Flavan-3-ols, occurring in monomeric, as well as in oligomeric and polymeric forms (also known as condensed tannins or proanthocyanidins), are among the most abundant and bioactive dietary polyphenols, but their in vivo health effects in humans may be limited because of their recognition as xenobiotics. Bioavailability of flavan-3-ols is largely influenced by their degree of polymerization; while monomers are readily absorbed in the small intestine, oligomers and polymers need to be biotransformed by the colonic microbiota before absorption. Therefore, phenolic metabolites, rather than the original high molecular weight compounds found in foods, may be responsible for the health effects derived from flavan-3-ol consumption. Flavan-3-ol phenolic metabolites differ in structure, amount and excretion site. Phase II or tissular metabolites derived from the small intestine and hepatic metabolism are presented as conjugated derivatives (glucuronic acid or sulfate esters, methyl ether, or their combined forms) of monomeric flavan-3-ols and are preferentially eliminated in the bile, whereas microbial metabolites are rather simple conjugated lactones and phenolic acids that are largely excreted in urine. Although the colon is seen as an important organ for the metabolism of flavan-3-ols, the microbial catabolic pathways of these compounds are still under consideration, partly due to the lack of identification of bacteria with such capacity. Studies performed with synthesized or isolated phase II conjugated metabolites have revealed that they could have an effect beyond their antioxidant properties, by interacting with signalling pathways implicated in important processes involved in the development of diseases, among other bioactivities. However, the biological properties of microbe-derived metabolites in their actual conjugated forms remain largely unknown. Currently, there is an increasing interest in their effects on intestinal infections, inflammatory intestinal diseases and overall gut health. The present review will give an insight into the metabolism and microbial biotransformation of flavan-3-ols, including tentative catabolic pathways and aspects related to the identification of bacteria with the ability to catabolize these kinds of polyphenols. Also, the in vitro bioactivities of phase II and microbial phenolic metabolites will be covered in detail.

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Insights into the metabolism and microbial biotransformation of dietary flavan-3-ols and the bioactivity of their metabolites

Epidemiological studies have demonstrated that elevated levels of plasma total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C) are the major risk factors for coronary heart disease (CHD), whereas high concentrations of plasma high-density lipoprotein cholesterol (HDL-C) and a low ratio of TC to HDL-C are protective against CHD. A relationship between plasma TC and the risk of CHD is well established at concentrations above 240 mg/dL. In addition to the use of three main classes of cholesterol-lowering medications, including HMG-CoA reductase inhibitors, anion-exchange resins, and fibrates, a nutritionally balanced diet that reduces saturated fat and cholesterol intake has traditionally been the first goal of dietary therapy in lowering plasma TC. In recent years, nutraceuticals and functional foods have attracted much interest as possible alternative therapies for lowering plasma TC, especially for hypercholesterolemia patients, whose blood cholesterol level is marginally high (200-240 mg/dL) but not high enough to warrant the prescription of cholesterol-lowering medications. This review summarizes the findings of recent studies on the production, application, efficacy, and mechanisms of popular cholesterol-lowering nutraceuticals and functional foods.

Cholesterol-Lowering Nutraceuticals and Functional Foods

The present study examined the antioxidative activity of water and ethanol extracts of green and black tea leaves against the oxidation of heated sunflower oil and lard. Oxidation was conducted at 110 °C in the Rancimat test. Total polyphenols and catechin contents in tea extracts were measured. The research showed that the total polyphenol content in green and black tea leaves was 205.2 and 148.7 mg/g, respectively. In tea leaves extracts, it ranged between 245.9 mg/g and 837.7 mg/g and depended on the extraction solvent and the kind of tea used (p <0.001). The highest polyphenol content was observed in samples extracted with 95% ethanol, lower contents were found with the use of water. Results showed that the highest antioxidant activity, measured as an induction period, with 1000 ppm green tea ethanol extract, was comparable to a-tocopherol activity in sunflower oil. In lard, the longest induction period was measured with 500 and 1000 ppm of green tea ethanol extract. Other tea extract concentrations were significantly less active. Statistical analysis of the tea extract antioxidant activity in lipids in the Rancimat test showed an essential influence of the catechin contents. Further statistical analysis also showed an influence of (−)-epicatechin gallate (ECG), (−)-epicatechin (EC), and (+)-catechin (C) contents in the tea extracts on the antioxidant activity in lipids. It was stated that the antioxidant activity was higher in tea extracts containing high levels of ECG, EC, and C.

Antioxidant activity of tea extracts in lipids and correlation with polyphenol content

Tea is the most widely consumed beverage in the world. Tea leaves are a source of polyphenols, especially catechins, a decisive group for their antioxidative activity. This paper reviews what is known of green tea species, its leaves processing and changes occurring in tea components. The main green tea polyphenols are catechins: (±)-catechin C, (-)-epicatechin EC, (+)-gallocatechin GC, (-)-epigallocatechin EGC, (-)-epicatechin gallate ECG, and (-)-epigallocatechin gallate EGCG. Antioxidant and antimicrobial activity of these compounds and crude extracts of teas are described. The review highlights also the potentials of green tea, its health benefits in terms of antimutagenic and anticarcinogenic properties as well as protective agents against cardiovascular diseases.

Tea polyphenols - their antioxidant properties and biological activity - a review.

