Normolipidaemic Activity of Liposomal-Encapsulated Superoxide Dismutase in Rats

To determine the regulatory effects of superoxide dismutase (SOD) on lipid metabolism a simple model of hyperlipidaemia induced by a hypercholesterolaemic (HCT) diet in rat was used. In animals fed a HCT diet, triglyceride (TG) were increased by 126%, total cholesterol (TCT) by 40%, very low density lipoprotein (VLDL) by 124% and the TCT/HDL ratio by 82%. The procedure would therefore appear to model some of the risk factors of atherogenesis.

In animals fed a hypercholesterolemic diet, liposomal Cu-SOD (200μg/kg i. m. every two days; 1000 μg/kg i. m./day) decreased TG by 29 and 49%, TCT by 14 and 36%, TCT/HDL ratio by 32 and 60%, VLDL by 52 and 55% respectively and increased high density lipoprotein cholesterol (HDL-C) by 17 and 46% respectively.

The present experiments show therefore that the administration of liposomal SOD has a marked effect on lipid parameters (particularly TCT and TG) and might therefore reduce the atherogenic risk by increasing HDL and decreasing VLDL and cholesterol atherogenicity ratio (CAR).     

Cardiovascular disease in the JCR:LA-cp rat

The JCR:LA-cp rat is one of a number of strains that carry the mutant autosomal recessive cp gene. Animals, of all strains, that are homozygous, for the gene (cp/cp) become obese, insulin resistant, and hypertriglyceridemic. Heterozygotes or homozygous normal rats (+/+)are lean and metabolically normal. The JCR:LA-cp rat is unique in the development of a frank vasculopathy with atherosclerotic lesions and associated ischemic myocardial lesions. The cardiovascular disease is strongly correlated with the hyperinsulinemia, which develops as the animals mature from 4 to 8 weeks of age. The hyperinsulinemia can be decreased by marked food restriction, ethanol consumption, or reduction of the postprandial glucose and insulin responses through the use of a-glucosidase inhibitors. Any treatment that reduces plasma insulin levels is associated with a reduction in cardiovascular disease. In contrast, a reduction in plasma triglyceride concentrations, alone, has no effect on end-stage lesions. JCR:LA-cp rats, particularly those that are cp/cp, are, however, sensitive to cholesterol in the diet, unlike other strains that are highly resistant. Further, the rats have abnormal vascular smooth muscle cells that, especially in the cp/cp animals, are hyperplastic and activated and migrate into the intimal space. Our findings suggest that susceptibility to cardiovascular disease requires hypermsulinemic stress coupled with excessive dietary intake and the presence of one or more other necessary, but not sufficient, genetic factors. One of these may be a genetic abnormality of vascular smooth muscle cells. A similar situation may occur in humans.     

Responses of Serum Lipids and Adipose Tissue Lipases to Lipopolysaccharide Administration in Normal and Hepatoma-bearing Rats

The effects of in vivo lipopolysaccharide administration on serum lipid metabolism were studied in normal and hepatoma-bearing rats. Changes in serum lipid levels and adipose tissue lipase (lipoprotein lipase and hormone-sensitive lipase) activities following injection of lipopolysaccharide into normal rats resembled those in hepatoma- bearing rats. These results suggest the presence of some common factor(s) involved in the incidence of abnormal lipid metabolism upon lipopolysaccharide injection and hepatoma transplantation.     

Transgenic mice express human MPO -463G/A alleles at atherosclerotic lesions, developing hyperlipidemia and obesity in -463G males

Myeloperoxidase (MPO) is an oxidant-generating enzyme present in macrophages at atherosclerotic lesions and implicated in coronary artery disease (CAD). Although mouse models are important for investigating the role of MPO in atherosclerosis, neither mouse MPO nor its oxidation products are detected in lesions in murine models. To circumvent this problem, we generated transgenic mice expressing two functionally different human MPO alleles, with either G or A at position -463, and crossed these to the LDL receptor-deficient (LDLR(-/-)) mouse. The -463G allele is linked to higher MPO expression and increased CAD incidence in humans. Both MPO alleles were expressed in a subset of lesions in high-fat-fed LDLR(-/-) mice, notably at necrotic lesions with cholesterol clefts. MPOG-expressing LDLR(-/-) males (but not females) developed significantly higher serum cholesterol, triglycerides, and glucose, all correlating with increased weight gain/obesity, implicating MPO in lipid homeostasis. The MPOG- and MPOA-expressing LDLR(-/-) males also exhibited significantly larger aortic lesions than control LDLR(-/-) males. The human MPO transgenic model will facilitate studies of MPO involvement in atherosclerosis and lipid homeostasis.     

