BIOMEDICINE & PHARMACOTHERAPY
·
2018
·
IF 3.457
Yuhui Wang,Jinyang Shen,Xiaolin Yang,Ye Jin,Zhonglin Yang,Rufeng Wang,Fuming Zhang,Robert J. Linhardt
Background Glucocorticoid hormones are implicated in the pathogenesis of Alzheimer’s disease (AD) and other diseases including diabetes, hyperlipidemia , and osteoporosis . Akebia saponin D (ASD) possesses numerous pharmacological activities , including as an anti-AD, anti-hyperlipidemia, anti-diabetes, and anti-osteoporosis agent. The anti-AD effect of ASD is possibly through its regulation of glucocorticoid levels. Purpose The present study was undertaken to investigate the neuroprotective effects of ASD on Aβ 25-35 -induced cognitive deficits and to elucidate its underlying mechanism of action. Methods The AD rat model was established by an intracerebroventricular injection of Aβ 25-35 into the lateral ventricles. Spatial learning and anxiety state were assessed by Morris water maze task and elevated plus-maze assay, respectively. The degree of hypertrophy of adrenal gland was analyzed using the viscera coefficient. Corticosterone and ACTH concentrations in the plasm were measured using biochemical assay kits. The activity of 11β-hydroxysteroid dehydrogenase type-1 (11β-HSD1) in liver and groin fat pad was assessed by measuring cortisol production. Results Compared with the control group, AD rats displayed significant spatial learning and reference memory impairments, serious anxiety disorders, obvious hypertrophy of adrenal gland, elevated corticosterone and ACTH levels in the plasma, and increased 11β-HSD1 activity in liver and groin fat pad. ASD could significantly ameliorate the memory deficits and anxiety symptoms, markedly reduce the viscera coefficient of adrenal gland, observably decrease corticosterone and ACTH concentrations, and showed no effect on the activity of 11β-HSD1. Conclusions These results indicate that ASD might exert a significant neuroprotective effect on cognitive impairment, driven in part by reducing systemic corticosterone level by down-regulation of the hypothalamic-pituitary-adrenal (HPA) axis.
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PubMed
高影响因子
International Journal of Nanomedicine
·
2016
·
IF 4.32
Jinyang Shen,Jianping Bi,Hongli Tian,Ye Jin,Yuan Wang,Xiaolin Yang,Zhonglin Yang,Junping Kou,Fei Li
Background Akebia saponin D (ASD) exerts various pharmacological activities but with poor oral bioavailability. In this study, a self-nanoemulsifying drug delivery system (SNEDDS) based on the drug–phospholipid complex technique was developed to improve the oral absorption of ASD.Methods ASD–phospholipid complex (APC) was prepared using a solvent-evaporation method and characterized by infrared spectroscopy, differential scanning calorimetry, morphology observation, and solubility test. Oil and cosurfactant were selected according to their ability to dissolve APC, while surfactant was chosen based on its emulsification efficiency in SNEDDS. Pseudoternary phase diagrams were constructed to determine the optimized APC-SNEDDS formulation, which was characterized by droplet size determination, zeta potential determination, and morphology observation. Robustness to dilution and thermodynamic stability of optimized formulation were also evaluated. Subsequently, pharmacokinetic parameters and oral bioavailability of ASD, APC, and APC-SNEDDS were investigated in rats.Results The liposolubility significantly increased 11.4-fold after formation of APC, which was verified by the solubility test in n-octanol. Peceol (Glyceryl monooleate [type 40]), Cremophor® EL (Polyoxyl 35 castor oil), and Transcutol HP (Diethylene glycol monoethyl ether) were selected as oil, surfactant, and cosurfactant, respectively. The optimal formulation was composed of Glyceryl monooleate (type 40), Polyoxyl 35 castor oil, Diethylene glycol monoethyl ether, and APC (1:4.5:4.5:1.74, w/w/w/w), which showed a particle size of 148.0±2.7 nm and a zeta potential of −13.7±0.92 mV after dilution with distilled water at a ratio of 1:100 (w/w) and good colloidal stability. Pharmacokinetic studies showed that APC-SNEDDS exhibited a significantly greater Cmax1 (733.4±203.8 ng/mL) than ASD (437.2±174.2 ng/mL), and a greater Cmax2 (985.8±366.6 ng/mL) than ASD (180.5±75.1 ng/mL) and APC (549.7±113.5 ng/mL). Compared with ASD, Tmax1 and Tmax2 were both remarkably shortened by APC-SNEDDS. The oral bioavailability in rats was enhanced significantly to 183.8% and 431.8% by APC and APC-SNEDDS, respectively.Conclusion These results indicated that APC-SNEDDS was a promising drug delivery system to enhance the oral bioavailability of ASD.