Effect of phytosterols and their oxidation products on lipoprotein profiles and vascular function in hamster fed a high cholesterol diet

Policosanol is a group of long chain primary alcohols and has been shown to reduce blood cholesterol levels and to inhibit the oxidation of low-density lipoprotein (LDL). The present study examined (i) the effect of policosanol supplementation in the diet on the fecal excretion of neutral and acidic sterols in hamsters and (ii) the antioxidant activity of policosanol in human LDL. Golden Syrian hamsters were divided into four groups (n = 12/each) fed one of the four diets containing 0 (control), 0.38, 0.75, and 1.50 g kg(-1) policosanol for 6 weeks. It was found that hamsters given 0.38-1.5 g kg(-1) diets had a serum total cholesterol level lowered by 15-25% and had a high-density lipoprotein cholesterol elevated by 7-16.8%. It was found that policosanol increased the excretion of acidic sterols by 25-73%. Contrary to that in previous reports, policosanol had no apparent anti-LDL oxidation activity when 1-tetracosanol, 1-hexacosanol, and 1-octacosanol were incubated in human LDL. Policosanol also possessed no scavenging activity on the free radical2,2-diphenyl-1-picrylhydrazyl. These data provide evidence that in addition to the effect of HMG-CoA reductase, the cholesterol-lowering activity of policosanol is partially mediated by its inhibition on the absorption of bile acids, but these data disprove the claim that policosanol is an antioxidant.

Policosanol has no antioxidant activity in human low-density lipoprotein but increases excretion of bile acids in hamsters.

The present study examined the antioxidant activity of black tea theaflavins and catechin derivatives in canola oil. Oxidation was conducted at 95°C by monitoring the oxygen consumption and decreases in the linoleic and α-linolenic acids of canola oil. All were tested at a concentration of 0.5 mM. Catechins, including (−)-epicatechin, (−)-epicatechin gallate, (−)-epigallocatechin, and (−)-epigallocatechin gallate (EGCG), were more effective than theaflavins, namely, theaflavin-1, theaflavin-3-gallate, theaflavin-3′-gallate, and theaflavin-3,3′-digallate (TF3), against the lipid oxidation of canola oil. Among the four theaflavins, TF3 was the most effective, whereas among the four catechins, FGCG was the most potent. Under the same conditions, all theaflavins and catechins were more powerful than BHT as an antioxidant in heated canola.oil. Little or no difference in antioxidant activity was observed between each catechin and epimer pair. Methylation of the 3′-OH led to a significant loss of antioxidant activity of the catechins.

Antioxidant activity of tea theaflavins and methylated catechins in canola oil

The present study was to test the relative hypercholesterolaemic and atherogenic potency of oxidised cholesterol (OxC) and non-oxidised cholesterol in hamsters. An OxC mixture, prepared by heating pure cholesterol (100 g) at 160 degrees C in air for 72 h, contained 78 % cholesterol and 22 % OxC. Fifty Golden Syrian hamsters were randomly divided into five groups of ten animals and fed the control diet, a 0.05 % cholesterol diet (C-0.05), a 0.10 % cholesterol diet (C-0.1), a 0.05 % OxC mixture diet (OxC-0.05) or a 0.10 % OxC mixture diet (OxC-0.1), respectively. The OxC-0.05 and OxC-0.1 groups were more hypercholesterolaemic and had serum total cholesterol 22 and 12 % higher than the corresponding C-0.05 and C-0.1 hamsters (P < 0.05). The OxC-0.1 group demonstrated greater deposition of cholesterol and had a larger area of atherosclerotic plaque in the aorta than the corresponding C-0.1 hamsters (P < 0.05). Similarly, the aorta in the OxC-0.1 group showed greater inhibition on acetylcholine-induced relaxation compared with that in the C-0.1 hamsters. It was concluded that OxC was much more hypercholesterolaemic and atherogenic than cholesterol.

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Oxidised cholesterol is more hypercholesterolaemic and atherogenic than non-oxidised cholesterol in hamsters.

Background and Aim Oxidized low-density lipoprotein (ox-LDL) causes atherosclerosis and endothelial dysfunction No study up to the present date has examined the relative contribution of all the oxidized components in ox-LDL to inhibition on vascular function Our aim was to investigate the effects of individual oxidized components at concentrations similar to those in ox-LDL on the impairment of endothelium-dependent relaxation in rat aorta Methods and Results Rat thoracic aorta was pre-treated with lysophosphatidylcholine (LPC), cholesterol oxidized products (COPs), oxidized linoleic acid (ox-18:2) and oxidized linolenic acid (ox-18:3) at concentrations similar to those in human ox-LDL Ox-LDL as a whole caused 61% inhibition while LPC, COPs and ox-18:2 at concentrations similar to those in ox-LDL caused 12%, 24% and 19% inhibition, respectively, on endothelium-dependent relaxation, suggesting that COPs produced the most adverse effect followed by ox-18:2 and LPC in an additional way Three COPs including 7-ketocholesterol, 7α-hydroxycholesterol and 7β-hydroxycholesterol showed inhibition on endothelium-dependent relaxation with E max being reduced to 79–87% compared with the control E max (95%) At Western blot analysis phosphorylation of eNOS at Ser1177 site and total eNOS were not altered by ox-LDL treatment, indicating that ox-LDL did not affect nitric oxide (NO) synthesis capacity Ox-LDL might react directly with NO and lower NO bioavailability Conclusion The present study demonstrated the relative contribution of individual oxidized components in ox-LDL in the inhibition of endothelium-dependent relaxation in rat aorta This inhibitory effect could be caused by the reduction of NO bioactivity

Chi Ho Ng

Papers

Policosanol has no antioxidant activity in human low-density lipoprotein but increases excretion of bile acids in hamsters.

Antioxidant activity of tea theaflavins and methylated catechins in canola oil

Oxidised cholesterol is more hypercholesterolaemic and atherogenic than non-oxidised cholesterol in hamsters.

Relative contribution of individual oxidized components in ox-LDL to inhibition on endothelium-dependent relaxation in rat aorta