Discovery and synthesis of novel substituted benzocoumarins as orally active lipid modulating agents

The synthesis of a series of benzocoumarin keto-enamine schiff bases is reported. The novel compounds were evaluated for their antihyperlipidemic activity in the hyperlipidemic hamster model. The compound 11 at a dose of 10 mg/kg body weight significantly lowered the plasma triglyceride levels (TG) by 70%, total cholesterol (TC) by 47%, accompanied by an increase in HDL-C/TC ratio by 80% in hyperlipidemic hamsters to a greater degree than the reference drugs atorvastatin and lovastatin.     

Synthesis and antihyperlipidemic activity of novel glycosyl fructose derivatives

A series of novel di and trisaccharide derivatives containing d-fructose moiety at the reducing end have been synthesized and evaluated for their antihyperlipidemic activity in hyperlipidemic hamster model. Among 11 glycosyl fructose derivatives five compounds showed potent antihyperlipidemic activity either by enhancing high-density lipoprotein (HDL) cholesterol concentration and/or lowering triglyceride (TG) level.     

Antioxidant and antihyperlipidemic activities of polysaccharides from sea cucumber Apostichopus japonicus

Polysaccharides (AJP) were prepared from Apostichopus japonicus by protease hydrolysis method. Antioxidant activity in vitro and antihyperlipidemic activity in vivo was investigated. Chemical composition analysis indicated that AJP was mainly composed of glucosamine, galactosamine, glucuronic acid, mannose, glucose, galactose and fucose, with an average molecular weight of about 36.2kDa. The antioxidant capacities of AJP were, respectively, evaluated by the assays of scavenging DPPH, hydroxyl and superoxide radicals, and reducing power in vitro. It showed potent free radical scavenging activities and reducing power. Serum total cholesterol (TC), triglyceride (TG) and low-density lipoprotein (LDL-C) decreased significantly and high-density lipoprotein cholesterol (HDL-C) increased significantly after treatment of hyperlipidemic Wistar rats with AJP. These results suggest that AJP may prove to be a potential candidate of the natural antioxidants as a therapeutic agent for hyperlipidemia.     

Lipid lowering activity of novel N-(benzoylphenyl)pyridine-3-carboxamide derivatives in Triton WR-1339-induced hyperlipidemic rats

Abstract

Context: Dyslipidemia is a major risk factor for the development of cardiovascular diseases. Many dyslipidemic patients do not achieve their target lipid levels with the currently available medications, and most of them may experience many side effects.

Objective: The present work aimed toward identifying a new class of novel nicotinic acid-carboxamide derivatives as promising antihyperlipidemic compounds.

Materials and methods: Six novel N-(benzoylphenyl)pyridine-3-carboxamide derivatives were synthesized using acid chloride pathways. All structures were confirmed using ¹H-NMR, ¹³C-NMR, IR, and HRMS. The evaluation of biological activity was conducted using Triton WR-1339-induced hyperlipidemic rats model.

Results: This study revealed that some of the newly synthesized novel N-(benzoylphenyl)pyridine-3-carboxamide derivatives mainly C4 and C6 possessed significant antihyperlipidemic activities on lipid components TG and TC (p value?<0.05).

Discussion and conclusion: This research opens the door for new potential antihyperlipidemic compounds derived from nicotinic acid that need further optimization of their biological activities.     

Hypolipidemic and antioxidative effects of the plant glycoprotein (36 kDa) from Rhus verniciflua stokes fruit in Triton WR-1339-induced hyperlipidemic mice

We investigated the hypolipidemic and antioxidative effects on male ICR mice of a glycoprotein isolated from Rhus verniciflua Stokes (RVS) fruit. The administration of the RVS glycoprotein (100 mg/kg) for two weeks resulted in a significant decrease in such plasma lipid levels as total cholesterol (TC), triglyceride (TG), and low-density lipoprotein (LDL). The levels of TC, TG and LDL in the hyperlipidemic model were significantly increased, whereas the high-density lipoprotein (HDL) level was considerably decreased. The 3-hydroxy-3-methylglutaryl CoA (HMG-CoA) reductase activity and the level of thiobarbituric acid-reactive substances (TBARS) were significantly elevated, whereas the production of nitric oxide (NO) was diminished. Moreover, the administration of the RVS glycoprotein prior to inducing hyperlipidemic mice suppressed the increase in the plasma lipid levels (TC, TG and LDL), and decrease in the HDL level in Triton WR-1339-induced hyperlipidemic mice. Furthermore, the RVS glycoprotein significantly inhibited the activity of HMG-CoA reductase and the levels of TBARS in the hyperlipidemic mice. In addition, the activities of detoxicant enzymes [catalase (CAT), superoxide dismutase (SOD), and glutathione peroxidase (GPx)] were gradually augmented after a supplement with the RVS glycoprotein. The results suggest that the RVS glycoprotein would be effective in preventing an increase in the plasma lipid levels and in improving the antioxidant levels. This protein might be useful as a therapeutic agent.     

