Hyperlipidemic Diet Research Articles

Influence of Functional Sweet White Lupin Biscuits on Lipid Profile and Food Efficiency of Induced Hyperlipidemia Rats

<p>In recent years, functional foods have attracted much interest to prevent nutrition-related diseases such as hyperlipidemia and weight gain. In this regard, this study was designed to examine the effect of use sweet white lupin (SWL) oil and flour with/without germination as a source of active healthy components to prepare functional biscuits for lowering blood lipids and growth. Functional biscuits were formulated by replacing wheat flour and butter in biscuit formulae by SWL extracted flour and SWL oil in the range of 20-30% (w/w) and 30-40% (v/w), respectively. Results indicated that the feed of hyperlipidemic rats on diets supplemented with different functional SWL biscuits for 6 weeks significantly (P < 0.05) reduced serum total cholesterol, triglycerides, low density lipoproteins, very low density lipoproteins, ratio of total cholesterol/high density lipoproteins cholesterol, ratio of low density lipoproteins/high density lipoproteins cholesterol and atherogenic index. Furthermore, the feed of functional SWL biscuits significantly reduced the body weight gain of rats and their food efficiency compared to that of rats fed on hyperlipidemic diet. On the other hand, there was an increase in the value of high density lipoproteins cholesterol and its ratio with total cholesterol. All these findings supported that the addition of 25% germinated SWL flour and 35% or 40% germinated SWL oil in biscuits gave interested results compared to the common wheat biscuits. Therefore, the proposed functional SWL biscuits could be able to regulate the blood cholesterol and the body growth levels of individuals and patients.</p>

Protective effect of Xiongbitongcapsule on liver injury in hyperlipemic rats

Objective To investigate the protective role of Xiongbitong capsule against liver injury in hyperlipemic rats.Methods Sixty Wistar male rats were randomly divided into 5 groups（12 rats in each group）： a blank group, a model group, a simvastatin group（10 mg/kg, 2 ml intragastric administration daily）, a Xiongbitong capsule high-dose group（25 mg/kg, 2 ml intragastric administration daily）, and a Xiongbitong capsule low-dose group（12.5 mg/kg, 2 ml intragastric administration daily）. Hyperlipidemia model in rats was indeuced by hyperlipidemic diet. The simvastatin group was intragastric administrated with simvastatin suspension 2 ml（10 mg/kg daily）, and the rats in the control group and the model group were intragastric administrated with equal volume of saline. After 10 weeks, the serum leves of total cholesterol（TC）, triacylglycerol（TG）, low-density lipoprotein cholesterol（LDL-C）, high-density lipoprotein cholesterol （HDL-C）, nitric oxide（NO）, endothelin1（ET-1）, and the whole blood viscosities（high-, medium-, low-shear）were measured. Liver injury were evaluated with histopathologic examination by H.E. staining. The expressions of intercellular adhesion molecule-1（ICAM-1）, monocyte chemoattractant protein-1（MCP-1）in hepatic tissue were measured by immunohistochemical staining.Results The serum leves of TC（1.47± 0.10 mmol/Lvs. 3.48±0.19 mmol/L）, TG（0.38±0.11 mmol/Lvs. 0.95±0.14 mmol/L）, LDL-C（1.48± 0.18 mmol/Lvs. 2.39±0.22 mmol/L）, ET-1（145.81±18.65 pg/mlvs. 177.70±17.70 pg/ml） in the Xiongbitong capsule high-dose group were significantly lower than those in the model group（allP〈0.01）, HDL-C（1.21±0.14 mmol/Lvs. 0.65±0.10 mmol/L）and NO（31.28±2.36μmol/Lvs. 19.61±1.28μmol/L） significantly lower than those in the model group（allP〈0.01）, the expressions of ICAM-1（0.133±0.019vs. 0.187±0.011）and MCP-1（0.153±0.014vs. 0.264±0.020）significantly lower than those in the model group（allP〈0.01）. The liver injury in the Xiongbitong capsule high-dose group decreased than that in the model group. Conclusions Xiongbitong capsule can protect against liver injury via regulating lipid metabolism, protecting endothelial function and down regulating expressions of MCP-1 and ICAM-1. Key words: Xiongbitong capsule; Hyperlipidemias; Endothelial cells; Nitric oxide; Monocyte chemoattractant proteins

Hypolipidemic and antioxidative effects of aqueous enzymatic extract from rice bran in rats fed a high-fat and -cholesterol diet.

