CHILD syndrome: successful treatment of skin lesions with topical lovastatin and cholesterol lotion

Abstract: CHILD syndrome (Congenital Hemidysplasia, Ichthyosiform erythroderma, Limb Defects) is a rare X-linked dominant disease. The authors report a 2-month-old patient presenting with typical features of CHILD syndrome that was treated with a topical solution containing cholesterol and lovastatin, with complete clearance of her CHILD nevus. The changes in skin lipid metabolism that explain the CHILD ichthyosiform nevus and their correction through topical application of cholesterol and lovastatin are discussed.

Molecular regulation of cholesterol metabolism: HDL-based intervention through drugs and diet.

The overloading of cholesterol in the arteries remains the principal cause of cardiovascular diseases. Since available anti-cholesterolemic drugs are not completely effective and have several severe adverse effects, the aim of this review is to analyze current research focused on the emerging, innovative therapeutic strategies based on both pharmacological and nutritional interventions to control cholesterol metabolism. Pharmacological interventions mainly involve the use of molecules capable of interfering with high-density lipoprotien (HDL) metabolism and the reverse cholesterol transport (RCT) through genetic control of apolipoprotein A-I (ApoA-I), agonism at liver X-receptor a (LXRa), or inhibition of cholesteryl ester transport protein (CETP), scavenger receptor BI(SR-BI), and ecto F0F1ATPase/synthase. Nutritional interventions are based on the use of fibres, phytosterols, and probiotics acting through interference with absorption and re-absorption of cholesterol by enterocyte and hepatocyte specific transporters, thus influencing RCT final step. The search for new drugs is still at the very beginning and new molecules are not yet ready to enter clinical use. However, several promising findings coming from innovative biotechnological research are expected shortly to produce probiotics, fibres, and phytosterols to be used as therapeutic tools. Among the most important advantages of natural products in respect to traditional drugs are the lack of severe adverse effects and their low cost.

Dietary cholesterol and estrogen administration elevate brain apolipoprotein E in mice by different mechanisms.

Apolipoprotein (apo) E plays an important role in the whole body cholesterol homeostasis. Recent studies suggest that it may also be involved in the local cholesterol transport in the brain, and influence the pathogenesis of Alzheimer's disease (AD) by interacting with the beta-amyloid protein and brain lipoprotein receptors. Since apoE expression is highest in the brain, next only to the liver and associated with the pathogenesis of AD, we hypothesized that dietary and hormonal intervention, known to regulate hepatic apoE expression may also regulate brain apoE and thereby influence local cholesterol transport. To test this hypothesis, groups of male C57BL mice were fed either regular rodent chow or high fat (HF) and high cholesterol enriched diet for 3 weeks. In a separate study, groups of male mice were administered pharmacological doses of 17-beta estradiol for 5 consecutive days and sacrificed on the 6th day. As expected, HF diet elevated liver apoE mRNA and apoE synthesis. Similar to liver, brain apoE mRNA and synthesis also increased, following HF feeding. Estradiol administration increased liver apoE synthesis without affecting apoE mRNA. Interestingly, estradiol administration also increased the brain apoE synthesis, but without altering the brain apoE mRNA. These studies suggested that dietary cholesterol and estrogen administration elevated the brain apoE by different mechanisms.

Cholesterol-lowering effect of organosulphur compounds from garlic: a possible mechanism of action.

