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Molecular mechanisms underlying the cholesterol-lowering effect of Ginkgo biloba extract in hepatocytes: a comparative study with lovastatin.

ABSTRACT: AIM: To explore the molecular mechanisms underlying the cholesterol-lowering effect of a Ginkgo biloba extract (GBE). METHODS: Enzyme activity, cholesterol flux and changes in gene expression levels were assessed in cultured hepatocytes treated with GBE or lovastatin. RESULTS: GBE decreased the total cholesterol content in cultured hepatocytes and inhibited the activity of HMG-CoA reductase, as determined by an in vitro enzyme activity assay. In addition, GBE decreased cholesterol influx, whereas lovastatin increased cholesterol influx. GBE treatment induced significant increases in the expression of cholesterogenic genes and genes involved in cholesterol metabolism, such as SREBF2, as determined by cDNA microarray and real-time RT-PCR. Furthermore, INSIG2, LDLR, LRP1, and LRP10 were differentially regulated by GBE and lovastatin. The data imply that the two compounds modulate cholesterol metabolism through distinct mechanisms. CONCLUSION: By using a gene expression profiling approach, we were able to broaden the understanding of the molecular mechanisms by which GBE lowers cellular cholesterol levels. Specifically, we demonstrated that GBE exhibited dual effects on the cellular cholesterol pool by modulating both HMG-CoA reductase activity and inhibiting cholesterol influx.

SUBMITTER: Xie ZQ

PROVIDER: S-EPMC4007179 | biostudies-literature | 2009 Sep

REPOSITORIES: biostudies-literature

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Molecular mechanisms underlying the cholesterol-lowering effect of Ginkgo biloba extract in hepatocytes: a comparative study with lovastatin.

Xie Zuo-quan ZQ Liang Gai G Zhang Lu L Wang Qi Q Qu Yi Y Gao Yang Y Lin Li-bo LB Ye Sai S Zhang Ji J Wang Hui H Zhao Guo-ping GP Zhang Qing-hua QH

Acta pharmacologica Sinica 20090824 9

<h4>Aim</h4>To explore the molecular mechanisms underlying the cholesterol-lowering effect of a Ginkgo biloba extract (GBE).<h4>Methods</h4>Enzyme activity, cholesterol flux and changes in gene expression levels were assessed in cultured hepatocytes treated with GBE or lovastatin.<h4>Results</h4>GBE decreased the total cholesterol content in cultured hepatocytes and inhibited the activity of HMG-CoA reductase, as determined by an in vitro enzyme activity assay. In addition, GBE decreased cholest ...[more]

PMID: 19701231

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Project description:Aging is a main risk factor for a number of debilitating diseases and contributes to an increase in mortality. Previous studies have shown that Ginkgo biloba extract (EGb) can prevent and treat aging-related diseases, but its pharmacological effects need to be further clarified. This study aimed to propose a network pharmacology-based method to identify the therapeutic pathways of EGb for aging. The active components of EGb and targets of sample chemicals were obtained from the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform (TCMSP) database. Information on aging-related genes was obtained from the Human Ageing Genomic Resources database and JenAge Ageing Factor Database. Subsequently, a network containing the interactions between the putative targets of EGb and known therapeutic targets of aging was established, which was used to investigate the pharmacological mechanisms of EGb for aging. A total of 24 active components, 154 targets of active components of EGb, and 308 targets of aging were obtained. Network construction and pathway enrichment were conducted after data integration. The study found that flavonoids (quercetin, luteolin, and kaempferol) and beta-sitosterol may be the main active components of EGb. The top eight candidate targets, namely, PTGS2, PPARG, DPP4, GSK3B, CCNA2, AR, MAPK14, and ESR1, were selected as the main therapeutic targets of EGb. Pathway enrichment results in various pathways were associated with inhibition of oxidative stress, inhibition of inflammation, amelioration of insulin resistance, and regulation of cellular biological processes. Molecular docking results showed that PPARG had better binding capacity with beta-sitosterol, and PTGS2 had better binding capacity with kaempferol and quercetin. The main components of EGb may act on multiple targets, such as PTGS2, PPARG, DPP4, and GSK3B, to regulate multiple pathways, and play an antiaging role by inhibiting oxidative stress, inhibiting inflammation, and ameliorating insulin resistance.

Project description:To investigate the ameliorated effects of an extract of Ginkgo biloba extract (GBE) on experimental cardiac remodeling in rats induced by acute cardiac infarction, and further explore the mechanism concentrated on myocardial type I collagen, transforming growth factor beta 1 (TGF-β1), matrix metalloproteinase 2 (MMP-2) and matrix metalloproteinase 9 (MMP-9), and provide the experimental data for clinical application of GBE.Rats were divided into five groups (n = 20) as following: sham operation group (group A), acute myocardial infarction model group (group B), acute myocardial infarction model + aspirin (10 mg/kg) treatment group (group C), acute myocardial infarction model + captopril (20 mg/kg) treatment group (group D) and acute myocardial infarction model + Ginkgo biloba extract (100 mg/kg) treatment group (group E). The rat acute myocardial infarction model was reproduced by ligaturing the left anterior descending artery excluding the sham operation group which did not ligation only completed the operational process. Each group was further subdivided into treatment regimens lasting 4 weeks and 8 weeks. Immunohistochemistry and real-time polymerase chain reaction (PCR) methods were used to detect the protein expression and mRNA transcriptional levels of rat myocardial TGF-β1, type I collagen, MMP-2 and MMP-9.Compared with group B, regardless of the length of treatment (4 or 8 weeks), the TGF-β1, MMP-2 and MMP-9 mRNA transcriptional levels, and the protein expression levels of type I collagen, MMP-2 and MMP-9 in groups D, C and E were significantly decreased (P < 0.01). Furthermore, the mRNA expression levels of TGF-β1 in groups D, C and E were significantly lower after 8 weeks compared to after 4 weeks (P < 0.01), as were the expression levels of type I collagen in groups D, C and E (P < 0.05). There was no statistically significant difference in the protein expression levels of MMP-2 and MMP-9 between groups E and C.GBE could inhibit experimental rat myocardial remodeling after acute myocardial infarction via reduced transcription of TGF-β1, MMP-2 and MMP-9 genes and by the decreased expression of type I collagen, MMP-2 and MMP-9 proteins in myocardial cells.