Purpose: The aqueous enzymatic extract from rice bran (AEERB) was rich in protein, γ-oryzanol and tocols. The aim of this study was to investigate the effects of AEERB on the regulation of lipid metabolism and the inhibition of oxidative damage. Methods: The antioxidant activity of AEERB in vitro was measured in terms of radical scavenging capacity, ferric reducing ability power (FRAP) and linoleic acid emulsion system-ferric thiocyanate method (FTC). Male Wistar rats were fed with a normal diet and a high-fat and high-cholesterol diet with or without AEERB. After treatment, biochemical assays of serum, liver and feces lipid levels, the antioxidant enzyme activity, malondialdehyde (MDA) and protein carbonyl were determined. Result: AEERB is completely soluble in water and rich in hydrophilic and lipophilic functional ingredients. AEERB scavenged DPPH• and ABTS•+ and exhibited antioxidant activity slightly lower than that of ascorbic acid in the linoleic acid system. The administration of AEERB reduced serum lipid levels and the atherogenic index compared with those of the hyperlipidemic diet group (HD). The administration of AEERB significantly lowered liver lipid levels, inhibited hepatic 3-hydroxyl-3-methylglutaryl CoA reductase activity, and efficiently promoted the fecal excretion of total lipids and total cholesterol (TC) (p < 0.05). Dietary AEERB enhanced antioxidant status in the serum, liver and brain by increasing the antioxidant enzyme activity of superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GSH-Px) and decreasing the content of MDA and protein carbonyl. Conclusions: The results indicated that AEERB might act as a potent hypolipidemic and antioxidant functional food.

Legumin from chickpea: hypolipidemic effect in the liver of hypercholesterolemic rats

Purpose– This paper aims to determine the effects of 11S globulin isolated from Chickpea (Cicer arietinumL.) on lipid metabolism in animals subjected to a hypercholesterolemic and hyperlipidemic diet and compared to the drug simvastatin.Design/methodology/approach– Thirty-six male Wistar rats, kept in individual cages and under appropriate conditions, were separated into groups that were fed a normal diet (STD) containing casein as protein source and according to AIN-93G; a high-cholesterol diet (HC), normal diet plus 1 per cent cholesterol and 0.5 per cent cholic acid and 20 per cent coconut oil; HC diet plus the isolated 11S globulin (300 mg/kg/day); and HC diet plus the simvastatin (50 mg/kg/day), both dissolved in saline and administered by gavage for 28 days. After this time, the animals were killed.Findings– The results indicated that the addition of 1 per cent cholesterol and 0.5 per cent cholic acid induced hypercholesterolemia in the animals without interfering with their weight gain. Analyses of total cholesterol (TC), HDL-cholesterol (HDL-C) and triglycerides (TG) in the plasma, and TC and TG in the liver were made. The results show that the protein isolated from chickpea, and given as a single daily dose, did not affect the levels of plasma TC and its fractions, although decreasing the TG levels. Unlike the simvastatin, the chickpea protein significantly reduced TC and TG in the liver relative to HC group.Originality/value– A single daily dose of 11S globulin from chickpea contributed as only as additional 2.8 per cent of dietary protein intake. These findings demonstrate that 11S chickpea protein acts as a functional agent in the lipid metabolism in addition to its nutritional properties.

Anti-hypercholesterolemic effect of Pistacia lentiscus fatty oil in egg yolk-fed rabbits: a comparative study with simvastatin

AimThe current study was undertaken to assess anti-hyperlipidemic activity of Pistacia lentiscus fatty oil (PLFO) in rabbits following a hyperlipidemic diet. MethodTwenty healthy female (WNZ) rabbits were divided into four groups of five animals each: (a) normal control (NC group) receiving standard diet, (b) hyperlipidemic control (EY) group receiving standard diet and gavaged daily with egg yolk (10 mL), (c) hyperlipidemic + PLFO (EY + PLFO) group receiving as the EY group and treated daily with PLFO (2 mL/kg BW, (d) hyperlipidemic + simvastatin (EY + SVS) group receiving as the EY group and treated once daily with 2.5 mg/kg BW of simvastatin. At the end of the six-week experimental period, the lipidemic profiles of the different groups were investigated. ResultsIn the EY group, the egg yolk resulted in a significant increase of total cholesterol (TC), triglycerides (TG), HDL-C, LDL-C, and the LDL-C/HDL-C ratio. Both the EY + PLFO and EY + SVS groups, when compared to the EY group, showed a significant decrease of TC, TG, LDL-C, and the LDL-C/HDL-C ratio. However, with respect to HDL-C the differences were not significant. The TGs were significantly lower (P < 0.001) in the simvastatin-treated group when compared to rabbits treated in the PLFO group. ConclusionThe study concludes that P. lentiscus fatty oil (PLFO) possesses anti-hyperlipidemic properties at least in reducing total cholesterol, LDL-cholesterol and triglycerides.

