), butyric acid (R = 0.586, p = 0.000), isovaleric acid (R = 0.374, p = 0.017), valeric acid (R = 0.535, p = 0.000), and caproic acid (R = 0.371, p = 0.018). Antibiotics disrupted the intestinal microbiota structure and weakened the therapeutic effects of EA.Conclusion: EA effectively improved glucose metabolism in T2DM rats. The hypoglycemic effects of EA were associated with the regulation of gut microbiota, SCFAs, and GLP-1.
研究领域:
医学
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糖尿病研究
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微生物学
·
代谢组学
·
针灸疗法
✓ 已验证
产品关联
DOI
PubMed
高影响因子
ANTIOXIDANTS & REDOX SIGNALING
·
2025
·
IF 6.1
Wenhui Yan,Xin Cui,Tingli Guo,Na Liu,Zhuanzhuan Wang,Yuzhuo Sun,Yuanrui Shang,Jieyun Liu,Yuanyuan Zhu,Yangyang Zhang,Lina Chen
Aims: Metabolic dysfunction-associated steatotic liver disease (MASLD) is a prevalent hepatic disorder worldwide. Arachidonic acid 15-lipoxygenase (ALOX15), an enzyme catalyzing the peroxidation of polyunsaturated fatty acids, plays a crucial role in various diseases. Here, we sought to investigate the involvement of ALOX15 in MASLD.Results: In this study, we observed upregulation of ALOX15 in the liver of high-fat diet (HFD)- and streptozotocin (STZ)-induced mice. Metabolomic analysis revealed elevated levels of ALOX15 metabolites, 12(S)-hydroperoxyeicosatetraenoic acid and 15(S)-hydroperoxyeicosatetraenoic acid. Transcriptomic analysis showed that the increased fatty acid uptake regulated by the PPARγ/CD36 pathway predominated in lipid accumulation. To elucidate the mechanism underlying ALOX15-induced lipid accumulation, HepG2 cells were transfected with a lentivirus expressing ALOX15 or small interfering RNA targeting ALOX15 and exposed to palmitic acid (PA). Both ALOX15 overexpression and PA exposure led to increased intracellular free fatty acid and triglyceride, resulting in lipotoxicity. ALOX15 overexpression aggravated the effect of PA, while the knockdown of ALOX15 attenuated PA-induced lipotoxicity. Moreover, the treatment with PPARγ antagonist GW9662 or CD36 inhibitor sulfosuccinimidyl oleate sodium effectively reduced lipid accumulation and lipotoxicity resulting from ALOX15 overexpression and PA exposure, indicating the involvement of the PPARγ/CD36 pathway in ALOX15-mediated lipid accumulation. Furthermore, liraglutide, a widely used glucagon-like peptide 1 receptor (GLP-1R) agonist (GLP-1RA), improved hepatic lipid accumulation in HFD/STZ-induced mice by suppressing the ALOX15/PPARγ/CD36 pathway.Innovation and Conclusion: Our study underscores the potential of ALOX15 as an emerging therapeutic target for MASLD. In addition, the GLP-1RA may confer hepatoprotection by regulating ALOX15, enhancing our comprehension of the mechanisms underpinning their protection on MASLD. Antioxid. Redox Signal. 00, 000–000.