Antihyperlipidemic potential of diosmin in Swiss Albino mice with high-fat diet induced hyperlipidemia

The aim of this study was to investigate the antihyperlipidemic potential of Diosmin (DS) in mice fed with a high-fat diet (HFD). Animals were divided in five groups (n = 6). The total duration of the study was 90 days split into two intervals. During the first 45-day interval, mice were administered with HFD, whereas during the second 45-day interval they were co-administered HFD plus DS or the standard drug atorvastatin. DS was administered at the dose of 100 and 200 mg/kg;p.o. DS treatment to HFD-induced hyperlipidemic mice caused significant decrements in the levels of total cholesterol, triglycerides, LDL-C and VLDL-C. Moreover, DS resulted in significant increase in the levels of HDL-C and improvements in total protein levels, whereas it caused remarkable decreases in SGOT, SGPT and ALP enzymatic activities in hyperlipidemic mice. Histopathological examination of hyperlipidemic mice revealed a disorganized hepatic tissue, fatty changes, and mononuclear cell infiltration, which were all ameliorated by DS administration. The results revealed that DS possesses potential ameliorating benefits again.st hyperlipidemia induced by HFD on lipid profile, liver function enzymes and hepatic histoarchitecture. Further investigations are highly recommended and clinical trials are warranted in order to assess the efficacy and to fully dissect the mode-of-action underpinning the observed antihyperlipidemic effect of DS.     

Hypolipidemic and antihyperlipidemic effects of Lagenaria siceraria (Mol.) fruit extracts

Bottle gourd [(Lagenaria siceraria (Mol.) Stand.] fruit is ascribed with many therapeutic effects. The present study was undertaken to explore the antihyperlipidemic effect of four different extracts viz. petroleum ether, chloroform, alcoholic and aqueous extracts from bottle gourd in Triton-induced hyperlipidemic rats and their hypolipidemic effects in normocholesteremic rats. The study is comprised preliminary phytochemical screening of the extracts. Oral administration of the extracts, at doses of 200 and 400 mg/kg body weight in rats, dose-dependently inhibited the total cholesterol, triglycerides, low-density lipoproteins level, and significantly increased the high density lipoproteins level. However, petroleum ether extract did not show the significant effects. Both the chloroform and alcoholic extract exhibited more significant effects in lowering total cholesterol, triglycerides and low density lipoproteins along with increase in HDL as compared to the others. Preliminary phytochemical screening revealed the presence of flavonoids, sterols, cucurbitacin saponins, polyphenolics, proteins, and carbohydrates. The results obtained suggest marked antihyperlipidemic and hypolipidemic activity of the extracts.     

Hypolipidemic activity of Achyranthus aspera Linn in normal and triton induced hyperlipemic rats.

The alcoholic extract of A. aspera, at 100 mg/kg dose lowered serum cholesterol (TC), phospholipid (PL). triglyceride (TG) and total lipids (TL) levels by 60, 51, 33 and 53% respectively in triton induced hyperlipidemic rats. The chronic administration of this drug at the same doses to normal rats for 30 days, lowered serum TC, PL, TG and TL by 56, 62, 68 and 67% respectively followed by significant reduction in the levels of hepatic lipids. The faecal excretion of cholic acid and deoxycholic acid increased by 24 and 40% respectively under the action of this drug. The possible mechanism of action of cholesterol lowering activity of A. aspera may be due to rapid excretion of bile acids causing low absorption of cholesterol.     