Hyperlipidemic diet causes loss of olfactory sensory neurons, reduces olfactory discrimination, and disrupts odor-reversal learning.

Currently, 65% of Americans are overweight, which leads to well-supported cardiovascular and cognitive declines. Little, however, is known concerning obesity's impact on sensory systems. Because olfaction is linked with ingestive behavior to guide food choice, its potential dysfunction during obesity could evoke a positive feedback loop to perpetuate poor ingestive behaviors. To determine the effect of chronic energy imbalance and reveal any structural or functional changes associated with obesity, we induced long-term, diet-induced obesity by challenging mice to high-fat diets: (1) in an obesity-prone (C57BL/6J) and obesity-resistant (Kv1.3(-/-)) line of mice, and compared this with (2) late-onset, genetic-induced obesity in MC4R(-/-) mice in which diabetes secondarily precipitates after disruption of the hypothalamic axis. We report marked loss of olfactory sensory neurons and their axonal projections after exposure to a fatty diet, with a concomitant reduction in electro-olfactogram amplitude. Loss of olfactory neurons and associated circuitry is linked to changes in neuronal proliferation and normal apoptotic cycles. Using a computer-controlled, liquid-based olfactometer, mice maintained on fatty diets learn reward-reinforced behaviors more slowly, have deficits in reversal learning demonstrating behavioral inflexibility, and exhibit reduced olfactory discrimination. When obese mice are removed from their high-fat diet to regain normal body weight and fasting glucose, olfactory dysfunctions are retained. We conclude that chronic energy imbalance therefore presents long-lasting structural and functional changes in the operation of the sensory system designed to encode external and internal chemical information and leads to altered olfactory- and reward-driven behaviors.

Diet-induced increase in plasma oxidized LDL promotes early fibrosis in a renal porcine auto-transplantation model

BackgroundIn kidney transplantation, the prevalence of hypercholesterolemia as a co-morbidity factor known to affect graft function, is rising due to the increased number of older donors in response to organ shortage as well as to the hyperlipidemic effects of immunosuppressors in recipient. This study aimed to characterize the effects of hypercholesterolemia on renal graft outcome, investigating the role of oxidized low-density lipoprotein (OxLDL).MethodsIn vivo, we used a porcine preclinical model of renal auto-transplantation modulated by two experimental diets: a normal (n = 6) or a hyperlipidemic diet (n = 5) maintained during the 3 month follow-up after the surgical procedure. Kidney function and OxLDL levels were monitored as well as fibrosis, LOX-1 and TGF beta signaling pathways. In vitro, we used human artery endothelial cells subjected to OxLDL to investigate the TGF beta profibrotic pathway and the role of the scavenger receptor LOX-1.ResultsHyperlipidemic diet-induced increase in plasma OxLDL levels at the time of surgery correlated with an increase in proteinuria 3 months after transplantation, associated with an early graft fibrosis combined with an activation of renal TGF beta signaling. These data suggest a direct involvement of OxLDL in the hyperlipidemic diet-induced activation of the pro-fibrotic TGF beta pathway which seems to be activated by LOX-1 signaling. These results were supported by studies with endothelial cells incubated in culture medium containing OxLDL promoting TGF beta expression inhibited by LOX-1 antibody.ConclusionsThese results implicate OxLDL in the hyperlipidemic diet-promoted fibrosis in transplanted kidneys, suggesting LOX-1 as a potential therapeutic target and reinforce the need to control cholesterol levels in kidney transplant recipients.

Cymbopogon citratus Stapf (DC) Extract Ameliorates Atherogenic Cardiovascular Risk in Diabetes-Induced Dyslipidemia in Rats