研究领域:
肝病学
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内分泌学
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分子生物学
·
药理学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Drug Design Development and Therapy
·
2023
·
IF 4.8
Huan Xue,Hao-Jie Xing,Bin Wang,Chao Fu,Yu-Shan Zhang,Xi Qiao,Chao Guo,Xiao-Li Zhang,Bin Hu,Xin Zhao,Li-Jiao Deng,Xiao-Chan Zhu,Yi Zhang,Yun-Feng Liu
Purpose The glucagon-like peptide-1 receptor (GLP-1R) is an effective therapeutic target for type 2 diabetes mellitus (T2DM) and non-alcoholic steatohepatitis (NASH). Research has focused on small-molecule GLP-1R agonists because of their ease of use in oral formulations and improved patient compliance. However, no small-molecule GLP-1R agonists are currently available in the market. We aimed to screen for a potential oral small-molecule GLP-1R agonist and evaluated its effect on blood glucose and NASH.Methods The Connectivity map database was used to screen for candidate small-molecule compounds. Molecular docking was performed using SYBYL software. Rat pancreatic islets were incubated in different concentrations glucose solutions, with cinchonine or Exendin (9–39) added to determine insulin secretion levels. C57BL/6 mice, GLP-1R−/− mice and hGLP-1R mice were used to conduct oral glucose tolerance test. In addition, we fed ob/ob mice with the GAN diet to induce the NASH model. Cinchonine (50 mg/kg or 100 mg/kg) was administered orally twice daily to the mice. Serum liver enzymes were measured using biochemical analysis. Liver tissues were examined using Hematoxylin-eosin staining, Oil Red O staining and Sirius Red staining.Results Based on the small intestinal transcriptome of geniposide, a recognized small-molecule GLP-1R agonist, we identified that cinchonine exerted GLP-1R agonist-like effects. Cinchonine had a good binding affinity for GLP-1R. Cinchonine promoted glucose-dependent insulin secretion, which could be attenuated significantly by Exendin (9–39), a specific GLP-1R antagonist. Moreover, cinchonine could reduce blood glucose in C57BL/6 and hGLP-1R mice, an effect that could be inhibited with GLP-1R knockout. In addition, cinchonine reduced body weight gain and food intake in ob/ob-GAN NASH mice dose-dependently. 100 mg/kg cinchonine significantly improved liver function by reducing the ALT, ALP and LDH levels. Importantly, 100 mg/kg cinchonine ameliorated hepatic steatosis and fibrosis in NASH mice.Conclusion Cinchonine, a potential oral small-molecule GLP-1R agonist, could reduce blood glucose and ameliorate NASH, providing a strategy for developing small-molecule GLP-1R agonists.
研究领域:
药理学
·
内分泌学
·
肝病学
·
分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Scientific Reports
·
2017
·Vol. 7
·期 1
·1-11
·
IF 4.259
Ma Jie,Li Huan,Hu Xiangnan,Yang Lu,Chen Qi,Hu Congli,Chen Zhihao,Tian Xiaoyan,Yang Yang,Luo Ying,Gan Run,Yang Junqing
Dipeptidyl peptidase IV (DPP-IV) inhibitor has been expected to be a new class of anti-diabetic agent. The present study was designed to characterize the pharmacological profiles of CMD-05, a novel DPP-IV inhibitor discovered in our laboratory, in vitro and in vivo . The IC 50 of CMD-05 on DPP-IV inhibitory activity was approximately 12 nM while vildagliptin was 3.5 nM in vitro . In diabetes rat model established by high fat diet/low dose streptozotocin, CMD-05 inhibited DPP-IV activity, significantly improved glucose tolerance, increased GLP-1 and insulin levels in plasma. Long-term administration of CMD-05 decreased HbA1c and TG levels and improved the islet function without significantly effect on body weight. Furthermore, CMD-05 reduced INS-1 cell apoptosis and increased GLP-1 secretion in NCI-H716. After oral administration, CMD-05 reached peak concentration at 30 min with half-life of 288 minutes and the inhibitory rate of DPP-IV greater than 50% lasted for 15 h. In fasted normal rats, CMD-05 didn’t cause significant hypoglycemia. CMD-05 had a lower cytotoxicity than vildagliptin in vitro and its maximum tolerance dose in mice is beyond 2000 mg/kg. These results indicated that CMD-05 has similar activity with vildagliptin in vivo and has a much longer half-life and lower cytotoxicity than vildagliptin.
研究领域:
药理学
·
内分泌学
·
糖尿病研究
✓ 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）