Antihyperlipidemic activity of high sulfate content derivative of polysaccharide extracted from Ulva pertusa (Chlorophyta)

In this study, high sulfate content ulvan (HU) was prepared with sulfur trioxide/N,N-dimethylformamide (SO₃-DMF) in formamide, and the antihyperlipidemic activity of ulvan and HU in mice was determined. Obvious differences in antihyperlipidemic activity between natural ulvan and HU were observed, moreover, the antihyperlipidemic activity of HU-fed 250 mg/kg was the strongest, compared to natural ulvan fed group, triglyceride (TG) and low density lipoprotein cholesterol (LDL-C) concentrations were significantly decreased 28.1% (P < 0.05) and 28.4% (P < 0.01), respectively. It was likely that the sulfate content had significant effect on the antihyperlipidemic activity. On the other hand, the results proved that the antihyperlipidemic activity was not concentration dependent for HU-fed mice.     

Antihyperlipidemic and antioxidant effects of feather protein hydrolysate in high‐fat diet‐fed mice

The hyperlipidemia is a serious health problem that increases the risk of many complications including cardiovascular disease. This study aims to evaluate the possible antihyperlipidemic effects of the feather protein hydrolysate (FPH) in a mice fed with a high‐fat diet (HFD)‐fed mice during 5 weeks. The FPH administration improved dose‐dependent lipid profile, as well as the liver and renal dysfunction indices in hyperlipidemic mice. The FPH also restored the antioxidant status in liver, kidney, and heart by lowering the lipid peroxidation and enhancing the antioxidant enzymes (catalase (CAT), glutathione peroxidase (GPx) and superoxide dismutase [SOD]). Moreover, the histological studies proved that FPH administration prevents hepatic steatosis, glomerular hyperfiltration risk, and cardiac muscle hypertrophy. Accordingly, the FPH is a promising novel medicinal ingredient for possible use in the hyperlipidemic treatment and related complications.     

Synthesis of novel N-(2-hydroxy-2-p-tolylethyl)-amide and N-(2-oxo-2-p-tolylethyl)-amide derivatives and their antidyslipidemic and antioxidant activity

In continuation of our drug discovery program on metabolic diseases, we identified an alkaloidal amide, that is, Aegeline (V) from the plant Aegle marmelos leaves as a dual acting agent (antihyperlipidemic and antihyperglycemic). We therefore synthesized a series of alkaloidal amides [N-(2-hydroxy-2-p-tolylethyl)-amides and N-(2-oxo-2-p-tolylethyl)-amide derivatives] related to Aegeline and screened for their in vivo antihyperlipidemic activity in Triton induced hyperlipidemia model. The synthetic compounds 4, 17 and 20 showed equipotent activity to the natural product, that is, Aegeline (V). These compounds also showed strong antioxidant activity, which support their antihyperlipidemic activity. Compound 12 showed better antihyperlipidemic and antioxidant profile than the natural product V.     

Overexpression of apolipoprotein AV in the liver reduces plasma triglyceride and cholesterol but not HDL in ApoE deficient mice

It has been shown that adenovirus-mediated overexpression of human ApoAV (hApoAV) in C57BL/6 mice results in decreased plasma triglyceride (TG) and total cholesterol (TC) levels with a major reduction occurring in the HDL fraction. In order to study the effect of ApoAV on hypercholesterolemic mice, an adenoviral vector expressing hApoAV was constructed and injected into ApoE deficient mice. High levels of hApoAV mRNA in the liver and ApoAV proteins in the liver and plasma were detected. The treatment reduced plasma TG levels by 50% and 75%, and TC levels by 45% and 58% at day 3 and 7, respectively, after treatment as compared with a control group treated with Ad-hAP (human alkaline phosphatase). Plasma HDL-C levels remained unaltered, which were different from normolipidemic mice. These findings suggest that ApoAV might serve as a therapeutic agent for hyperlipidemic disorder.     

The Pharmacological effects of novel 5-fluoro-N-(9,10-dihydro-9,10-dioxoanthracen-8-yl)-1H-indole-2-carboxamide derivatives on plasma lipid profile of Triton-WR-1339-induced Wistar rats