Aims: Diabetic dyslipidemia is a recognized risk factor for coronary heart disease (CHD). Plant medicinal agents such as Cymbopogon citratus (C. citratus) have shown potential as alternative therapies for reducing cardiovascular risk factors. The aim of this study was to investigate the effect of C. citratus leaf extract on the atherogenic index of plasma (AIP) in diabetic dyslipidemic rats (n=35). Materials and Methods: A C. citratus extract was prepared by ethanol extraction of leaf material. Rats were divided into seven groups (n=5) as follows: (a) Normal diet control, (b) Hyperlipidemic diet (HLD) control, (c) HLD + 65mg/kg streptozotocin (STZ) control (d) HLD + STZ + 250mg/kg C. citratus extract (CCE), (e) HLD + STZ + 500mg/kg CCE, (f) HLD + STZ + 1000mg/kg CCE, and (g) HLD + STZ + 5mg/kg atorvastatin + 600μg/g glibenclamide. Animals were treated with HLD for 14 days and then injected intraperitoneally with 65mg/kg STZ. Confirmed diabetic dyslipidemic animals were treated intragastrically with CCE at doses of 250, 500, and 1000mg/kg, with 5mg/kg atorvastatin, and with 600μg/g glibenclamide for 30 days. Results: The extract, which tested positive for tannins, saponins, alkaloids, flavonoids, etc. lowered fasting blood glucose and glycosylated hemoglobin levels, and doseOriginal Research Article British Journal of Medicine & Medical Research, 4(28): 4695-4709, 2014 4696 dependently decreased the serum levels of T-chol, LDL, VLDL, and β-HMG-CoA reductase, while simultaneously increasing HDL levels. The AIP was lowered in a dosedependent manner by 33, 43.7, and 52.4% in groups treated with 250, 500, and 1000 mg/kg of CCE respectively. Conclusion: The results indicate that the C. citratus extract had an ameliorative effect on hyperglycemia, hyperlipidemia, obesity, and atherogenic index of plasma.

The effects of Corylus Avellana on serum lipid profile and oxidative stress in hyperlipidemic-diabetic rats

Abstract Background and Aim: There is limited evidence suggesting that nuts improve plasma antioxidant potential. The aim of this study is to investigate the effects of hazelnut consumption on serum lipids, atherogenic indexes and oxidant-antioxidant status in hyperlipidemic-diabetic rats. Methods: Wistar-albino rats of both sexes, weighing 200-250 g were used in this study. The group of animals used in this study, which consisted of 32 rats, were divided into 4 groups: control, control + hazelnut, hyperlipidemic-diabetic, hyperlipidemic-diabetic + hazelnut. Each group was fed with control or hyperlipidemic diets with the same amount of hazelnut (0.63%) added for 12 weeks. Diabetes has been induced by streptozotocin (STZ) injection in diabetic groups. Blood glucose, serum lipids, glutathione (GSH), lipid peroxidation (LPO) and atherogenic indexes (AI and AIP) have been evaluated after the experiment was over. Results: In hyperlipidemic-diabetic group atherogenic indexes, LPO and serum lipid levels were found to have increased significantly, whereas HDL-cholesterol (HDL-C) and GSH levels were found to have decreased significantly in comparison with the control group (p < 0.01). Hyperglycemia was also seen to have increased in this group. Impaired antioxidant-oxidant balance was noted to have improved, GSH increased while triglyceride (TG) decreased significantly (p < 0.01). Hazelnut consumption also increased blood GSH levels and atherogenic index levels in the control group. Conclusions: Consumption of hazelnut at this dose (0.63%) may improve oxidant-antioxidant balance in healthy and hyperlipidemic-diabetic status without increasing blood lipids. Keywords: Hazelnut, hyperlipidemia, diabetes, lipids, glutathione, lipid peroxidation.

English

The present study evaluates anti-hyperlipidaemic and anti-atherogenic activities in Triton WR-1339 and high cholesterol diet induced hyperlipidemia in rat models. Chloroform, ethyl acetate and ethanol extracts of whole plant of Blepharis maderaspatensis were evaluated for their anti-hyperlipidaemic and anti-atherogenic activities using Triton WR-1339 induced hyperlipidaemic rats (acute study) and high cholesterol diet induced (chronic study) experimental models. Hyperlipideamia was developed by intraperitonial injection of Triton WR-1339 (200 mg/kg body weight) in acute study and feeding with cholesterol rich diet in chronic study. The animals were divided into various groups and intragastric administration of various extracts of B. maderaspatensis (100 mg/kg) body weight was given in both models. After the completion of the treatment, they were evaluated for serum total cholesterol, triglycerides, high density lipoprotein (HDL), low density lipoprotein (LDL), very low density lipoprotein (VLDL), atherogenic index (AI), coronary risk index (CRI) and were compared with the rats treated with simvastatin (20 mg/kg) of the body weight. Pre-treatment of ethanol extracts of B. maderaspatensis significantly reduced the serum total cholesterol, triglycerides, LDL, VLDL, AI and CRI as comparable with simvastatin. Key words: Serum lipids, atherogenic index, cholesterol diet, coronary risk index, Triton WR-1339, Blepharis maderaspatensis, high cholesterol diet.

