scholarly journals Discovery of Potential Inhibitors of Squalene Synthase from Traditional Chinese Medicine Based on Virtual Screening and In Vitro Evaluation of Lipid-Lowering Effect

Molecules ◽  
2018 ◽  
Vol 23 (5) ◽  
pp. 1040 ◽  
Author(s):  
Yankun Chen ◽  
Xi Chen ◽  
Ganggang Luo ◽  
Xu Zhang ◽  
Fang Lu ◽  
...  
Keyword(s):  
Chinese Medicine ◽  
Traditional Chinese Medicine ◽  
Virtual Screening ◽  
Squalene Synthase ◽  
Lipid Lowering ◽  
In Vitro Evaluation ◽  
Lowering Effect ◽  
Potential Inhibitors ◽  
Lipid Lowering Effect

scholarly journals SUN-550 CARF Through Its Lipid Lowering Effect May Play a Pivotal Role in the Development of Non-Alcoholic Fatty Liver Diseases

2020 ◽  
Vol 4 (Supplement_1) ◽  
Author(s):  
Kamrul M Hasan ◽  
Meher Parveen ◽  
Alondra Pena ◽  
Amiya P Sinha-Hikim ◽  
Theodore C Friedman
Keyword(s):  
Lipid Metabolism ◽  
Fatty Liver ◽  
Hepg2 Cells ◽  
In Vitro Model ◽  
Lipid Lowering ◽  
Alcoholic Fatty Liver ◽  
Lowering Effect ◽  
Vitro Model ◽  
Lipid Lowering Effect

Abstract CARF (Collaborator of ARF), a member of ARF-MDM2-p53 pathway and an emerging multifunctional protein, regulates cellular fate in response to various stresses including oxidative DNA damage and replicative stresses. However, its role in metabolic syndrome (MS) and associated diseases has not been studied. This study, using our well established in vivo and in vitro model systems, examines the role of CARF in the development of non-alcoholic fatty liver disease (NAFLD). Indeed, we have found that, compared to control, CARF expression along with Sirt1, pAMPK and pACC (common biological markers of NAFLD) was significantly decreased in the nicotine and high-fat-diet (HFD) in combination or HFD alone induced fatty livers. Additionally, CARF expression was down regulated in palmitate (PA)-treated HepG2 cells, an in vitro model of steatosis, suggesting that CARF expression is negatively regulated in MS, such as NAFLD. Our study further revealed that shRNA mediated knockdown or lentiviral mediated over expression of CARF induced or reduced endogenous fat accumulation, respectively, in HepG2 cells. We also found that overexpression of CARF lowered the exogenous fat accumulation in PA treated HepG2 cells. RNA seq analysis after CARF knockdown in HEK-293T cells further revealed that genes associated with lipid metabolism and triglyceride (TG) synthesis such as diacylglycerol O-acyltransferase2 (DGAT2), acyl-CoA synthetase long-chain family member 4 and 6 (ACSL4, ACSL6) were upregulated in CARF-depleted cells. Likewise, we also found increased expression of DGAT2 in CARF-depleted HepG2 cells, which enhanced TG synthesis. Intriguingly, consistent with the lipid lowering effects of metformin, an antidiabetic drug, we further found that CARF expression along with pAMPK and Sirt1 were significantly increased in metformin-treated HepG2 cells. However, we also found increased pACC levels in CARF over-expressing cells which was further enhanced in metformin-treated cells, suggesting, for the first time, that CARF may contribute to lipid lowering effect of metformin by inhibiting lipogenesis. We conclude that CARF has a lipid lowering effect in hepatocytes and its down regulation in response to MS perturbs lipid metabolism that may lead to the development of NAFLD.

scholarly journals A Component Formula of Chinese Medicine for Hypercholesterolemia Based on Virtual Screening and Biology Network

2018 ◽  
Vol 2018 ◽  
pp. 1-11 ◽  
Author(s):  
Xiaoqian Huo ◽  
Fang Lu ◽  
Liansheng Qiao ◽  
Gongyu Li ◽  
Yanling Zhang
Keyword(s):  
Chinese Medicine ◽  
Virtual Screening ◽  
Regulatory Element ◽  
Pharmacophore Model ◽  
Lipid Lowering ◽  
Hmg Coa Reductase ◽  
Element Binding Protein ◽  
Sterol Regulatory Element ◽  
Coa Reductase