A novel series of 5-fluoro-N-(9,10-dihydro-9,10-dioxoanthracen-8-yl)-1H-indole-2-carboxamides (3c–3g) were synthesized. The present study was undertaken to investigate the possible antihyperlipidemic effect of these novel compounds on hyperlipidemic rats. Hyperlipidemia was induced by a single intraperitoneal injection of Triton WR-1339 (300 mg/kg). The tested animals were divided into normal control (NCG), hyperlipidemic control (HCG), compounds 3c-, 3d-, 3e-, 3f-, 3g- and bezafibrate (BF)-treated groups. At a dose of 15 mg/kg, compounds 3c–3g and BF (100 mg/kg) significantly (p < 0.0001) reduced elevated plasma triglycerides levels after 12 and 24 h compared to the hyperlipidemic control group. However, only compounds 3e and 3g obviously showed a significant (p < 0.0001) reduction in plasma total cholesterol levels after 12 and 24 h. Moreover, high-density lipoprotein cholesterol levels were significantly increased in all treated groups. The current study demonstrates that 5-fluoro-N-(9,10-dihydro-9,10-dioxoanthracen-8-yl)-1H-indole-2-carboxamides (3c–3g) have a definite antihyperlipidemic potential and these beneficial activities may contribute to their cardioprotective and antiatherosclerotic role.     

Hypocholesterolemia of Rhizoma Coptidis alkaloids is related to the bile acid by up-regulated CYP7A1 in hyperlipidemic rats

This study is to investigate the cholesterol-lowering effect and the new mode of action of coptis alkaloids on high lipid diet-induced hyperlipidemic rats. Coptis alkaloids extract (CAE) was prepared by alcohol extraction from Rhizoma Coptidis that have been quality-controlled according to the protocol. The cholesterol-lowering effect of CAE was evaluated on SD rats fed with high-lipid diet. Serum level of lipid, Bile acid and cholesterol in the liver and feces of the rats were measured using colorimetric assay kit. RT-PCR and Western blot were used to analyze the mRNA and protein expression of cholesterol metabolism-related genes including cholesterol 7α-hydroxylase (CYP7A1), peroxisome proliferator-activated receptor-alpha (PPARα) and farnesoid X receptor (FXR) in the livers of the rats. A HPLC analysis was used to assess the activity of CYP7A1. The results showed that CAE reduced the levels of serum total cholesterol (TC), triglycerides (TG), low-density lipoprotein cholesterol (LDL-C). CYP7A1 gene expression and its activity was up-regulated dose-dependently accompanying with the increased level of bile acid and the reduced cholesterol level in the livers of the CAE treated hyperlipidemic rats. Meanwhile, the mRNA expression of PPARα was also up-regulated in dose-dependent way accompanying the down-modulation of the FXR mRNA expression in the livers of the CAE treated hyperlipidemic rats. The results indicate that the cholesterol-lowering effect of coptis alkaloid extract is at least partly attributed to its promoting the cholesterol conversion into bile acids by up-regulating the gene expression of CYP7A1 and thus increasing its activity in the liver of the hyperlipidemic rats, which might related to the positive regulation of PPARα and the negative modulation of FXR.     

Synthesis and antihyperlipidemic activity of acetylated derivative of ulvan from Ulva pertusa

In this study, acetylated ulvan (AU) was prepared with acetic anhydride in N,N-dimethylacetamide, and the antihyperlipidemic activity of natural ulvan and its acetylated ulvan derivative (AU) in mice was determined. Obvious differences in antihyperlipidemic activity between natural ulvan and its derivative were observed, moreover, AU showed stronger antihyperlipidemic activity on triglyceride (TG) and low density lipoprotein cholesterol (LDL-C).     

Cardiovascular, antihyperlipidemic and antioxidant effects of oleanolic and ursolic acids in experimental hypertension.

Cardiovascular (systolic and diastolic blood pressure, heart rate), antihyperlipidemic (tryglycerides, total cholesterol and lipoprotein fractions), antioxidant (glutathione peroxidase--GPx, and superoxide dismutase--SOD), diuretic/saluretic and hypoglycemic activity of 98% pure oleanolic (OA) and ursolic (UA) acid were studied in Dahl salt-sensitive (DSS), insulin resistant rat model of genetic hypertension. Both OA and UA displayed low toxicity, with LC50 0.10 and 0.95 mg/ml, respectively. Although both triterpenoids did not have direct hypotensive effect, after 6-week application in a daily dose 60 mg/kg b.w., i.p., they prevented the development of severe hypertension. The antihypertensive effect was attributed to their potent diuretic-natriuretic-saluretic activity; direct cardiac effect (heart rate decrease by 34% and 32%, respectively); antihyperlipidemic (more than two times decrease of LDL and triglycerides); antioxidant (GPx increase by 12% and 10%, respectively; SOD increase by 12% and 22%, respectively), and hypoglycemic (blood glucose decrease by 20% and 50%, respectively) effects on the DSS rats. Except for the antihyperlipidemic effects, the other described above in vivo antihypertensive effects of OA and UA are reported for the first time and the underlying mechanisms are currently under investigation.     