Nitric oxide improves molecular imaging of inflammatory atheroma using targeted echogenic immunoliposomes

ObjectiveThis study aimed to demonstrate whether pretreatment with nitric oxide (NO) loaded into echogenic immunoliposomes (ELIP) plus ultrasound, applied before injection of molecularly targeted ELIP can promote penetration of the targeted contrast agent and improve visualization of atheroma components. MethodsELIP were prepared using the pressurization-freeze method. Atherosclerosis was induced in Yucatan miniswine by balloon denudation and a hyperlipidemic diet. The animals were randomized to receive anti-intercellular adhesion molecule-1 (ICAM-1) ELIP or immunoglobulin (IgG)-ELIP, and were subdivided to receive pretreatment with standard ELIP plus ultrasound, NO-loaded ELIP, or NO-loaded ELIP plus ultrasound. Intravascular ultrasound (IVUS) data were collected before and after treatment. ResultsPretreatment with standard ELIP plus ultrasound or NO-loaded ELIP without ultrasound resulted in 9.2 ± 0.7% and 9.2 ± 0.8% increase in mean gray scale values, respectively, compared to baseline (p < 0.001 vs. control). Pretreatment with NO-loaded ELIP plus ultrasound activation resulted in a further increase in highlighting with a change in mean gray scale value to 14.7 ± 1.0% compared to baseline (p < 0.001 vs. control). These differences were best appreciated when acoustic backscatter data values (RF signal) were used [22.7 ± 2.0% and 22.4 ± 2.2% increase in RF signals for pretreatment with standard ELIP plus ultrasound and NO-loaded ELIP without ultrasound respectively (p < 0.001 vs. control), and 40.0 ± 2.9% increase in RF signal for pretreatment with NO-loaded ELIP plus ultrasound (p < 0.001 vs. control)]. ConclusionNO-loaded ELIP plus ultrasound activation can facilitate anti-ICAM-1 conjugated ELIP delivery to inflammatory components in the arterial wall. This NO pretreatment strategy has potential to improve targeted molecular imaging of atheroma for eventual true tailored and personalized management of cardiovascular diseases.

Influence of integral and decaffeinated coffee brews on metabolic parameters of rats fed with hiperlipidemic diets

The objective of this study was to evaluate the inf luence of integral and decaffeinated coffee brews (arabica L and C. canephora Pierre) on the metabolic paramet ers of rats fed with hyperlipidemic diet. Thirty ma le Wistar rats (initial weight of 270 g ± 20 g) were used in the study, which were divided into six groups five each. The treatments were normal diet, hyperlipidemic diet, h yperlipidemic diet associated with integral coffee arabica or canephora brews (7.2 mL/kg/day) and hyperlipidemic diet associated to decaffeinated arabica, or caneph ora brews, using the same dosage. After 41 days, performance a nalyses were conducted.The rats were then euthanize d and the carcasses were used for the analysis of dried ether extract and crude protein. Fractions of adipose ti ssue were processed for histological analysis. There was a re duction in weight gain and accumulation of lipids i n the carcasses, lower diameter of adipocytes and a lower relative weight of the liver and kidneys of rats fwith hyperlipidemic diet associated with integral coffee brew. Integral coffee brew reduced the obesity in the rats receiving hyperlipidemic diet, but the same effect did not occur with the decaffeinated types.

Increased Tau Phosphorylation and Impaired Brain Insulin/IGF Signaling in Mice Fed a High Fat/High Cholesterol Diet

Previous studies demonstrated that a high fat/high cholesterol (HFC) diet results in a loss of working memory in mice correlated with neuroinflammatory changes and increased AβPP processing (Thirumangalakudi et al. (2008) J Neurochem 106, 475-485). To further explore the nature of the molecular correlates of cognitive impairment, in this study, we examined changes in tau phosphorylation, insulin/IGF-1 signaling (IIS) including GSK3, and levels of specific synaptic proteins. Immunoblot analysis of hippocampal tissue from C57BL/6 mice fed HFC for 2 months with anti-phospho-tau (i.e., PHF1 and phospho-Thr-231 tau) antibodies demonstrated the presence of hyperphosphorylated tau. The tau phosphorylation correlated with activated GSK3, a prominent tau kinase normally kept inactive under the control of IIS. That IIS itself was impaired due to the hyperlipidemic diet was confirmed by a down-regulation of insulin receptor substrate-1 and phospho-Akt levels. Although no significant changes in the levels of the pre-synaptic protein (i.e., synaptophysin) in response to HFC were apparent in immunoblot analysis, there was a clear down-regulation of the post-synaptic protein, PSD95, and drebrin, a dendritic spine-specific protein, indicative of altered synaptic plasticity. The results, in concert with previous findings with the same model, suggest that high dietary fat/cholesterol elicits brain insulin resistance and altered IIS leading to Alzheimer's disease-like cognitive impairment in 'normal' mice.

