CURRENT MICROBIOLOGY
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2025
·Vol. 82
·期 9
·1-18
·
IF 2.6
Xu Wenyi,Guan Yinghua,Tian Liping,Fu Yu,Zhang Yinghui,Liu Yanhong,Hu Yanfei,Zhao Bowen,Wu Chongming
The global prevalence of type 2 diabetes mellitus (T2DM) is currently surging, posing significant health and socioeconomic burdens. Probiotics have emerged as promising interventions due to their safety and potential metabolic benefits. Gut microbiota plays a critical role in the pathophysiology of metabolic diseases in humans, offering valuable insights for therapeutic strategies such as probiotics. Here, aiming to identify novel probiotics from the human gut microbes to combat T2DM, a total of 203 human intestinal bacterial strains were screened in vitro to evaluate their enzymatic inhibition of α-glucosidase and α-amylase, in which Lacticaseibacillus paracasei Glu-07 (= QH-142 = CGMCC 23796) exhibited the highest inhibitory efficacy (81.05% and 72.56% for α-glucosidase and α-amylase, respectively). In HepG2 cells, L. paracasei Glu-07 elevated glucose uptake and consumption by 22.4% and 85.8%. Oral administration of strain Glu-07 in diabetic mice significantly improved hyperglycemia, hyperlipidemia, and restored the structure and composition of gut microbiota toward a healthier profile. Mechanistically, strain Glu-07 activated the AMPK-AKT1-GSK3β/FOXO1 signaling pathways by modulating the expression of key genes, enhanced glycolysis and fatty acid ꞵ-oxidation, and inhibited gluconeogenesis and lipogenesis. It also stimulated GLP-1 secretion, potentially via triggering the GPR41/43-GLP-1 axis, and increased the abundance of beneficial gut microbes, such as Akkermansia muciniphila (~ threefold). The dual regulations synergistically support strain Glu-07 as a promising probiotic candidate for T2DM management.
研究领域:
微生物学
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糖尿病研究
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分子生物学
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药理学
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营养科学
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代谢性疾病
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胃肠病学
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高影响因子
PROCESS BIOCHEMISTRY
·
2017
·
IF 2.497
Nian Cheng,Lei Yang,Ning Dai,Zhongping Hu,Fan Yang,Rong Chen,Xiyao Cheng,Jingjing Zhou,Yongqi Huang,Zhengding Su
Glucagon-like peptide-1 (GLP-1) is a natural incretin hormone released from intestinal L-cells in response to hormonal, neural and nutrient stimuli. Liraglutide is derived from human GLP-1 by substituting Lys34 with Arg and conjugating a palmitic acid to Lys26 via a glutamate spacer, which has a long-lasting hypoglycemic effect. The precursor of liraglutide is a K34R mutant of GLP-1 (GLP-1 R34 ) and was produced previously by either yeast protein expression system or peptide solid phase synthesis. However, degradation of secreted proteins limits the effectiveness of yeast protein expression system and peptide solid phase synthesis requires the use of large amounts of organic solvents and expensive condensation agents. In this study, we reported a novel method to prepare GLP-1 R34 using E. coli protein expression system. The GLP-1 R34 peptide was overexpressed as an MFH-GLP-1 R34 fusion protein and was released from the fusion protein through formic acid cleavage. The target peptide was purified by reverse-phase chromatography and ion exchange chromatography. Our work demonstrated a high-productive process for large-scale preparation of the liraglutide precursor with high purity.
