Oxidative modification of DNA, proteins and lipids by reactive oxygen species (ROS) plays a role in aging and disease, including cardiovascular, neurodegenerative and inflammatory diseases and cancer. Extracts of fresh garlic that are aged over a prolonged period to produce aged garlic extract (AGE) contain antioxidant phytochemicals that prevent oxidant damage. These include unique water-soluble organosulfur compounds, lipid-soluble organosulfur components and flavonoids, notably allixin and selenium. Long-term extraction of garlic (up to 20 mo) ages the extract, creating antioxidant properties by modifying unstable molecules with antioxidant activity, such as allicin, and increasing stable and highly bioavailable water-soluble organosulfur compounds, such as S-allylcysteine and S-allylmercaptocysteine. AGE exerts antioxidant action by scavenging ROS, enhancing the cellular antioxidant enzymes superoxide dismutase, catalase and glutathione peroxidase, and increasing glutathione in the cells. AGE inhibits lipid peroxidation, reducing ischemic/reperfusion damage and inhibiting oxidative modification of LDL, thus protecting endothelial cells from the injury by the oxidized molecules, which contributes to atherosclerosis. AGE inhibits the activation of the oxidant-induced transcription factor, nuclear factor (NF)-kappa B, which has clinical significance in human immunodeficiency virus gene expression and atherogenesis. AGE protects DNA against free radical--mediated damage and mutations, inhibits multistep carcinogenesis and defends against ionizing radiation and UV-induced damage, including protection against some forms of UV-induced immunosuppression. AGE may have a role in protecting against loss of brain function in aging and possess other antiaging effects, as suggested by its ability to increase cognitive functions, memory and longevity in a senescence-accelerated mouse model. AGE has been shown to protect against the cardiotoxic effects of doxorubicin, an antineoplastic agent used in cancer therapy and against liver toxicity caused by carbon tetrachloride (an industrial chemical) and acetaminophen, an analgesic. Substantial experimental evidence shows the ability of AGE to protect against oxidant-induced disease, acute damage from aging, radiation and chemical exposure, and long-term toxic damage. Although additional observations are warranted in humans, compelling evidence supports the beneficial health effects attributed to AGE, i.e., reducing the risk of cardiovascular disease, stroke, cancer and aging, including the oxidant-mediated brain cell damage that is implicated in Alzheimer's disease.

/pdf/antioxidant-health-effects-of-aged-garlic-extract-2jx5ycey3x.pdf

Antioxidant Health Effects of Aged Garlic Extract

Plants used against cancer - an extension of the work of Jonathan Hartwell.

The medicinal use of garlic dates back thousands of years, but there was little scientific support of its therapeutic and pharmacologic properties until recently. In the past decade, the cancer-protective effects of garlic have been well established by epidemiologic studies and animal experiments. However, the cardiovascular-protective properties of garlic are less well understood. In particular, despite the reported hypocholesterolemic effect of garlic, the mechanism of the effect is unclear. In a recent randomized, double-blind, placebo-controlled intervention study, we showed that aged garlic extract (AGE) supplementation was effective in lowering plasma concentration of total cholesterol by 7% and LDL cholesterol by 10% in hypercholesterolemic men compared with subjects consuming a placebo. Supplementation of AGE in animal diets similarly reduced plasma concentrations of total cholesterol and triacylglycerol by 15 and 30%, respectively. In subsequent experiments using cultured rat hepatocytes, we found 44--87% inhibition of cholesterol synthesis by the water-extractable fraction (WEF), methanol-extractable fraction (MEF) and petroleum ether-extractable fraction (PEF) of fresh garlic, and Kyolic (liquid form of AGE). These observations suggested that hydrophilic and hydrophobic compounds of garlic are inhibitory to cholesterol synthesis. Because S-allylcysteine (SAC) alone was less potent than Kyolic, which contains SAC and other sulfur compounds, a maximal inhibition appears to require a concerted action of multiple compounds of garlic. In a series of experiments, we further characterized the inhibitory potency of individual water-soluble and lipid-soluble compounds of garlic. Among water-soluble compounds, SAC, S-ethylcysteine (SEC), and S-propylcysteine (SPC) inhibited cholesterol synthesis by 40--60% compared with 20--35% by gamma-glutamyl-S-allylcysteine (GSAC), gamma-glutamyl-S-methylcysteine (GSMC) and gamma-glutamyl-S-propylcysteine (GSPC). Lipid-soluble sulfur compounds (i.e., diallyl sulfide, diallyl disulfide, diallyl trisulfide, dipropyl sulfide and dipropyl trisulfide) at low concentrations (0.05--0.5 mol/L) slightly (10--15%) inhibited cholesterol synthesis but became highly cytotoxic at high concentrations (1.0--4.0 mol/L). All water-soluble compounds, except S-allylmercaptocysteine, were not cytotoxic, judging from the release of cellular lactate dehydrogenase into the culture medium. Taken together, the results of our studies indicate that the cholesterol-lowering effects of garlic extract, such as AGE, stem in part from inhibition of hepatic cholesterol synthesis by water-soluble sulfur compounds, especially SAC.