Anti-atherosclerotic Potential of Achyranthes aspera Husk and its Crude Saponins in Experimental Rats

Achyranthes aspera L. (Amaranthaceae) is used traditionally in Indian system of medicine as diuretic, astringent, purgative, anticancer, dropsy, piles, and skin eruptions. To explore anti-atherosclerotic potential of crude saponins and ethanol extract of A. aspera seeds husk on hyperlipidemic diet induced rats model was used to increase the lipid profile. After 2 weeks, all the animals showed symptoms of hyperlipidemia and were treated with 100, 200 and 400 mg/kg ethanol extract (EE) respectively, while saponins (SAPN) at a dose of 10 mg/kg by gavage for 28 days. Serum total cholesterol (TC), triglyceride (TG), low density lipoprotein (LDL), high density lipoprotein (HDL), serum glucose and atherogenic index (A.I.) level were estimated on 0th, 14th and 42th day by using autoanalyser. EE of husks decreases TC 40.71-46.77 %, TG 23.95-37.27 %, LDL 56.49-65.50 %, serum glucose 17.48-25.54 % and A.I. 51.27-77.05 % significantly (P < 0.01). SAPN (10 mg/kg bodyweight) decreased TC, TG, LDL, glucose and A.I. by 48.21 %, 29.47 %, 72.26 %, 21.23 % and 82.29 % respectively (P < 0.01). EE and SAPN increased HDL level significantly (P < 0.01). The findings of the present work indicate the reversal of elevated A.I., TC, TG, LDL, serum glucose and AI level significantly associated with atherosclerosis.

Fibroblast Growth Factor Inducible (Fn14)-specific Antibodies Concomitantly Display Signaling Pathway-specific Agonistic and Antagonistic Activity

Fn14 is a therapeutic target in various diseases. Anti-Fn14 antibodies activate the alternative NFκB pathway but not other Fn14-related activities induced by soluble or membrane-bound TWEAK. FcγR-bound anti-Fn14 antibodies, however, activate the full spectrum of Fn14-associated activities. Anti-Fn14 antibodies elicit agonistic activities differing from those of the natural Fn14 ligand TWEAK. These findings influence the rationale of designing Fn14-targeted therapies. The Fn14-specific monoclonal antibodies PDL192 and P4A8, which are under consideration in clinical trials, showed no agonistic activity with respect to IL8 production and cell death induction. However, oligomerization with protein G or binding to Fcγ receptors converted both anti-Fn14 antibodies into potent agonists. TNF-like weak inducer of apoptosis (TWEAK), the ligand of Fn14, occurs naturally in two forms with partly different signaling capabilities, as a membrane-bound ligand and as a soluble trimeric molecule. Although membrane TWEAK strongly triggers all Fn14-associated pathways, soluble TWEAK predominately triggers the alternative nuclear factor κB (NFκB) pathway and enhances TNF-induced cell death but has only a poor effect on the classical NFκB pathway and chemokine production. Thus, the oligomerized and FcγR-bound anti-Fn14 mAbs mimicked the activity of membrane TWEAK. Notably, both anti-Fn14 antibodies significantly triggered p100 processing, the hallmark of the alternative NFκB pathway, and therefore resembled soluble TWEAK. In contrast to the latter, however, the anti-Fn14s showed no effect on TNF receptor 1-induced cell death and P4A8 even blocked the corresponding TWEAK response. Thus, we showed that Fn14 antibodies display an alternative NFκB pathway-specific agonistic activity but fail to phenocopy other activities of soluble TWEAK, whereas oligomerized or FcγR-bound Fn14 antibodies fully mimic the activity of membrane TWEAK. In view of the trivalent nature of the TWEAK-Fn14 interaction, this suggests that the alternative NFκB pathway is uniquely responsive already to Fn14 dimerization enabling antibodies to elicit an unnatural response pattern distinct from that of the naturally occurring Fn14 ligands.