研究领域:
生物化学
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分子生物学
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药物开发
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DOI
高影响因子
ACS Applied Materials & Interfaces
·
2026
·
IF 7.8
Sandeep Karki,Sahil Malhotra,Muhammad Ijaz,Qiancheng Zhang,Estela Bini,Bridget Hogg,Thomas Lijnse,Eoin D. O’Cearbhaill,Brian J. Rodriguez,David J. Brayden
Buccal administration of peptide therapeutics offers a noninvasive alternative to injections but remains constrained by limited peptide epithelial permeability and physicochemical instability. Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are important therapeutics with limited noninvasive administration options. Here, we present a buccal peptide delivery platform integrating electrostatic nanocomplexation, design of experiments (DoE)-guided optimization, and solid-state stabilization. Chitosan oligosaccharide (COS) was complexed with a model GLP-1 RA peptide molecule to generate monodisperse nanocomplexes (∼100 nm) with low polydispersity and a positive surface charge (∼+20 mV). Lyophilization preserved nanocomplex integrity during storage at 4 °C for at least one month, enabling dispersibility and retention of colloidal characteristics and GLP-1 RA secondary structure. Nanocomplexes exhibited minimal cytotoxicity in TR-146 cells at 1 mg/mL over 180 min. Mechanistic analyses demonstrated membrane lipid remodelling, dynamin-dependent endocytic involvement, and redistribution of tight junction and desmosomal proteins, supporting a model involving nanocomplex uptake leading to modulation of epithelial barrier properties. The nanocomplexes were then incorporated into a bilayer film composed of a pullulan/sodium carboxymethyl cellulose mucoadhesive layer and an Eudragit RLPO backing layer. GLP-1 RA permeation across porcine buccal mucosae from the nanocomplexes in solution reached ∼13% at 3 h (Papp ∼3.8 × 10–6 cm/s) while incorporation of complexes in bilayers yielded ∼3.4% permeation (Papp ∼1.2 × 10–6 cm/s) compared to the absence of flux for the GLP-1 RA in solution. These findings demonstrate that peptide nanocomplexes can be successfully incorporated into mucoadhesive films. This approach offers advantages over films comprising permeation enhancers.
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Frontiers in Microbiology
·
2019
·
IF 4.259
Zhang Jian-Mei,Sun Yin-Shuang,Zhao Li-Qin,Chen Tian-Tian,Fan Mei-Na,Jiao Hong-Chao,Zhao Jing-Peng,Wang Xiao-Juan,Li Fu-Chang,Li Hai-Fang,Lin Hai
The impact of gut microbiota and its metabolites on fat metabolism have been widely reported in human and animals. However, the critical mediators and the signal transductions are not well demonstrated. As ovipara, chicken represents a specific case in lipid metabolism that liver is the main site of lipid synthesis. The aim of this study is to elucidate the linkage of gut microbiota and fat synthesis in broiler chickens. The broilers were subjected to dietary treatments of combined probiotics (Animal bifidobacterium: 4 × 108 cfu/kg; Lactobacillus plantarum: 2 × 108 cfu/kg; Enterococcus faecalis: 2 × 108 cfu/kg; Clostridium butyrate: 2 × 108 cfu/kg, PB) and guar gum (1 g/kg, GG), respectively. Results showed that dietary supplementation of PB and GG changed the cecal microbiota diversity, altered short chain fatty acids (SCFAs) contents, and suppressed lipogenesis. In intestinal epithelial cells (IECs), SCFAs (acetate, propionate, and butyrate) up-regulated the expression of glucagon-like peptide-1 (GLP-1) via mitogen-activated protein kinase (MAPK) pathways, mainly via the phospho - extracellular regulated protein kinase (ERK) and phospho-p38 mitogen activated protein kinase (p38 MAPK) pathways. GLP-1 suppressed lipid accumulation in primary hepatocytes with the involvement of (AMP)-activated protein kinase/Acetyl CoA carboxylase (AMPK/ACC) signaling. In conclusion, the result suggests that SCFAs-induced GLP-1 secretion via MAPK pathway, which links the regulation of gut microbiota on hepatic lipogenesis in chickens.
研究领域:
动物营养学
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微生物学
·
分子生物学
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生理学
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INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES
·
2026
·
IF 8.7
Qiang-Ming Li,Qiao-Qiao Zhang-Yang,Ya-Yi Tan,Xiang-Ling Wu,Xue-Qiang Zha,Zhen-Zi Shang,Jian-Ping Luo,Feng-Yun Zhang
Alzheimer's disease (AD) is the most prevalent neurodegenerative disorder. The stem of Dendrobium huoshanense is a traditional medicinal food. This study aimed to investigate the effect of cultivated D. huoshanense stem polysaccharide (cDHPS) on AD and elucidate its mechanisms using an Aβ 1–42 -induced AD mouse model. Results showed that cDHPS significantly improved the cognitive dysfunction and ameliorated the hippocampal neuronal injury of AD mice. Meanwhile, cDHPS effectively alleviated the neuroinflammation of AD mice not only by decreasing the expression of caspase-1, NOD-like receptor family pyrin domain-containing 3 (NLRP3), and apoptosis-associated speck-like protein containing a CARD (ASC), as well as their downstream inflammatory cytokines, but also by inhibiting the activation of microglia and astrocytes. Furthermore, the levels of glucagon-like peptide-1 (GLP-1) in the hippocampus, plasma, and intestine of AD mice were markedly elevated by cDHPS, along with an increase in intestinal short-chain fatty acids (SCFAs) levels. However, the treatment of exendin 9–39, a GLP-1 receptor antagonist, weakened the protective effect of cDHPS against AD, and the depletion of SCFAs reversed the beneficial effects of cDHPS on cognitive dysfunction, hippocampal neuronal injury, neuroinflammation, and GLP-1 secretion in AD mice. These results suggest that cDHPS could protect against AD by modulating the SCFAs/GLP-1 axis-mediated neuroinflammation suppression.
