INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES
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2025
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IF 8.5
Tong Ye,Qile Chen,Shujuan Yang,Haifang Liu,Yan Zhou,Yuhong Feng,Jiacheng Li,Yujuan Wang,Gaobo Yu,Jun Dai
Achieving high bioavailability of dendrobine (DDB) necessitates the development of simplified available and efficient delivery systems. Pickering emulsions (PEs) derived from biomass represent a promising option. However, the physicochemical properties of PEs interfacial films were insufficient to prevent DDB leakage, thereby reducing bioavailability. Herein, a supramolecular host-guest interfacial recognition strategy was proposed in-situ between amphipathic sodium alginate-functionalized cyclodextrin (SAE-CD) and hydrophobic DDB at oil-water interface, further forming the SAE-based supra-amphiphiles to efficient stabilize the high internal phase Pickering emulsions (HIPPEs) with gel-like characteristics. A multiscale methodology was empolyed to investigate the interfacial assembly behavior and emulsification properties of supra-amphiphilic SAE-CD/DDB interfacial system, focusing on molecular interactions, interfacial adsorption, and overall stability. Notably, the SAE-CD/DDB-based supramolecular assembly/disassembly behaviors could be self-adjusted for regulating the aggregation particle size and thickness of interfacial self-assembled films. The SAE-CD/DDB co-stabilized HIPPEs exhibited favorable drug release capabilities, enabling sustained effects of DDB. Overall, the SAE-CD/DDB co-stabilized HIPPEs demonstrated excellent properties in terms of stability, drug loading capacity, and sustained release performance, highlighting their potential for in oral delivery and sustained-release systems.
研究领域:
食品科学
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药剂学
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材料科学
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DOI
PubMed
高影响因子
ACTA PHARMACOLOGICA SINICA
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2021
·Vol. 43
·期 4
·1059-1071
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IF 6.15
Pan Hong,Shi Fu-guo,Fang Chao,Shi Jing-shan
Dendrobine is the main sesquiterpene alkaloid of Dendrobium nobile Lindl, which exhibits potent neuroprotective activity. However, its metabolism and disposition are little known. In this study, we investigated the metabolic characteristics of dendrobine in vitro and in rats. The metabolic stability and temporal profile of metabolites formation of dendrobine were assayed in human/rat liver microsomal and S9 fractions. Dendrobine metabolites were separated and identified mainly by UPLC-Q/Orbitrap MS. After oral administration of dendrobine (50 mg/kg) to rats, the accumulative excretion rate of dendrobine in feces, urine, and bile was 0.27%, 0.52%, and 0.031%, respectively, and low systematic exposure of dendrobine (AUC 0–∞ = 629.2 ± 56.4 ng·h/mL) was observed. We demonstrated that the elimination of dendrobine was very rapid in liver microsomal incubation (the in vitro elimination t 1/2 in rat and human liver microsomes was 1.35 and 5.61 min, respectively). Dendrobine underwent rapid and extensive metabolism; cytochrome P450, especially CYP3A4, CYP2B6, and CYP2C19, were mainly responsible for its metabolism. Aldehyde dehydrogenase, alcohol dehydrogenase and aldehyde oxidase were involved in the formation of carboxylic acid metabolites. By the aid of in-source fragmentation screening, hydrogen/deuterium exchange experiment, post-acquisition processing software, and available reference standards, 50 metabolites were identified and characterized in liver microsomal incubation and in rats. The major metabolic pathways of dendrobine were N -demethylation, N -oxidation, and dehydrogenation, followed by hydroxylation and glucuronidation. Collectively, the metabolic fate of dendrobine elucidated in this study not only yields benefits for its subsequent metabolism study but also facilitates to better understanding the mode of action of dendrobine and evaluating the pharmacologic efficiency of the high exposure metabolites.
