BackgroundWS070117 is a novel small molecule compound that significantly improves lipid metabolism disorders in high-fat-diet (HFD) induced hyperlipidemia in hamsters.Methods and ResultsWe evaluated liver/body weight ratio, liver histology, serum and hepatic lipid content in HFD-fed hamsters treated with WS070117 for 8 weeks. Comparing with HFD fed hamsters, WS070117 (2 mg/kg per day and above) reduced serum triglyceride (TAG), total cholesterol (TC), low density lipoprotein cholesterol (LDL-C) and hepatic cholesterol and triglyceride contents. Oil Red O staining of liver tissue also showed that WS070117 improved lipid accumulation. We then carried out an experiment in the oleic acid (OLA)-induced steatosis model in HepG2 cell to investigate the lipid-lowering effect of WS070117. Oleic acid (0.25 mM) markedly induced lipid accumulation in HepG2 cells, but WS070117 (10 μM) inhibited cellular lipid accumulation. In OLA-treated HepG2 cells, WS070117 (above 1 μM) treatment reduced lipid contents which synthesized from [1-14C] labeled acetic acid. Because WS070117 is an analog of adenosine, we evaluated the effect of WS070117 on AMP-activated protein kinase (AMPK) signaling. The results showed that the activation of AMPK in OLA-induced steatosis in HepG2 cells was up-regulated by treatment with 0.1, 1 and 10 μM WS070117. The hepatic cellular AMPK phosphorylation is also up regulated by WS070117 (6 and 18 mg/kg) treatment in HFD fed hamsters.ConclusionThese new findings identify WS070117 as a novel molecule that regulates lipid metabolism in the hyperlipidemia hamster model. In vitro and in vivo studies suggested that WS070117 may regulate lipid metabolism through stimulating the activation of AMPK and its downstream pathways.
Atherosclerosis (AS) is a progressive disease that contributes to cardiovascular disease and shows a complex etiology, including genetic and environmental factors. To understand systemic metabolic changes and to identify potential biomarkers correlated with the occurrence and perpetuation of diet-induced AS, we applied H NMR-based metabolomics to detect the time-related metabolic profiles of plasma, urine, and liver extracts from male hamsters fed a high fat and high cholesterol (HFHC) diet. Conventional biochemical assays and histopathological examinations as well as protein expression analyses were performed to provide complementary information. We found that diet treatment caused obvious aortic lesions, lipid accumulation, and inflammatory infiltration in hamsters. Downregulation of proteins related to cholesterol metabolism, including hepatic SREBP2, LDL-R, CYP7A1, SR-BI, HMGCR, LCAT, and SOAT1 was detected, which elucidated the perturbation of cholesterol homeostasis during the HFHC diet challenge. Using "targeted analysis", we quantified 40 plasma, 80 urine, and 60 liver hydrophilic extract metabolites. Multivariate analyses of the identified metabolites elucidated sophisticated metabolic disturbances in multiple matrices, including energy homeostasis, intestinal microbiota functions, inflammation, and oxidative stress coupled with the metabolisms of cholesterol, fatty acids, saccharides, choline, amino acids, and nucleotides. For the first time, our results demonstrate a time-dependent metabolic progression of multiple biological matrices in hamsters from physiological status to early AS and further to late-stage AS, demonstrating thatH NMR-based metabolomics is a reliable tool for early diagnosis and monitoring of the process of AS.
In this study, (1)H NMR-based metabonomics was applied to evaluate the beneficial effects of cordycepin (3'-deoxyadenosine), a natural monomer compound, on endogenous metabolic profiles of liver and plasma from hyperlipidemic Syrian golden hamsters. Hyperlipidemia was successfully established in hamsters fed by a high-fat diet for 2 weeks. The hyperlipidemic hamsters were treated with an oral administration of simvastatin (2 mg kg(- 1)) or cordycepin (140 mg kg(- 1)) for consecutive 4 weeks. The metabolic profiles of plasma and intact liver tissues were established using (1)H NMR spectroscopy. The results showed higher contents of lipids (triglyceride and cholesterol), lactate, acetate, alanine, glutamine together with lower contents of choline-containing compounds (e.g. phosphocholine, phosphatidylcholine, and glycerophosphocholine), glucose, and glycogen in plasma and liver samples from hyperlipidemic hamsters than those in controls. Cordycepin afforded a little lipid-regulating activity on plasma but more beneficial effects on liver, implicating that cordycepin might have a protective effect on liver under fatty liver condition.