OBJECTIVES: Hyperlipidemia constitutes a major etiopathological factor for atherosclerosis. The medicinal value of garlic is best known for its lipid lowering effects and antiatherogenic effects. The mechanism by which lipid soluble organosulphur compounds from garlic reduce plasma lipids has not been fully investigated. The author had previously shown that the hepatic activity of beta-hydroxy-beta-methylglutaryl-CoA (HMG-CoA) reductase, the rate limiting enzyme in cholesterol biosynthesis and the incorporation of radiolabeled (1, 2 14C), acetate into hepatic free and esterified cholesterol was significantly decreased in rat treated with garlic derived organosulphur compounds. We hypothesised that the antiatherogenic effect of the organosulphur compounds may be attributed to the formation of protein internal disulphide and thus inactivation of thiol (-SH) group enzymes such as HMG-CoA reductase and the multienzyme complex of fatty acid synthesis. The objective of the present study is to elucidate the inhibitory mechanism by in vitro studies. METHOD: Lipid soluble organosulphur compounds from garlic were treated in vitro with Luke's cysteine reagent (representing the thiol (-SH) group of enzymes) and the interaction products were separated by paper chromatography. RESULT: The result indicated that the organosulphur compounds were capable of interacting with the thiol (-SH) group of cysteine and thus forming cysteine derivatives. CONCLUSION: The antiatherogenic effects of these organosulphur compounds can be attributed to such reactions that inhibit HMG-CoA reductase and other lipogenic enzymes. The anticarcinogenic effects of these compounds may also be due to inhibitory reactions on enzymes that activate carcinogens.

Intestinal cholesterol synthesis and mobilisation to blood in sucrose-feeding and alcohol-intake.

Small intestines synthesize cholesterol to a greater extent than liver. Between starch-fed and sucrose-fed rats, using (14C) glucose, it was found that the synthesis of cholesterol by the jejunum of small intestines was greater in the sucrose-fed group than starch-fed group. By a novel experimental technique and using (14C) glucose, it was found that the contribution towards buffer representing lymph was greater in the sucrose-fed group (13.3%) than the controls (11%). Hypercholesterolemia on sucrose feeding may be at least partly due to contribution by the small intestines. Regarding alcohol, using (14C) glucose it was found that total synthesis of cholesterol by the small intestines was decreased in alcohol-fed rats. There was no difference in the cholesterol retained by the intestinal tissue between the controls and alcohol-fed animals while, the secretion towards buffer (lymph) was 9% as against 11. This indicates that there is contribution of cholesterol to blood from small intestines in alcohol-intake also but due to overall decrease in the intestinal synthesis of cholesterol, contribution of intestines to hypercholesterolemia may not be substantial as in the case of sucrose feeding. This is because in sucrose-feeding there is increased cholesterol synthesis.

Protective effect of policosanol on atherosclerotic lesions in rabbits with exogenous hypercholesterolemia

Policosanol is a mixture of higher aliphatic alcohols purified from sugar cane wax, with cholesterol-lowering effects demonstrable in experimental models and in patients with type II hypercholesterolemia. The protective effects of policosanol on atherosclerotic lesions experimentally induced by lipofundin in rabbits and rats and spontaneously developed in stumptail monkeys have been described. The present study was conducted to determine whether policosanol administered orally to rabbits with exogenous hypercholesterolemia also protects against the development of atherosclerotic lesions. Male New Zealand rabbits weighing 1.5 to 2 kg were randomly divided into three experimental groups which received 25 or 200 mg/kg policosanol (N = 7) orally for 60 days with acacia gum as vehicle or acacia gum alone (control group, N = 9). All animals received a cholesterol-rich diet (0.5 percent) during the entire period. Control animals developed marked hypercholesterolemia, macroscopic lesions and arterial intimal thickening. Intima thickness was significantly less (32.5 +/- 7 and 25.4 +/- 4 µm) in hypercholesterolemic rabbits treated with policosanol than in controls (57.6 +/- 9 µm). In most policosanol-treated animals, atherosclerotic lesions were not present, and in others, thickness of fatty streaks had less foam cell layers than in controls. We conclude that policosanol has a protective effect on the atherosclerotic lesions occurring in this experimental model.