The human apoE7 and apoE4 transgenic mice models

To scrutinize the disorders caused by human mutant apoE7/apoE4, human apoE4 and E7 transgenic mice were established with microinjection technique to examine molecular genetic phenomena in vivo. The integration and expression of h-apoE mutant genes in transgenic mice were determined with Southern blot, Northern blot and ELISA. The current studies indicated that the transgenes and the phenotypes regarding expression of transgenes could be transmitted stably in transgenic lines. The levels of serum lipid in transgenic mice showed the characteristics of hyperlipidemia. Besides, behavior tests demonstrated the degeneration of learning and memory in transgenic mice. Short life span was observed in 2 transgenic lines. After fed with high lipid food high serum lipid was found both in normal and transgenic mice, but their mechanism regulating lipid metabolism was different. It was also verified that the human apoE mutants located at either N-terminal or C-terminal had the same pathogenesis regarding disorders of     

The effect of dietary copper on rat plasma apolipoprotein B,E plasma levels,and apolipoprotein gene expression in liver and intestine

The plasma levels of apo B and apo E, and the level of hepatic and intestinal mRNA coding for these apolipoproteins were investigated in weanling male rats pair-fed for 6 wk with a control or copperdeficient diet. Plasma cholesterol, triglycerides, and phospholipids were significantly increased, and plasma apo B and apo E levels were also markedly increased in copper-deficient rats as compared to control rats. Copper deficiency significantly increased triglyceride levels and decreased cholesterol levels in the liver. No major differences in the levels of hepatic and intestinal apo B and apo E mRNA occurred between control and copper-deficient rats. These data imply that hypertriglyceridemia dn hypercholesterolemia owing to the copper deficiency are not accompanied by modifications in the gene expression at the mRNA level in the liver and intestine of the apolipoproteins studied.     

Chronopharmacology of simvastatin on hyperlipidaemia in high‐fat diet‐fed obese mice

The chronopharmacology refers to the utilization of physiological circadian rhythms to optimize the administration time of drugs, thus increasing their efficacy and safety, or reducing adverse effects. Simvastatin is one of the most widely prescribed drugs for the treatment of hypercholesterolaemia, hyperlipidemia and coronary artery disease. There are conflicting statements regarding the timing of simvastatin administration, and convincing experimental evidence remains unavailable. Thus, we aimed to examine whether different administration times would influence the efficacy of simvastatin. High‐fat diet‐fed mice were treated with simvastatin at zeitgeber time 1 (ZT1) or ZT13, respectively, for nine weeks. Simvastatin showed robust anti‐hypercholesterolaemia and anti‐hyperlipidemia effects on these obese mice, regardless of administration time. However, simvastatin administrated at ZT13, compared to ZT1, was more functional for decreasing serum levels of total cholesterol, triglycerides, non‐esterified free fatty acids and LDL cholesterol, as well as improving liver pathological characteristics. In terms of possible mechanisms, we found that simvastatin did not alter the expression of hepatic circadian clock gene in vivo, although it failed to change the period, phase and amplitude of oscillation patterns in Per2::Luc U2OS and Bmal1::Luc U2OS cells in vitro. In contrast, simvastatin regulated the expression of Hmgcr, Mdr1 and Slco2b1 in a circadian manner, which potentially contributed to the chronopharmacological function of the drug. Taken together, we provide solid evidence to suggest that different administration times affect the lipid‐lowering effects of simvastatin.     

Antidiabetic properties of aqueous and methanol extracts from the trunk bark of Ceiba pentandra in type 2 diabetic rat

The type 2 diabetes is one of the major global health issues that affects millions of people. This study evaluated the antidiabetic activity of aqueous extracts (AECP) and methanol extracts (MECP) from Ceiba pentandra trunk bark on an experimental model of type 2 diabetes (T2D). This model was induced in rats by the combination of a high-fat diet (HFD) and a single dose of streptozotocin (40 mg/kg, intraperitoneal) at the seventh day of experimentation. Diabetes was confirmed on day 10 by fasting blood glucose more than or equal to 200 mg/dL. Diabetic animals still under HFD were treated orally and twice daily, with MECP and AECP (75 and 150 mg/kg) or metformin (40 mg/kg) for 14 days. During the experiment, blood glucose and animal weights were determined. Oral glucose tolerance test was performed on day 15, followed by animals sacrifice for blood, liver, and pancreas collection. Total cholesterol and triglyceride levels were evaluated in plasma, whereas malondialdehyde (MDA), glutathione (GSH), superoxide dismutase, and catalase were quantified in tissue homogenates. AECP and MECP significantly reduced the hyperglycemia by up to 62% and significantly improved the oral glucose tolerance test. The impaired levels of cholesterol and triglycerides registered in diabetic control were significantly reversed by both extracts at all the doses used. Alterations in diabetic pancreas weight, GSH, and MDA were also significantly reversed by plant extracts. AECP and MECP possess type 2 antidiabetic effects that could result from their ability to improve the peripheral use of glucose, lipid metabolism or from their capacity to reduce oxidative stress. These finding provide a new avenue for better control and management of early or advanced T2D.