研究领域:
药理学
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代谢组学
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神经科学
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药物代谢
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DOI
PubMed
高影响因子
PHYTOMEDICINE
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2026
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IF 11.3
Xiaojue Xiang,Xu Lin,Qifang Wu,Xiaoming Zhang,Xueliang Fu,Linya Wu,Haibin Tong,Zhenyu Dai
Dendrobium officinale extract DOE ameliorates metabolic disorders and diabetic cardiomyopathy. • DOE reduced myocardial injury, fibrosis, and oxidative stress via activating NRF2 pathway. • Dendrobine was the principal cardioprotective alkaloid in DOE against diabetic cardiomyopathy . • Dendrobine directly targets KEAP1 Kelch domain to disrupt the KEAP1-NRF2 interaction . Background Dendrobium officinale Kimura et Migo is a prestigious traditional Chinese medicine historically used for treating "Xiao-Ke" (diabetes and its complications). However, the specific material basis and direct molecular targets responsible for its efficacy against diabetic cardiomyopathy (DCM) remain largely obscure. This study aimed to systematically investigate whether dendrobine, the characteristic active alkaloid of DO, serves as the principal cardioprotective component by directly targeting the KEAP1-NRF2 signaling axis. Methods The therapeutic effects of D. officinale extract (DOE) and dendrobine were evaluated in vivo using db/db mice and in vitro using high-glucose (HG)-challenged H9c2 cardiomyocytes. Cardiac pathological remodeling, lipid peroxidation, and systemic metabolic profiles were comprehensively assessed. The direct interaction between dendrobine and KEAP1 was definitively characterized using Co-Immunoprecipitation (Co-IP), Cellular Thermal Shift Assay (CETSA), Drug Affinity Responsive Target Stability (DARTS), MicroScale Thermophoresis (MST), and 100-ns Molecular Dynamics (MD) simulations. Reverse pharmacological validation was performed using NRF2-specific siRNA and the inhibitor ML385. Results In vivo , DOE significantly ameliorated systemic insulin resistance, hyperlipidemia, and myocardial pathological remodeling in db/db mice while robustly suppressing myocardial oxidative stress (MDA, 4-HNE) by upregulating NRF2-driven antioxidant enzymes (HO-1, NQO1, GPX4). In vitro , dendrobine dose-dependently replicated these cardioprotective and antioxidative efficacies. Mechanistically, dendrobine promoted NRF2 nuclear translocation and initiated the downstream antioxidant cascade. Crucially, MST and CETSA revealed that dendrobine binds directly to KEAP1 with high affinity ( K d = 1.18 μM), functioning as a competitive protein-protein interaction (PPI) inhibitor to disrupt the KEAP1-NRF2 complex. MD simulations and mutagenesis validation pinpointed the Kelch domain of KEAP1 (specifically residue Arg415) as the binding pocket. Finally, silencing or inhibiting NRF2 abolished the anti-hypertrophic and cytoprotective effects of dendrobine, and the in vivo administration of dendrobine successfully recapitulated the metabolic regulation and KEAP1/NRF2-mediated cardioprotection of DOE in db/db mice. Conclusion Dendrobine, the principal alkaloid of D. officinale , effectively ameliorates diabetic cardiomyopathy by functioning as a novel, direct competitive inhibitor of the KEAP1-NRF2 interaction. This targeted disruption liberates NRF2 to restore myocardial redox homeostasis, highlighting dendrobine as a promising lead compound for DCM therapy. Download: Download high-res image (395KB) Download: Download full-size image
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高影响因子
PHYTOMEDICINE
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2022
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IF 6.656
Qiang-Ming Li,Xiang Li,Shuang-Qiao Su,Yu-Tong Wang,Tong Xu,Xue-Qiang Zha,Li-Hua Pan,Zhen-Zi Shang,Feng-Yun Zhang,Jian-Ping Luo
Background Parkinson's disease (PD) is an age-related neurodegenerative disorder without effective treatments. Mesencephalic astrocyte-derived neurotrophic factor (MANF) has been suggested to be capable of protecting against PD by inhibiting endoplasmic reticulum (ER) stress-mediated neuronal apoptosis. Purpose This study was aimed to evaluate the antiparkinsonian effect of dendrobine and reveal its underlying mechanisms from the perspective of MANF-mediated ER stress suppression. Methods Behavioral assessments of PD mice as well as LDH/CCK-8 assay in SH-SY5Y cells and primary midbrain neurons were carried out to detect the antiparkinsonian effect of dendrobine. Immunofluorescence, western blot, flow cytometry and shRNA-mediated MANF knockdown were used to determine the apoptosis of dopaminergic neurons and the expressions of ER stress-related proteins for investigating the underlying mechanism of dendrobine. Results Dendrobine significantly ameliorated the motor performance of PD mice and attenuated the injuries of dopaminergic neurons. Dendrobine could also relieve neuronal apoptosis, up-regulate MANF expression and inhibit ER stress, which were largely abolished by shRNA-mediated MANF knockdown in PD model. Conclusion Dendrobine might protect against PD by inhibiting dopaminergic neuron apoptosis, which was achieved by facilitating MANF-mediated ER stress suppression. Our study suggested that dendrobine could act as a MANF up-regulator to protect against PD, and provided a potential candidate for exploring etiological agents of PD.
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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DOI
PubMed
高影响因子
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