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LE Magazine August 2002



Plasma level of homocysteine is inversely-associated with the development of collateral circulation in patients with single-vessel coronary artery disease.

Homocysteine induces endothelial injury and inhibits endothelial cell proliferation, which is a key role in angiogenesis. The purpose of this study was to investigate whether the plasma level of homocysteine is associated with the development of collaterals in patients with single-vessel coronary artery disease (CAD). Among a series of 105 male patients with angiographic estimation, 49 with single-vessel CAD were intensively investigated. Development of collaterals was classified by Rentrop’s method. Univariate and multivariate analyses revealed that hyperhomocysteinemia negatively affected the development of collaterals (p=0.0015 and 0.0011, odds ratio 0.69, 95% confidence interval 0.52-0.90), whereas the duration of angina and percent stenosis evaluated by quantitative coronary angiography had a positive affect. Moreover, the level of homocysteine in the group with poorly developed collaterals (n=7, Rentrop class 0 and 1) was significantly higher than that in the group with well-developed collaterals (n=12, Rentrop class 2 and 3) of the patients with single-vessel disease showing total occlusion (p=0.034). This study clearly demonstrates that the plasma level of homocysteine is independently and inversely associated with the development of collateral circulation in CAD patients. Homocysteine might be a new undesirable aspect of ischemic heart disease through its inhibition of collateral development.

Circ J 2002 Feb;66(2):158-62

Risk factors for progression of aortic atheroma in stroke and transient ischemic attack patients.

BACKGROUND AND PURPOSE: Aortic atheroma is an independent risk factor for stroke and undergoes temporal progression. Clinical and risk factor associations of such progression are unknown. Hyperhomocysteinemia has been linked with atherosclerosis, including that in the cerebral vasculature. This study investigated associations between elevated homocysteine levels and other stroke vascular risk factors and the risk of aortic atheroma progression in patients with cerebrovascular disease. METHODS: Fifty-seven stroke and 21 transient ischemic attack patients underwent multiplanar transesophageal echocardiograms within one month of symptom onset and again at nine months. Aortic atheroma was graded and stratified by use of existing criteria. Stroke risk factors; use of anticoagulant, antiplatelet and hypolipidemic drugs; and clinical and etiological subtypes of stroke were recorded and compared in patients stratified for the presence or absence of aortic atheroma progression. RESULTS: Of the 78, 29 (37%) progressed, 32 (41%) remained unchanged, and 17 (22%) regressed. Progression was most marked at the aortic arch (P=0.005), followed by the ascending segment (P<0.04). In nearly two-thirds of the patients in whom aortic atheroma remained unchanged over nine months, no atheroma was evident on baseline transesophageal echocardiogram. Only homocysteine levels > or =14.0 micromol/L (P=0.02), total anterior cerebral infarct (P=0.02), and large-artery atherosclerosis (P=0.005) significantly correlated with progression. CONCLUSIONS: Among vascular risk factors, elevated homocysteine levels are associated with aortic atheroma progression. Stroke and transient ischemic attack patients with aortic atheroma should undergo assessment of homocysteine levels, which, if elevated, may be treated with vitamins in an effort to arrest aortic atheroma progression.

Stroke 2002 Apr;33(4):930-5

CLA/Weight Loss

Efficacy of dietary CLA and CLA+Guarana (ADIPILL) on body adiposity, and adipocytes cell number and size.

We have compared in mice the effect of a dietary supplementation with either conjugated linoleic acids (CLA) or CLA and guarana (CLA-G) on adiposity. After six weeks, mice were sacrified and all fat pads were removed and adipocytes number and size were measured in subcutaneous (SCAT) and gonadal (GAT) fat pad. CLA as well as CLA-G supplementation induced a strong lipoatrophy, fat mass showing a three-fold decrease in both groups. This effect was more pronouced in gonadal than in subcutaneous site, GAT being reduced 10 times and SCAT four times. Plasma leptin was decreased in CLA and CLA-G treated mice by 40% and 55% respectively. In the CLA group, the decreased fat mass was due to dramatic reduction in adipocyte size without change in cell number. In the CLA-G group, both adipocyte size and number were reduced (-50%). These results demonstrate that dietary CLA are able to decrease adiposity by reducing its capacity to store lipids without affecting adipocyte differentiation. When guarana is added to CLA, an additional effect of cell number is induced. The mechanisms underlying this effect (cell differentiation/apoptosis) and its potential in preventing body fat accretion in the long-term remain to be investigated.

Experimental Biology Meeting, New Orleans. April 20-24, 2002.

The efficacy of conjugated linoleic acid in mammary cancer prevention is independent of the level or type of fat in the diet.