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PubMed
高影响因子
Food & Function
·
2020
·Vol. 11
·期 12
·10852-10863
·
IF 4.171
Mingbao Gu,Jie Jin,Chenghao Ren,Ximiao Chen,Weiyang Gao,Xiangyang Wang,Yaosen Wu,Naifeng Tian,Zongyou Pan,Aimin Wu,Yifei Zhou,Xiaolei Zhang
As an ordinary joint vestigial disease, osteoarthritis (OA) contributes to a considerable proportion of disability cases worldwide. Inflammation, as the main pathological factor, mediates the occurrence and development of OA. Akebia Saponin D (ASD), also known as Asperosaponin VI, is one of the active components extracted from Dipsaci Radix and is rich in Dipsacus loose tea. It has shown sound therapeutic effects on various diseases; nevertheless, its role in OA therapy is not completely understood. This study demonstrated the anti-inflammatory activity of ASD in OA through a series of in vivo and in vitro experiments. In vitro experiments revealed that ASD might prohibit the production of inflammatory mediators in IL-1β treated chondrocytes such as COX-2, iNOS, NO, PGE2, IL-6, and TNF-α. Meanwhile, it may also inhibit the production of ADAMTS-5 and MMP13 and promote the production of Aggrecan and Collagen II. The mechanism study demonstrated that ASD exerted an anti-inflammatory effect by activating the NRF2 target, upregulating the expression of HO-1, and preventing P65 from binding to DNA. In vivo experiments demonstrated that ASD might improve the progression of OA in a DMM mouse model. These research results provide evidence for the potential application of ASD in OA therapy.
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高影响因子
RSC Advances
·
2016
·Vol. 6
·期 76
·72439-72446
·
IF 3.289
Jinyang Shen,Ye Jin,Hongli Tian,Yuan Wang,Xiaolin Yang,Zhonglin Yang,Changrun Guo,Fei Li
Akebia saponin D (ASD), a triterpenoid saponin with numerous pharmacological activities, is isolated from the rhizome of Dipsacus asper Wall. However, the poor oral bioavailability of ASD restricts its development and clinical use. The purpose of this research is to develop a solid dispersion (ASD-SD) to improve the oral bioavailability of ASD. Poloxamer 407 was employed to prevent ASD from aggregation and Cremophor® RH 40 was used to inhibit multidrug resistance associated protein (MRP) mediated efflux in several new formulations. The particle size was remarkably reduced from 380 nm (ASD) to 230 nm (ASD-SD1 [composition: ASD : Poloxamer 407 : Cremophor® RH 40; ratio: 5 : 9 : 1, w/w/w]). The cumulative release percentage of molecular ASD from dialysis bags was improved from 63.78% (ASD) to 97.12% (ASD-SD1). Single-pass intestinal perfusion studies showed that the absorption of ASD in ASD-SD2 (composition: ASD : Poloxamer 407; ratio: 5 : 9, w/w) was increased approximately 1.8-fold compared to ASD which was mainly due to the particle size reduction, and further promoted by ASD-SD1 about 2.1-fold compared to ASD-SD2 which might be through the MRP inhibition of Cremophor® RH 40. Furthermore, the oral bioavailability in rats was enhanced significantly to 156.9% and 233.1% by ASD-SD2 and ASD-SD1, respectively. Therefore, ASD-SD1 could be a promising drug delivery system to improve the oral absorption of ASD which might be by destroying self-micelles and inhibiting MRP-mediated efflux.
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高影响因子
Frontiers in Pharmacology
·
2021
·
IF 5.811
Li Pengfei,Peng Jun,Li Yuexin,Gong Lili,Lv Yali,Liu He,Zhang Tianhong,Yang Song,Liu Hongchuan,Li Jinglai,Liu Lihong
Background: Akebia saponin D (ASD) has a variety of biological activities and great medicinal potential, but its oral bioavailability is so low as to limit its development. Its pharmacokinetic profiles and excretion and metabolism in vivo have not been fully elucidated. This study was an attempt in this area.Methods: A simple LC-MS/MS method to simultaneously quantify ASD and its metabolites M1∼M5 in rat plasma, feces, urine and bile was established with a negative ESI model using dexketoprofen as the internal standard. Meanwhile, the UPLC-HR/MS system was used to screen all possible metabolites in the urine, feces and bile of rats, as compared with blank samples collected before administration. Absolute quantitative analysis was for M0, M3, M4, and M5, while semi-quantitative analysis was for M1, M2, and Orbitrap data.Results: The AUC0-t values after intravenous administration of 10 mg/kg and intragastrical administration of 100 mg/kg ASD were 19.05 ± 8.64 and 0.047 ± 0.030 h*μg/ml respectively. The oral bioavailability was determined to be extremely low (0.025%) in rats. The exposure of M4 and M5 in the oral group was higher than that of M0 in the terminal phase of the plasma concentration time profile, and ASD was stable in the liver microsome incubation system of rats, but metabolism was relatively rapid during anaerobic incubation of intestinal contents of rats, suggesting that the low bioavailability of ASD might have been attributed to the poor gastrointestinal permeability and extensive pre-absorption degradation rather than to the potent first pass metabolism. This assertion was further verified by a series of intervention studies, where improvement of lipid solubility and intestinal permeability as well as inhibition of intestinal flora increased the relative bioavailability to different extents without being changed by P-gp inhibition. After intravenous administration, the cumulative excretion rates of ASD in the urine and bile were 14.79 ± 1.87%, and 21.76 ± 17.61% respectively, but only 0.011% in feces, suggesting that the urine and bile were the main excretion pathways and that there was a large amount of biotransformation in the gastrointestinal tract. Fifteen possible metabolites were observed in the urine, feces and bile. The main metabolites were ASD deglycosylation, demethylation, dehydroxylation, decarbonylation, decarboxylation, hydroxylation, hydroxymethylation, hydroxyethylation and hydrolysis.Conclusion: The pharmacokinetics, bioavailability, metabolism and excretion of ASD in rats were systematically evaluated for the first time in this study. It has been confirmed that the ultra-low oral bioavailability is due to poor gastrointestinal permeability, extensive pre-absorption degradation and biotransformation. ASD after iv administration is not only excreted by the urine and bile, but possibly undergoes complex metabolic elimination.
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高影响因子
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