Abstract 151: Thrombosis Prone Plaques Exhibit Inflammation Prior to Rupture: Intravascular Detection via Macrophage-targeted Optical Imaging

Introduction Inflammation modulates atherogenesis and the destabilization of plaques. However, the role of macrophages in plaque rupture is incompletely understood. Here we investigated the in vivo spatial distribution of plaque macrophages prior to triggered plaque rupture, using intravascular molecular imaging and a near-infrared fluorescence (NIRF) macrophage targeted agent, CLIO-CyAm7. We hypothesized that CLIO-CyAm7 would illuminate macrophages in vivo and preferentially localize to plaques that are vulnerable to plaque rupture. Methods Atherosclerosis was induced in rabbits (n=14) using a 12-week hyperlipidemic diet with alternating 1% high cholesterol and normal chow, concomitant with aortic balloon injury at 2 weeks. Rabbits were injected with 2.5mg/kg (n=8) or 5mg/kg (n=6) of CLIO-CyAm7 at 24 or 48 hours, respectively, prior to thrombosis triggering using Russell’s Viper Venom and histamine over 48 hours. The 2.5mg/kg subgroup was imaged in vivo using NIRF imaging and intravascular ultrasound (IVUS), immediately prior to thrombosis triggering. After sacrifice, ex vivo imaging, fluorescence microscopy (FM), Carstairs and Ram-11 immunostaining were performed. Results FM identified significantly higher CLIO-CyAm7 signal in areas of atherosclerosis compared to normal segments of the aorta (2.5mg/kg and 5.0mg/kg, p=0.03 and p=0.03). This signal was primarily localized at the intimal-luminal border of atheroma, with some penetration in the media and adventitia. CLIO-CyAm7 colocalized with a subset of superficial macrophages. Carstairs staining identified fibrin-rich thrombi, indicating plaque rupture in 6 of 14 rabbits (43%). There was increased CLIO-CyAm7 in areas underlying thrombus and particularly at the shoulder of ruptured plaques. Plaque macrophages were detectable via in vivo intravascular NIRF imaging. Areas of atherosclerosis, determined by IVUS, showed significantly higher NIRF peak signal-to-noise ratio than normal segments of the aorta (40.2±16.9 and 5.9±1.9, p=0.02). Conclusion Macrophages are consistently present in plaques that undergo triggered rupture, and can be detected via CLIO-CyAm7 intravascular NIRF molecular imaging. In vivo macrophage imaging may identify thrombosis-prone plaques.

Hypolipidemic Activity of Okra is Mediated Through Inhibition of Lipogenesis and Upregulation of Cholesterol Degradation

Little is known about the hypolipidemic activity of okra; therefore, we investigated the hypolipidemic activity of okra and its interaction with gene expression of several key components involved in lipid homeostasis. Male C57BL/6 mice were randomly divided into three groups and fed with hyperlipidemic diet or two hyperlipidemic diets supplemented with 1% or 2% okra powder for eight weeks. Results demonstrated that okra dose-dependently decreased serum and hepatic total cholesterol and triglyceride, and enhanced fecal excretion of bile acids. Gene expression analysis revealed that okra upregulated cholesterol 7α-hydroxylase (CYP7A1) expression, downregulated expression of sterol regulatory element-binding protein 1c (SREBP1c) and fatty acid synthase (FAS), with no effect on sterol regulatory element-binding protein 2 (SREBP2), 3-hydroxy-3-methylglutaryl-CoA reductase (HMGR), low-density lipoprotein receptor (LDLR) and carnitine palmitoyltransferase-1A (CPT1A). It was suggested that hypolipidemic activity of okra was mediated most likely by upregulation of cholesterol degradation through CYP7A1 and by inhibition of lipogenesis through SREBP1c and FAS. Okra raw and fractionated polysaccharide showed strong bile acid binding capacity in vitro, which may contribute to the hypolipidemic activity observed. In conclusion, okra has potential application in the management of hyperlipidemia and its associated metabolic disorders.

2,3,4′,5-Tetrahydroxystilbene-2-O-β-D-glucoside Suppresses Expression of Adhesion Molecules in Aortic Wall of Dietary Atherosclerotic Rats and Promonocytic U937 Cells