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Chinese Medicine
·
2026
·Vol. 21
·期 1
·20
·
IF 5.7
Yang Yanan,Shao Yuwei,Tian Jun,Wang Yuezhu,Zhu Ye,Pan Siying,Wei Xiali,Jiang Linyan,Wang Xiaoke,Shu Qing
Background Electroacupuncture (EA) has demonstrated efficacy in ameliorating obesity through its marked appetite-suppressing effects. This study aims to elucidate the peripheral-central communication mechanism underlying EA's appetite inhibition mediated by the “vagal afferent fiber–nucleus tractus solitarius (NTS)–hypothalamic arcuate nucleus (ARC)” neural circuit. Methods High-fat diet-induced obese rats received EA or transcutaneous auricular vagus nerve stimulation (taVNS) for 8 weeks. Furthermore, we employed chemogenetic approaches to activate NTS glucagon-like peptide-1 (GLP-1) neurons (NTS GLP−1 ) and utilized capsaicin for gastric vagal deafferentation (GVND). Outcomes included metabolic profiles, vagal electrophysiology, expression of NTS GLP−1 and hypothalamic appetite-regulating neuropeptides, and neuronal activation markers. Results We observed reduced expression of GLP-1 in the NTS of obese rats. Chemogenetic activation of NTS GLP−1 significantly suppressed appetite, mitigated obesity, and modulated hypothalamic pro-opiomelanocortin (POMC) and neuropeptide Y (NPY). Following EA intervention in obese rats, concurrent activation of NTS GLP−1 and vagal afferent fibers was observed. Similar to chemogenetic NTS GLP−1 activation, EA upregulated the anorexigenic peptide POMC while downregulating the orexigenic peptide NPY in the ARC. Chemogenetic inhibition of GLP-1 neurons during EA application partially inhibited its anti-obesity and anorectic effects. Further investigations revealed that both EA and taVNS effectively reduced food intake and alleviated obesity. While both interventions activated vagal pathways and NTS GLP−1 , EA induced a significantly stronger activation of vagal afferent fibers compared to taVNS. Critically, GVND prior to EA application attenuated its anti-obesity effects. Conclusion The therapeutic benefits of EA in appetite suppression and obesity mitigation are mediated by selective regulation of the “vagal–GLP-1–ARC” neural circuit. Graphical s
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JOURNAL OF NANOSCIENCE AND NANOTECHNOLOGY
·
2021
·Vol. 21
·期 2
·1378-1384
·
IF 0
Zhang Yang,Zhuang Shaowei,Jiang Shengyang,Zhang Jiehan,Chen Yu
Complications of diabetes are the main cause of death and disability in diabetic patients. Cardiovascular diseases, especially diabetic cardiomyopathy, are one of the major complications and causes of death in type 2 diabetes. Peptide drugs have a better effect on improving cellular
oxidative damage, reducing tissue inflammation and inhibiting intracellular calcium overload. The application of nanotechnology to the preparation of peptide drugs and myocardial injury can effectively improve myocardial stun, arrhythmia and myocardial systolic dysfunction in patients with
type 2 diabetes. The use of nanotechnology to develop more stable Glucagon-like peptide 1 analogues or sustained-release preparations, improve patient compliance and improve the efficacy of diabetes, is of great significance for the prevention and treatment of diabetic cardiomyopathy. Therefore,
this study used nanotechnology to prepare PLGA-GLP-1 nanoparticles using polyglycolic acid glycolic acid as a drug carrier, which achieved long-acting drug and its morphology by transmission electron microscopy. At the same time, this study explored the anti-cardiomyocyte injury and anti-myocardial
damage of PLGA-GLP-1 nanocomposite peptide and its molecular mechanism by using animal models and cell models. Experimental studies have shown that PLGA-GLP-1 nanocomposite peptide has a protective effect on myocardial injury in diabetic rats. Its mechanism is related to the PLGA-GLP-1 nanocomposite
peptide enhancing the body’s antioxidant capacity, anti-cardiomyocyte apoptosis, and promoting mitochondrial DNA repair in cardiomyocytes.