The objective of the present study was to investigate whether the anticarcinogenic activity of conjugated linoleic acid (CLA) is affected by the amount and composition of dietary fat consumed by the host. Because the anticancer agent of interest is a fatty acid, this approach may provide some insight into its mechanism of action, depending on the outcome of these fat feeding experiments. For the fat level experiment, a custom formulated fat blend was used that simulates the fatty acid composition of the U.S. diet. This fat blend was present at 10, 13.3, 16.7 or 20% by weight in the diet. For the fat type experiment, a 20% (w/w) fat diet containing either corn oil (exclusively) or lard (predominantly) was used. Mammary cancer prevention by CLA was evaluated using the rat dimethylbenz[a]anthracene model. The results indicated that the magnitude of tumor inhibition by 1% CLA was not influenced by the level or type of fat in the diet. It should be noted that these fat diets varied markedly in their content of linoleate. Fatty acid analysis showed that CLA was incorporated predominantly in mammary tissue neutral lipids, while the increase in CLA in mammary tissue phospholipids was minimal. Furthermore, there was no evidence that CLA supplementation perturbed the distribution of linoleate or other fatty acids in the phospholipid fraction. Collectively these carcinogenesis and biochemical data suggest that the cancer preventive activity of CLA is unlikely to be mediated by interference with the metabolic cascade involved in converting linoleic acid to eicosanoids. The hypothesis that CLA might act as an antioxidant was also examined. Treatment with CLA resulted in lower levels of mammary tissue malondialdehyde (an end product of lipid peroxidation), but failed to change the levels of 8-hydroxydeoxyguanosine (a marker of oxidatively damaged DNA). Thus, while CLA may have some antioxidant function in vivo in suppressing lipid peroxidation, its anticarcinogenic activity cannot be accounted for by protecting the target cell DNA against oxidative damage. The finding that the inhibitory effect of CLA maximized at 1% (regardless of the availability of linoleate in the diet) could conceivably point to a limiting step in the capacity to metabolize CLA to some active product(s) which is essential for cancer prevention.

Carcinogenesis 1996 May;17(5):1045-50

Protection of conjugated linoleic acids against 2-amino-3-methylimidazo[4,5-f]quinoline-induced colon carcinogenesis in the F344 rat: a study of inhibitory mechanisms.

Grilled ground beef contains a number of heterocyclic amine carcinogens, such as 2-amino-3-methylimidazo[4,5-f] quinoline (IQ), as well as anticarcinogenic conjugated linoleic acids (CLA). In the present study, CLA was administered to male F344 rats by gavage on alternating days in weeks 1-4, while IQ was given by gavage every other day in weeks 3 and 4 (100 mg/kg body wt). Rats were killed 6 h after the final carcinogen dose 16 in order to score colonic aberrant crypt foci (ACF). In the ACF study, CLA had no effect on the size of the foci, but inhibited significantly (P < 0.05) the number of ACF/colon, from 4.3 +/- 2.4 in controls to 1.1 +/- 1.3 in CLA-treated rats (mean +/- SD, n = 10). Rats given CLA also had significantly lower IQ-DNA adducts in the colon as determined by 32P-postlabeling analysis; relative adduct labeling levels (RAL x 10(7) for the major adduct were 9.13 +/- 2.6 in controls versus 5.42 +/- 1.8 in CLA-treated animals (P < 0.05). Mechanism studies indicated that CLA and other fatty acids interact with certain heterocyclic amines in a manner consistent with substrate-ligand binding. However, no such interaction occurred with IQ, and CLA failed to inhibit significantly the mutagenicity of N-hydroxy-IQ in the Salmonella assay. Liver microsomes from CLA-treated rats exhibited lower activities for dealkylation of 7-ethoxyresorufin and methoxyresorufin and activated IQ to DNA binding species less effectively than microsomes from control animals. Direct addition of CLA to the in vitro incubation inhibited IQ-DNA binding and was associated with increased recovery of unmetabolized parent compound. In the Salmonella assay, CLA inhibited the mutagenic activity of IQ in the presence of S9 or ram seminal vesicle microsomes. Collectively, these results support a mechanism involving inhibition of carcinogen activation by CLA, as opposed to direct interaction with the procarcinogen, scavenging of electrophiles or selective induction of phase I detoxification pathways.

Carcinogenesis 1995 Dec;16(12):3037-43

Conjugated dienoic linoleate: a polyunsaturated fatty acid with unique chemoprotective properties.

Conjugated dienoic linoleate (CLA), a linoleic acid derivative, has received considerable attention as a chemoprotective agent in the past few years because it has been shown experimentally to inhibit rat mammary tumorigenesis, mouse forestomach neoplasia and mouse skin carcinogenesis. CLA has several unique structural and functional properties resulting in chemical and physiological effects that are different from those of all-cis, nonconjugated polyunsaturated fatty acids. In turn, these unique qualities appear to modulate cellular processes involved in carcinogenesis. This review will introduce the chemical background of conjugated dienoic linoleate, examine findings describing its chemoprotective qualities, present possible mechanisms of chemoprotection, and correlate the possible significance of dietary CLA modulation to carcinogenesis to humans.

Nutr Rev 1995 Apr;53(4 Pt 1):83-9

Dietary conjugated linoleic acid normalizes impaired glucose tolerance in the Zucker diabetic fatty fa/fa rat.

Conjugated linoleic acid (CLA) is a naturally occurring fatty acid which has anti-carcinogenic and anti-atherogenic properties. CLA activates PPAR alpha in liver, and shares functional similarities to ligands of PPAR gamma, the thiazolidinediones, which are potent insulin sensitizers. We provide the first evidence that CLA is able to normalize impaired glucose tolerance and improve hyperinsulinemia in the pre-diabetic ZDF rat. Additionally, dietary CLA increased steady state levels of aP2 mRNA in adipose tissue of fatty ZDF rats compared to controls, consistent with activation of PPAR gamma. The insulin sensitizing effects of CLA are due, at least in part, to activation of PPAR gamma since increasing levels of CLA induced a dose-dependent transactivation of PPAR gamma in CV-1 cells cotransfected with PPAR gamma and PPRE X 3-luciferase reporter construct. CLA effects on glucose tolerance and glucose homeostasis indicate that dietary CLA may prove to be an important therapy for the prevention and treatment of non-insulin-dependent diabetes mellitus (NIDDM).

Biochem Biophys Res Commun 1998 Mar 27;244(3):678-82

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