We sought to investigate whether TSG suppressed the ICAM-1/VCAM-1 expression in dietary atherosclerotic rats and in Ox-LDL-induced U937 cells. For this purpose, 60 male Sprague-Dawley rats were randomly-and-equally divided into six groups. Atherosclerosis was induced by feeding rats a hyperlipidemic diet. TSG (120, 60 or 30 mg/kg/day) was administered by oral gavage. Simvastatin (2 mg/kg/day) was administered as positive control whereas physiological saline (0.9% NaCl) served as untreated control. After 12 weeks, rats were euthanized by ethyl carbonate (1,200 mg/kg) and aortic wall samples were collected. Besides, U937 cells were stimulated for 48 h by Ox-LDL (80 μg/mL) with and without TSG (120, 60, 30 μg/L) or simvastatin (100 μg/L). ICAM-1/VCAM-1 mRNA expression was determined by RT-PCR and protein expression was detected by immunohistochemistry and/or western blotting. The data show that ICAM-1/VCAM-1 mRNA/protein expression was significantly enhanced in atherosclerotic aortas compared with normal diet group. Ox-LDL-induced ICAM-1/VCAM-1 mRNA/protein expression in U937 cells. Importantly, TSG significantly inhibited ICAM-1/VCAM-1 expression in atherosclerotic aortas in a dose-dependent manner. TSG-pretreatment also inhibited ICAM-1/VCAM-1 expression in Ox-LDL-induced U937 cells. Therefore, we concluded that TSG suppressed the expression of adhesion (ICAM-1/VCAM-1) molecules both in vivo (in aortic wall of dietary atherosclerotic rats) and in vitro (U937 cells).

Modulation of cytochrome P450 enzymes in response to continuous or intermittent high-fat diet in pigs

1. To date, no information has been available on the modulation of cytochrome P450 enzymes (CYPs) following the administration of a hyperlipidemic diet in pigs.2. We investigated the potential modulation of xenobiotic-metabolizing CYPs in liver, heart and duodenum of pigs subjected to a high-fat/high-cholesterol diet for 2 months continuously (C-HFD) or on alternate weeks (A-HFD).3. The administration of the high-fat diet resulted in considerably increased plasma cholesterol levels although the animals were still able to manage the lipid overload efficiently, and no sign of effective tissue inflammation occurred in livers. Plasma lipid profile and liver histology indicated a better adaptive response of the A-HFD pigs compared to the C-HFD group. We showed a post-transcriptional induction of hepatic CYP2E1 activity in C-HFD pigs and a transcriptional induction of hepatic CYP3As – especially in the A-HFD group. No further CYP modulation was observed in either liver or extra-hepatic tissues.4. In conclusion, the administration of a high-fat diet in pigs resulted in limited effects on the drug metabolism system. The better adaptive response of A-HFD pigs compared to C-HFD pigs is a very interesting observation since the intermittent administration of the diet reflects the mode of human behavior more closely.

Hypolipidemic effects of lactic acid bacteria fermented cereal in rats.

BackgroundThe objectives of the present study were to investigate the efficacy of the mixed culture of Lactobacillus acidophilus (DSM 20242), Bifidobacterium bifidum (DSM 20082) and Lactobacillus helveticus (CK60) in the fermentation of maize and the evaluation of the effect of the fermented meal on the lipid profile of rats.MethodsRats were randomly assigned to 3 groups and each group placed on a Diet A (high fat diet into which a maize meal fermented with a mixed culture of Lb acidophilus (DSM 20242), B bifidum (DSM 20082) and Lb helveticus (CK 60) was incorporated), B (unfermented high fat diet) or C (commercial rat chow) respectively after the first group of 7 rats randomly selected were sacrificed to obtain the baseline data. Thereafter 7 rats each from the experimental and control groups were sacrificed weekly for 4 weeks and the plasma, erythrocytes, lipoproteins and organs of the rats were assessed for cholesterol, triglyceride and phospholipids.ResultsOur results revealed that the mixed culture of Lb acidophilus (DSM 20242), B bifidum (DSM 20082) and Lb helveticus (CK 60) were able to grow and ferment maize meal into ‘ogi’ of acceptable flavour. In addition to plasma and hepatic hypercholesterolemia and hypertriglyceridemia, phospholipidosis in plasma, as well as cholesterogenesis, triglyceride constipation and phospholipidosis in extra-hepatic tissues characterized the consumption of unfermented hyperlipidemic diets. However, feeding the animals with the fermented maize diet reversed the dyslipidemia.ConclusionThe findings of this study indicate that consumption of mixed culture lactic acid bacteria (Lb acidophilus (DSM 20242), Bifidobacterium bifidum (DSM 20082) and Lb helveticus (CK 60) fermented food results in the inhibition of fat absorption. It also inhibits the activity of HMG CoA reductase. This inhibition may be by feedback inhibition or repression of the transcription of the gene encoding the enzyme via activation of the sterol regulatory element binding protein (SREBP) transcription factor. It is also possible that consumption of fermented food enhances conversion of cholesterol to bile acids by activating cholesterol-7α-hydroxylase.