研究领域:
药学
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心血管病学
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糖尿病学
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PubMed
BIOORGANIC CHEMISTRY
·
2026
·
IF 5.1
Sheng-Li Wu,Xiao-Feng He,Pianchou Gongpan,Xiao-Yan Huang,Chang-An Geng
DCA stimulated GLP-1 secretion in STC-1 and NCI-H716 cells. • DCA decreased fasting blood glucose levels by promoting GLP-1 secretion in db/db mice. • DCA ameliorated glucose intolerance and insulin resistance and lowered serum TC levels. • DCA promoted GLP-1 secretion through specific activation on TGR5/PKA/MEK/ERK pathway. Type 2 diabetes mellitus (T2DM) is a heterogeneous metabolic disorder characterized by insulin resistance and progressive β cell dysfunction. Deoxycalyxin A (DCA), a unique diarylheptanoid-chalcone hybrid isolated from Alpinia katsumadai , was identified as a novel stimulator of GLP 1 secretion in both STC-1 (EC 50 : 10.7 μM) and NCI-H716 (EC 50 : 13.4 μM) cells. Oral administration of DCA (40 and 80 mg/kg) in db/db mice significantly reduced fasting blood glucose, ameliorated glucose intolerance and insulin resistance by enhancing endogenous GLP-1 secretion, and lowered the total serum cholesterol levels. Mechanistic study demonstrated that DCA identify the TGR5 receptor, which induces a significant increase in intracellular cyclic AMP (cAMP) levels, which activates PKA with subsequent sequential phosphorylation of MEK1/2 and ERK activation, ultimately enhancing GLP-1 secretion. Our findings identify DCA as a novel TGR5 agonist to stimulate GLP-1 secretion via the TGR5/PKA/MEK/ERK pathway, which has the potential to be developed as a promising antidiabetic lead with a distinct mechanism of action. DCA, a unique diarylheptanoid-chalcone from Alpinia katsumadai , is a novel TGR5 agonist to stimulate GLP-1 secretion via PKA/MEK/ERK pathway, which has the potential to be developed as a promising antidiabetic candidate. Download: Download high-res image (123KB) Download: Download full-size image
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JOURNAL OF THE AMERICAN SOCIETY FOR MASS SPECTROMETRY
·
2026
·
IF 2.9
Jin Xu,Anqi Zhou,Mengjiao Xu,Qiaoshuang Chen,Chenjing Xu,Jinhao Li,Na Li,Zhixin Li,Guodong Wu,Weitao Zhang,Shuhai Xu,Qiaoling Ni,Tao Liu,Chunguang Zheng,Wei Yu,Xi Chen,Lankun Song,Min Xia,Qingcheng Guo,Lusha Ji,Weizhu Qian,Sheng Hou,Jun Li,Ziqiao Sun,Xuekun Wang,Fubo Han,Hao Wang,Jing Li,Dapeng Zhang,Huaizu Guo
Fc-containing GLP-1 therapeutics exhibit complex post-translational modification (PTM) heterogeneity, necessitating advanced analytical methods for quality control (QC) and process analytical technology (PAT). We developed a reverse-phase liquid chromatography (RP-LC) method for the PTM-specific profiling of these biologics. Using dulaglutide (IgG4-Fc) as a model, critical parameters─including mobile-phase additives, acid concentration, and shallow gradients─were optimized to resolve PTM variants (e.g., hydroxylation, N-terminal truncation, disulfide reduction, glycosylation) within 40 min. Mass spectrometry (MS) compatibility was enabled by adopting difluoroacetic acid (DFA) as an alternative ion-pairing reagent to support intact-mass characterization of variants. This enabled the identification of additional PTMs not readily resolved under the initial RP-LC conditions, including site-specific HyK-Gal-Glc O-glycosylation and process-dependent truncations. The method also allowed for the direct quantification of critical impurities and the detection of process-induced variants across biosimilar clones. The method was further demonstrated on the IgG2-subtype GLP-1-Fc-fusion (supaglutide), showing applicability across the two Fc subtypes examined without additional optimization. This robust, MS-compatible RP-LC platform provides a rapid, accurate, and comprehensive (RAC) means of conducting PTM-specific QC for Fc-GLP-1 therapeutics, supporting PAT implementation and accelerating biosimilar and next-generation drug development.