These two authors contributed equally to this work.It had been reported that cordycepin could activate AMP-activated protein kinase. One possible mechanism is that cordycepin mediated AMP-activated protein kinase activation by conversion into cordycepin monophosphate, which acts as an AMP analog to activate AMP-activated protein kinase. To confirm the aforementioned hypothesis, we investigate the binding of cordycepin monophosphate to AMP-activated protein kinase using molecular docking. The modeling results indicate that cordycepin monophosphate binds to AMPactivated protein kinase with high affinity. The hydrogen bonds provide attractive forces between molecules. Our results further identify the key residues contributing to the interaction. Also, the modeling results predict that cordycepin monophosphate and AMP would have similar binding modes with AMP-activated protein kinase. Further investigation of AMP-activated protein kinase activation in vitro provides the evidence that cordycepin monophosphate functioned as an AMP mimic to activate AMP-activated protein kinase. The AMP-activated protein kinase (AMPK) has been proposed to act as a sensor of cellular energy status capable of regulating vital metabolic pathways in the cell (1). Changes in AMPK activity have been shown to regulate energy consuming biosynthetic pathways, such as fatty acid and sterol synthesis, and adenosine triphosphate (ATP)-producing catabolic pathways, such as fatty acid oxidation. AMPK has therefore been proposed as a major therapeutic target for obesity and obesity-linked metabolic disorders such as hyperlipidemia. AMPK is a heterotrimeric complex consisting of a catalytic subunit (a) and two regulatory subunits (b and c). The c subunits of AMPK have been shown to contain AMP-binding sites (2). Regulation of AMPK activity is typically affected through the binding of AMP to allosteric sites. As AMPK represent potential drug targets for metabolic diseases, efforts were initiated to discover AMP mimics that bind to AMPbinding sites with high affinity and high enzyme specificity (3). Numerous investigators have focused on the nucleoside analogs that generate nucleoside monophosphates (NMPs) inside cells (4,5). For example, 5-aminoimidazole-4-carboxamide 1-bD-ribofuranoside (AICAR), a nucleoside analog discovered in the late 1980s, was one of the AMPK stimulators (6). AICAR mediated AMPK activation by conversion into ZMP (AICAR monophosphate), which acts as an AMP analog to activate AMPK without affecting the cellular AMP:ATP ratio.Cordycepin, a nucleoside analog 3¢-deoxyadenosine, is a bioactive compound present in traditional Chinese medicine Cordyceps. In recent years, many pharmacological properties of cordycepin have been reported, including antiviral (7), antifungal (8) and antitumor activity (9). Recently, cordycepin was shown to function as an activator of the AMPK pathway (10). One possible mechanism is that cordycepin mediated AMPK activation by conversion into cordycepin monophosphate, which acts as an AMP analog to activate AM...
The α1‐adrenoceptor (α1‐AR) antagonists are potential candidates for the treatment of blood pressure. Higenamine (HG) is a novel α1‐AR antagonist. In this study, we investigated the effects of HG in HEK293A cells transfected with α1A‐, α1B‐, and α1D‐AR in vitro, rat mesenteric artery ex vivo, Wistar–Kyoto rats and spontaneously hypertensive rats in vivo. The radioligand binding assay showed that HG competitively inhibited the binding of [3H]‐prazosin to α1‐AR in a concentration‐dependent manner. The affinities (pKi) of HG for the cloned α1A‐, α1B‐, and α1D‐AR were 6.57, 6.48, and 6.35, respectively, indicating that HG displayed no selectivity for the three α1‐AR subtypes. In in vitro studies, HG was able to blunt inositol monophosphate production. It also displayed an inhibitory effect on the influx and entry of calcium ions and phosphorylation of extracellular signal‐regulated kinase 1 and 2 induced by phenylephrine (PE). In ex vivo studies, PE caused a dose‐dependent inotropic response curve, and the pA2 value for HG was 6.86 ± 0.29. In addition, the in vivo results showed that HG could decrease the blood pressure in normotension, spontaneous hypertension, and PE‐induced hypertension models. These results indicate that HG can directly bind to α1‐AR and it appears to be a novel antagonist for α1‐AR, which may contribute to its hypotensive effect.
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