Project description:BackgroundEnergy deficiency and mitochondrial failure have been recognized as a prominent, early event in Alzheimer's disease (AD). Recently, we demonstrated that chronic exposure to amyloid-beta (Abeta) in human neuroblastoma cells over-expressing human wild-type amyloid precursor protein (APP) resulted in (i) activity changes of complexes III and IV of the oxidative phosphorylation system (OXPHOS) and in (ii) a drop of ATP levels which may finally instigate loss of synapses and neuronal cell death in AD. Therefore, the aim of the present study was to investigate whether standardized Ginkgo biloba extract LI 1370 (GBE) is able to rescue Abeta-induced defects in energy metabolism.Methodology/principal findingsWe used a high-resolution respiratory protocol to evaluate OXPHOS respiratory capacity under physiological condition in control (stably transfected with the empty vector) and APP cells after treatment with GBE. In addition, oxygen consumption of isolated mitochondria, activities of mitochondrial respiratory enzymes, ATP and reactive oxygen species (ROS) levels as well as mitochondrial membrane mass and mitochondrial DNA content were determined. We observed a general antioxidant effect of GBE leading to an increase of the coupling state of mitochondria as well as energy homeostasis and a reduction of ROS levels in control cells and in APP cells. GBE effect on OXPHOS was even preserved in mitochondria after isolation from treated cells. Moreover, these functional data were paralleled by an up-regulation of mitochondrial DNA. Improvement of the OXPHOS efficiency was stronger in APP cells than in control cells. In APP cells, the GBE-induced amelioration of oxygen consumption most likely arose from the modulation and respective normalization of the Abeta-induced disturbance in the activity of mitochondrial complexes III and IV restoring impaired ATP levels possibly through decreasing Abeta and oxidative stress level.Conclusions/significanceAlthough the underlying molecular mechanisms of the mode of action of GBE remain to be determined, our study clearly highlights the beneficial effect of GBE on the cellular OXPHOS performance and restoration of Abeta-induced mitochondrial dysfunction.

Project description:Background: Balance training with vibrotactile neurofeedback (VNF) can improve balance and subjective impairment in age-related vertigo and dizziness. Ginkgo biloba dry extract EGb 761 has been shown to improve subjective impairment in chronic vertigo and the efficacy of conventional balance training. The combination was expected to work synergistically in this difficult-to-treat population. Objectives: To demonstrate the efficacy of VNF added to EGb 761 for age-related vertigo and dizziness. Design: Multicenter, prospective, controlled, randomized, single-blind, two-arm trial (German Clinical Trials Register https://www.drks.de No. DRKS00007633). Setting: Specialist offices and tertiary care outpatient department. Participants: One hundred and twenty subjects aged 60+ years with chronic dizziness for over 3 months, a Dizziness Handicap Inventory (DHI) Sum Score >25 and fall risk in balance-related situations as measured by the geriatric Standard Balance Deficit Test Composite Score (gSBDT-CS)>40. Patients with other distinct vestibular pathology (e.g., Meniére's disease, stroke, BPPV) were excluded. Intervention: EGb 761 (80 mg twice daily for 12 weeks) plus 10 days of individually adapted balance training with VNF, randomized 1:1 to sensitive (active) or non-sensitive (sham) neurofeedback. Measurements: The change in gSBDT-CS after 6 weeks (primary), other gSBDT outcomes, DHI, cognition, hearing, and safety. Results: One hundred nine of 120 enrolled subjects received both treatments at least once. Over 12 weeks, the gSBDT-CS improved by 6.7 (active) vs. 4.5 (sham). There was a difference in favor of the active treatment of -2.4 (95% CI -5.4; 0.6) after 6 weeks. Under active treatment, more pronounced effects occurred in all secondary analyses and in nearly all secondary endpoints. The DHI sum score decreased from 44.1 to 31.1 in the total sample with a treatment group difference after 6 weeks of -3.1, 95% CI (-7.1; 0.9). No safety issues were reported. Conclusion: Over 12 weeks, the combination of balance training with VNF and Ginkgo biloba dry extract EGb 761 reached a clinically relevant improvement of age-related vertigo and dizziness with a good pharmacological safety profile.

Dataset Information

Molecular mechanisms underlying the cholesterol-lowering effect of Ginkgo biloba extract in hepatocytes: a comparative study with lovastatin.

Publications

Molecular mechanisms underlying the cholesterol-lowering effect of Ginkgo biloba extract in hepatocytes: a comparative study with lovastatin.

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