Cholesterol gallstone formation: supersaturation, nucleation and gallbladder motility

Os autores revisam os fatores envolvidos na formaçäo dos calculos de colesterol da vesicula biliar: supersaturacao biliar de colesterol, nucleaçäo e formaçäo dos cristais de colesterol e hipomotilidade vesicular

Pathophysiology of cholesterol gallstone disease

The purpose of the present paper is to review the current knowledge about cholesterol gallstone disease. It is generally accepted that the formation of cholesterol gallstone requires three major pathogenic defect, namely, supersaturation, nucleation and crystal growth as well as disorder of gallbladder motility. The supersaturation is necessary but not sufficient to explain stone formation. It has been suggested that nucleation is the key factor for gallstone formation. However, those three factors are necessary for the formation of cholesterol gallstones, and the presence of just one or two factor does not lead to stones. We also touch briefly on the results form studies performed in Mexico in this area

Effect of policosanol on the hepatic cholesterol biosynthesis of normocholesterolemic rats

We have suggested previously, measuring 14C-acetate incorporation into free cholesterol, that oral administration of policosanol inhibits hepatic cholesterol biosynthesis in rats. Nevertheless, since acetate has limitations to study cholesterol synthesis in vivo, we now investigate rates of incorporation of labeled water into hepatic sterol after policosanol treatment. Absolute rates of incorporation of 3H-water in sterols were depressed by policosanol by about 20 percent, giving a more accurate degree of cholesterol biosynthesis inhibition in this species. Since policosanol did not inhibit labeled mevalonate incorporation into cholesterol in rat liver, we also studied the effect of policosanol on hydroxy-methylglutaryl-coenzyme A (HMG-CoA) reductase. Reductase activity assayed in microsomes treated with policosanol remained unchanged, suggesting that cholesterol synthesis is not inhibited by a direct action of policosanol on this enzyme

Policosanol inhibits cholesterol biosynthesis and enhances low density lipoprotein processing in cultured human fibroblasts

Policosanol is a mixture of aliphatic primary alcohols isolated and purified from sugar cane wax, that induces cholesterol-lowering effects in experimental models and human beings. When human lung fibroblasts were incubated with policosanol for 48 hours prior to the experiment, a dose dependent inhibition of 14C-acetate incorporation into total cholesterol was observed, whereas labeled mevalonate incorporation was not inhibited. Even when cholesterol synthesis was not strongly inhibited, low density lipoprotein (LDL) processing was markedly enhanced. Thus, LDL binding, internalization and degradation were significantly increased after policosanol treatment. In addition, despite the fact that'cholesterol generation was not inhibited at the lowest dose of policosanol assayed, LDL processing was significantly increased. The current data indicate that policosanol inhibits cholesterol synthesis at the earliest steps of the cholesterol biosynthetic pathway. On the other hand, this study suggests that the increase in LDL processing may be partially explained by the inhibition of cholesterol biosynthesis, even though an sterol-independent mechanism might be responsible for the enhancement of LDL-receptor activity

Effect of antimicrobials on cholesterol synthesis and content in liver and small intestines.

The antimicrobials tetracycline, ampicillin and bactrim (cotrimoxazole) decreased HMG CoA reductase activity in liver and small intestines of albino rats. Diminished incorporation of 1, 2, 14C acetate into cholesterol of small intestines in bactrim group was noted. There was a significant fall in cholesterol content of liver, duodenum, jejunum and ileum of the bactrim group and jejunum only in tetracycline group.

Medium composition influencing single cell protein and cholesterol production by saccharomyces cerevisiae var carlsbergensis

Sugarcane molasses was found to be good carbon source for growth and production of single cell protein [SCP] by Saccharomyces cerevisiae var. carlsbergensis. Appreciable SCP yield was attained in the presence of molasses at 1 percent sugar concentration, whereas 5 percent was coupled with a good growth and minimal cholesterol content. The addition of 0.5 percent urea as a nitrogen source allowed better fermentation yield and suppressed cholesterol production. Further improvement of biomass and SCP production was achieved on adding 0.3 percent KH[2] PO[4] and 0.15 percent Mg SO[4]. 7H[2]O to the molasses medium. The comparative analysis of yeast cells grown on the synthetic [Phaff] medium with that grown on optimized molasses medium revealed a percentage increase in the later case of 415 percent SCP content, 527 percent peptides, 1018 percent amino acids, 201 percent ammonia, 394 percent total soluble nitrogen, 394 percent total nitrogen and 522 percent in dry weight gain. The cholesterol content decreased by 40 percent on molasses medium