Cholesterol-Lowering Effect of Garlic Extracts and Organosulfur Compounds: Human and Animal Studies

Garlic has played an important dietary and medicinal role throughout the history of mankind. In some Western countries, the sale of garlic preparations ranks with those of leading prescription drugs. The therapeutic efficacy of garlic encompasses a wide variety of ailments, including cardiovascular, cancer, hepatic and microbial infections to name but a few. However, the elucidation of its mechanism for therapeutic action has proved to be more elusive and a unifying theory, which could account for its reported multifarious activities, is yet to emerge. Reactive oxygen species (ROS) seem to be at the core of many disease processes and it is an attractive and convenient hypothesis that garlic might exert its activities through modulatory effects on ROS. A literature search on garlic and its antioxidant potential churned up a surprisingly large amount of data, some of it good, some bad and some of its definitely ugly. Various preparations of garlic, mainly aged garlic extract (AGE), have been shown to have promising antioxidant potential. However, the presence of more than one compounds in garlic, with apparently opposite biological effects, has added to the complexity of the subject. Raw garlic homogenate has been reported to exert antioxidant potential but higher doses have been shown to be toxic to the heart, liver and kidney. So where do we stand today on this issue of garlic? Is garlic always good for health? How safe is it? Is it necessary to isolate the antioxidant compounds for its medicinal use in a more effective way? These issues are addressed in this review.

Garlic as an antioxidant: the good, the bad and the ugly

Aged garlic extract (AGE) is an odorless garlic preparation containing S-allylcysteine (SAC) as its most abundant compound. A large number of studies have demonstrated the antioxidant activity of AGE and SAC in both in vivo—in diverse experimental animal models associated to oxidative stress—and in vitro conditions—using several methods to scavenge reactive oxygen species or to induce oxidative damage. Derived from these experiments, the protective effects of AGE and SAC have been associated with the prevention or amelioration of oxidative stress. In this work, we reviewed different antioxidant mechanisms (scavenging of free radicals and prooxidant species, induction of antioxidant enzymes, activation of Nrf2 factor, inhibition of prooxidant enzymes, and chelating effects) involved in the protective actions of AGE and SAC, thereby emphasizing their potential use as therapeutic agents. In addition, we highlight the ability of SAC to activate Nrf2 factor—a master regulator of the cellular redox state. Here, we include original data showing the ability of SAC to activate Nrf2 factor in cerebral cortex. Therefore, we conclude that the therapeutic properties of these molecules comprise cellular and molecular mechanisms at different levels.

/pdf/the-antioxidant-mechanisms-underlying-the-aged-garlic-325o8wjbq5.pdf

The antioxidant mechanisms underlying the aged garlic extract- and S-allylcysteine-induced protection.

Oxygen radical injury and lipid peroxidation have been suggested as major causes of cancer, atherosclerosis and the aging process. In this study, we determined in vitro the effect of aged garlic extract (AGE) and one of its components, S-allyl cysteine (SAC), on hydrogen peroxide (H2O2)-induced oxidant injury using bovine pulmonary artery endothelial cells (PAEC). After overnight preincubation with AGE or SAC, PAEC monolayers were exposed to H2O2 for 3 h. Cell viability, lactate dehydrogenase (LDH) release and lipid peroxidation were measured to assess oxidant injury. Pretreatment with AGE at 2–4 mg/mL or SAC at 4 mg/mL significantly reversed the loss of cell viability induced by 50 and 100 μm of H2O2. AGE or SAC also exhibited a dose-dependent inhibition of both LDH release and lipid peroxidation induced by 50 μM of H2O2. The results show that both AGE and SAC can protect vascular endothelial cells from oxidant injury. The data thus suggest that these compounds may be useful for retardation of the aging process and for prevention of cancer and atherosclerosis.

Takeshi Yamasaki

Papers

Garlic compounds protect vascular endothelial cells from hydrogen peroxide-induced oxidant injury

Effect of allixin, a phytoalexin produced by garlic, on mutagenesis, DNA-binding and metabolism of aflatoxin B1

Modulation of cytochrome P-450IA1-mediated mutagenicity, DNA binding and metabolism of benzo[a]pyrene by Chinese medicinal herbs