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INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
·
2025
·Vol. 26
·期 23
·11548
·
IF 4.9
Haowen Fang,Xiaodong Sun,Yanting Ding,Siyuan Gu,Bing Niu,Qin Chen
This study aimed to develop a potent, safe, and cost-effective small-molecule hypoglycemic agent derived from Loureirin B, with preliminary evaluation of its efficacy and mechanistic underpinnings. Thirty structural analogs of Loureirin B were synthesized. Molecular docking identified LB-A as the lead compound targeting GLP-1R. Its hypoglycemic activity was initially assessed in a murine model. Molecular dynamics simulations, surface plasmon resonance (SPR), and circular dichroism (CD) were employed to characterize LB-A–GLP-1R interactions. The involvement of the GLP-1R/cAMP/PKA pathway and downstream mediators was examined using cellular assays, gene knockout, and Western blotting, with emphasis on FOXO1. LB-A exhibited the strongest binding affinity for GLP-1R among the analogs and significantly reduced blood glucose levels in mice. It formed hydrogen bonds and hydrophobic interactions with key residues (e.g., LYS197) and induced conformational changes in GLP-1R. LB-A activation of GLP-1R upregulated cAMP, PKA, and pCREB, suppressed PTEN/FOXO1 signaling, and subsequently stimulated insulin secretion. LB-A represents a novel small molecule agonist that ameliorates hyperglycemia in diabetic mice through specific activation of the GLP-1R/cAMP/PKA/pCREB/PTEN/FOXO1 pathway.
研究领域:
植物化学
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药理学
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内分泌学
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药物发现
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代谢调控
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PubMed
高影响因子
BIOORGANIC & MEDICINAL CHEMISTRY
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2016
·
IF 2.923
Xiaohui Bai,Youhong Niu,Jingjing Zhu,An-Qi Yang,Yan-Fen Wu,Xin-Shan Ye
Glucagon-like peptide-1 (GLP-1) is an endogenous insulinotropic hormone with wonderful glucose-lowering activity. However, its clinical use in type II diabetes is limited due to its rapid degradation at the N-terminus by dipeptidyl peptidase IV (DPP-IV). Among the N-terminal modifications of GLP-1, backbone-based modification was rarely reported. Herein, we employed two backbone-based strategies to modify the N-terminus of tGLP-1. Firstly, the amide N -methylated analogues 2 – 6 were designed and synthesized to make a full screening of the N-terminal amide bonds, and the loss of GLP-1 receptor (GLP-1R) activation indicated the importance of amide H-bonds. Secondly, with retaining the N-terminal amide H-bonds, the β-peptide replacement strategy was used and analogues 7 – 13 were synthesized. By two rounds of screening, analogue 10 was identified. Analogue 10 greatly improved the DPP-IV resistance with maintaining good GLP-1R activation in vitro, and showed approximately a 4-fold prolonged blood glucose-lowering activity in vivo in comparison with tGLP-1. This modification strategy will benefit the development of GLP-1-based anti-diabetic drugs.
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高影响因子
Stem Cell Reports
·
2026
·
IF 5.6
Zhe Yang,Xin Li,Niujian Wu,Ling Wang,Zhanjin Lu,Lingling Wang,Shisong Han,Hongyun Lu
Bone marrow mesenchymal stem cell (BMSC) lineage commitment contributes to metabolic bone diseases, but whether glucagon-like peptide-1 (GLP-1) regulates osteo-adipogenic fate remains unclear. Here, RNA sequencing was performed to identify potential pathways regulated by GLP-1 in BMSCs, followed by gain- and loss-of-function experiments. Furthermore, BMSC-specific Hif-2α knockout mice with glucocorticoid-induced osteoporosis were treated with semaglutide to evaluate skeletal effects. GLP-1 suppressed adipogenesis and promoted osteogenesis of BMSCs in a dose-dependent manner. Transcriptomic analysis identified PI3K-AKT and hypoxia signaling as major GLP-1-regulated pathways. Mechanistically, GLP-1 inhibited AKT activation during adipogenesis and reshaped AKT signaling dynamics during osteogenesis. Loss of HIF-2α largely abolished GLP-1-mediated regulation of AKT activity. In vivo , semaglutide improved trabecular bone mass in osteoporotic mice, whereas this bone-protective effect was markedly diminished in Hif-2α -knockout mice. Our findings suggest that GLP-1 modulates BMSC lineage commitment by inhibiting adipogenesis and enhancing osteogenesis through HIF-2α-associated regulation of AKT signaling.
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