长爪沙鼠速发型高脂血症模型的初步建立

目的建立长爪沙鼠速发型高脂血症模型的方法。方法用含1%胆固醇高脂饲料分别饲养大鼠、小鼠和沙鼠,检测其血清TC、HDL-c、LDL-c、TG,比较三种动物对饲料反映的特点。结果沙鼠组的TC、HDL-c及LDL-c在第1周时明显的升高,并且平稳的保持此升高趋势到第四周。而TG数值相对平稳,没有变化。而大鼠和小鼠的TC、HDL-c、LDL-c、TG值没有变化。结论通过饲喂高脂饲料可快速诱发长爪沙鼠形成高脂血症模型。     

Adiponectin improves endothelial function in hyperlipidemic rats by reducing oxidative/nitrative stress and differential regulation of eNOS/iNOS activity

Plasma adiponectin level is significantly reduced in patients with metabolic syndrome, and vascular dysfunction is an important pathological event in these patients. However, whether adiponectin may protect endothelial cells and attenuate endothelial dysfunction caused by metabolic disorders remains largely unknown. Adult rats were fed with a regular or a high-fat diet for 14 wk. The aorta was isolated, and vascular segments were incubated with vehicle or the globular domain of adiponectin (gAd; 2 mug/ml) for 4 h. The effect of gAd on endothelial function, nitric oxide (NO) and superoxide production, nitrotyrosine formation, gp91(phox) expression, and endothelial nitric oxide synthase (eNOS)/inducible NOS (iNOS) activity/expression was determined. Severe endothelial dysfunction (maximal vasorelaxation in response to ACh: 70.3 +/- 3.3 vs. 95.2 +/- 2.5% in control, P < 0.01) was observed in hyperlipidemic aortic segments, and treatment with gAd significantly improved endothelial function (P < 0.01). Paradoxically, total NO production was significantly increased in hyperlipidemic vessels, and treatment with gAd slightly reduced, rather than increased, total NO production in these vessels. Treatment with gAd reduced (-78%, P < 0.01) superoxide production and peroxynitrite formation in hyperlipidemic vascular segments. Moreover, a moderate attenuation (-30%, P < 0.05) in gp91(phox) and iNOS overexpression in hyperlipidemic vessels was observed after gAd incubation. Treatment with gAd had no effect on eNOS expression but significantly increased eNOS phosphorylation (P < 0.01). Most noticeably, treatment with gAd significantly enhanced eNOS (+83%) but reduced iNOS (-70%, P < 0.01) activity in hyperlipidemic vessels. Collectively, these results demonstrated that adiponectin protects the endothelium against hyperlipidemic injury by multiple mechanisms, including promoting eNOS activity, inhibiting iNOS activity, preserving bioactive NO, and attenuating oxidative/nitrative stress.     

Single intravenous injection of plasmid DNA encoding human paraoxonase-1 inhibits hyperlipidemia in rats

Paraoxonase-1 (PON1, EC 3.1.8.1) is a high-density lipoprotein (HDL)-associated antioxidant enzyme, and its activity correlates negatively with the level of plasma low-density lipoprotein cholesterol (LDL-C) and triglyceridemia (TG). In this study, we examined the therapeutic effect of plasmid DNA containing the human PON1 gene (pcDNA/PON1) in hyperlipidemic model rats. The rats were fed a high-fat and high-cholesterol diet for 25 days to produce a hyperlipidemic animal model. Single intravenous injection of pcDNA/PON1 into model rats prevented dyslipidemia and hepatic lipid accumulation. The mechanisms of pcDNA/PON1 in treating hyperlipidemia were associated with increases of serum antioxidant PON1 and SOD activities, and with reduction of the levels of total cholesterol (TC), LDL-C and TG. The results suggest the potential therapeutic effect of pcDNA/PON1 on hyperlipidemia.     

芝麻素散剂调血脂作用研究

目的：观察芝麻素散剂对实验性高脂血症大鼠血脂的影响。方法：在给大鼠喂以高脂饲料的同时灌胃芝麻素散剂14天后测定血清总胆固醇（TC）、甘油三酯（TG）和高密度脂蛋白胆固醇（LDL－C）水平。结果：芝麻素散剂明显抑制TC、LDL－C的升高。结论：芝麻素散剂对大鼠实验性高脂血症有显著的预防作用。