Hypercholesterolemia is a risk factor to atherosclerosis and coronary heart disease II. The abnormal rise of cholesterol in plasma is the main symptom. Cholesterol synthesis pathway is an important pathway of the origin of cholesterol, which is an essential pathway for the therapy of hypercholesterolemia. The 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMG-CoA reductase), squalene synthase (SQS), and sterol regulatory element binding protein-2 (SREBP-2) are closely connected with the synthesis of cholesterol. The inhibition of these targets can reduce the cholesterol in plasma. This study aimed to build a component formula including three Traditional Chinese Medicines (TCM) components with the inhibition activity of these targets by using virtual screening and biological network. Structure-based pharmacophore models of HMG-CoA reductase and SQS and ligand-based pharmacophore model of SREBP-2 were constructed to screen the Traditional Chinese Medicine Database (TCMD). Molecular docking was used for further screening of components of HMG-CoA reductase and SQS. Then, metabolic network was constructed to elucidate the comprehensive interaction of three targets for lipid metabolism. Finally, three potential active compounds were obtained, which are poncimarin, hexahydrocurcumin, and forsythoside C. The source plants of the compounds were also taken into account, which should have known action of lowering hyperlipidemia. The lipid-lowering effect of hexahydrocurcumin was verified by experiment in vitro. The components that originated from TCMs with lipid-lowering efficacy made up a formula with a synergistic effect through the computer aid drug design methods. The research provides a fast and efficient method to build TCM component formula and it may inspire the study of the explanation of TCM formula mechanism.

scholarly journals Identification of Multi-Target Anti-AD Chemical Constituents From Traditional Chinese Medicine Formulae by Integrating Virtual Screening and In Vitro Validation

2021 ◽  
Vol 12 ◽  
Author(s):  
Baoyue Zhang ◽  
Jun Zhao ◽  
Zhe Wang ◽  
Pengfei Guo ◽  
Ailin Liu ◽  
...  
Keyword(s):  
Molecular Docking ◽  
Chinese Medicine ◽  
Traditional Chinese Medicine ◽  
Virtual Screening ◽  
Cell Model ◽  
Chemical Constituents ◽  
New Drugs ◽  
Molecular Docking Study ◽  
Biological Validation

Alzheimer’s disease (AD) is a neurodegenerative disease that seriously threatens the health of the elderly. At present, no drugs have been proven to cure or delay the progression of the disease. Due to the multifactorial aetiology of this disease, the multi-target-directed ligand (MTDL) approach provides an innovative and promising idea in search for new drugs against AD. In order to find potential multi-target anti-AD drugs from traditional Chinese medicine (TCM) formulae, a compound database derived from anti-AD Chinese herbal formulae was constructed and predicted by the anti-AD multi-target drug prediction platform established in our laboratory. By analyzing the results of virtual screening, 226 chemical constituents with 3 or more potential AD-related targets were collected, from which 16 compounds that were predicted to combat AD through various mechanisms were chosen for biological validation. Several cell models were established to validate the anti-AD effects of these compounds, including KCl, Aβ, okadaic acid (OA), SNP and H2O2 induced SH-SY5Y cell model and LPS induced BV2 microglia model. The experimental results showed that 12 compounds including Nonivamide, Bavachromene and 3,4-Dimethoxycinnamic acid could protect model cells from AD-related damages and showed potential anti-AD activity. Furthermore, the potential targets of Nonivamide were investigated by molecular docking study and analysis with CDOCKER revealed the possible binding mode of Nonivamide with its predicted targets. In summary, 12 potential multi-target anti-AD compounds have been found from anti-AD TCM formulae by comprehensive application of computational prediction, molecular docking method and biological validation, which laid a theoretical and experimental foundation for in-depth study, also providing important information and new research ideas for the discovery of anti-AD compounds from traditional Chinese medicine.

scholarly journals Synthesis, Photoisomerization, Antioxidant Activity, and Lipid-Lowering Effect of Ferulic Acid and Feruloyl Amides

Molecules ◽  
2020 ◽  
Vol 26 (1) ◽  
pp. 89
Author(s):  
Chiara Lambruschini ◽  
Ilaria Demori ◽  
Zeinab El Rashed ◽  
Leila Rovegno ◽  
Elena Canessa ◽  
...  
Keyword(s):  
Antioxidant Activity ◽  
Ferulic Acid ◽  
Antioxidant Properties ◽  
Cellular Level ◽  
Lipid Lowering ◽  
Alcoholic Fatty Liver ◽  
Lowering Effect ◽  
Vitro Model ◽  
Lipid Lowering Effect

The Ugi four-component reaction employing naturally occurred ferulic acid (FA) is proposed as a convenient method to synthesize feruloyl tertiary amides. Applying this strategy, a peptoid-like derivative of ferulic acid (FEF77) containing 2 additional hydroxy-substituted aryl groups, has been synthesized. The influence of the configuration of the double bond of ferulic acid and feruloyl amide on the antioxidant activity has been investigated thanks to light-mediated isomerization studies. At the cellular level, both FA, trans and cis isomers of FEF77 were able to protect human endothelial cord vein (HECV) cells from the oxidative damage induced by exposure to hydrogen peroxide, as measured by cell viability and ROS production assays. Moreover, in steatotic FaO rat hepatoma cells, an in vitro model resembling non-alcoholic fatty liver disease (NAFLD), the molecules exhibited a lipid-lowering effect, which, along with the antioxidant properties, points to consider feruloyl amides for further investigations in a therapeutic perspective.

Sign in / Sign up

Export Citation Format

Share Document