Potential therapeutic effects of functionally active compounds isolated from garlic.

The medicinal properties of functionally active organosulfur compounds such as allin, diallyl disulfide, S-allylmercaptocysteine, and S-trityl-L-cysteine isolated from garlic have received great attention from a large number of investigators who have studied their pharmacological effects for the treatment of various diseases. These organosulfur compounds are able to prevent for development of cancer, cardiovascular, neurological, and liver diseases as well as allergy and arthritis. There have been also many reports on toxicities and pharmacokinetics of these compounds. The aim of this study is to review a variety of experimental and clinical reports, and describe the effectiveness, toxicities and pharmacokinetics, and possible mechanisms of pharmaceutical actions of functionally active compounds isolated from garlic.

Curative Effects of Thiacremonone against Acetaminophen-Induced Acute Hepatic Failure via Inhibition of Proinflammatory Cytokines Production and Infiltration of Cytotoxic Immune Cells and Kupffer Cells.

High doses of acetaminophen (APAP; N-acetyl-p-aminophenol) cause severe hepatotoxicity after metabolic activation by cytochrome P450 2E1. This study was undertaken to examine the preventive effects of thiacremonone, a compound extracted from garlic, on APAP-induced acute hepatic failure in male C57BL/6J. Mice received with 500 mg/kg APAP after a 7-day pretreatment with thiacremonone (10-50 mg/kg). Thiacremonone inhibited the APAP-induced serum ALT and AST levels in a dose-dependent manner, and markedly reduced the restricted area of necrosis and inflammation by administration of APAP. Thiacremonone also inhibited the APAP-induced depletion of intracellular GSH, induction of nitric oxide, and lipid peroxidation as well as expression of P450 2E1. After APAP injection, the numbers of Kupffer cells, natural killer cells, and cytotoxic T cells were elevated, but the elevated cell numbers in the liver were reduced in thiacremonone pretreated mice. The expression levels of I-309, M-CSF, MIG, MIP-1 α , MIP-1 ß , IL-7, and IL-17 were increased by APAP treatment, which were inhibited in thiacremonone pretreated mice. These data indicate that thiacremonone could be a useful agent for the treatment of drug-induced hepatic failure and that the reduction of cytotoxic immune cells as well as proinflammatory cytokine production may be critical for the prevention of APAP-induced acute liver toxicity.

Antiobesity effects of a sulfur compound thiacremonone mediated via down-regulation of serum triglyceride and glucose levels and lipid accumulation in the liver of db/db mice.

Garlic is widely used as a spice. Garlic extracts exert anticancer and antiinflammatory effects, but its antiobesity efficacy studies have produced conflicting results. The antiobesity effects of thiacremonone, a sulfur compound isolated from garlic, was evaluated in obese db/db mice. Thiacremonone was orally administrated to mice for 3 weeks. The thiacremonone-treated db/db mice showed a loss of body weight and decrease in blood triglyceride and glucose levels compared with the control mice. Histological analysis further revealed that thiacremonone significantly decreased lipid accumulation in the fatty livers of treated db/db mice. It was observed that GLUT-4 expression and glucose uptake were up-regulated by thiacremonone in 3T3-L1 adipocytes. Thiacremonone treatment also suppressed expression levels of acetyl-CoA carboxylase (ACC) and fatty acid synthase (FAS), which are involved in lipid metabolism, in the liver of db/db mice. In addition, thiacremonone enhanced peroxisome proliferator-activated receptor γ (PPARγ) expression in the fatty liver. Taken together, these results suggest that thiacremonone may play a vital role in improving the management of obesity and related metabolic syndromes via inhibition of lipid accumulation.

4-O-methylhonokiol inhibits colon tumor growth via p21-mediated suppression of NF-κB activity.

Biphenolic components in the Magnolia family have shown several pharmacological activities such as antitumor effects. This study investigated the effects of 4-O-methylhonokiol (MH), a constituent of Magnolia officinalis, on human colon cancer cell growth and its action mechanism. 4-O-methylhonokiol (0-30 µM) decreased constitutive activated nuclear factor (NF)-κB DNA binding activity and inhibited growth of human colon (SW620 and HCT116) cancer cells. It also caused G0-G1 phase cell cycle arrest followed by an induction of apoptotic cell death. However, knockdown with small interfering RNA (siRNA) of p21 or transfection with cyclin D1/Cdk4 binding site-mutated p21 abrogated MH-induced cell growth inhibition, inhibition of NF-κB activity as well as expression of cyclin D1 and Cdk4. Conversely, inhibition of NF-κB with specific inhibitor or siRNA augmented MH-induced apoptotic cell death. 4-O-methylhonokiol inhibited tumor growth, NF-κB activity and expression of antiapoptotic proteins; however, it increased the expression of apoptotic proteins as well as p21 in xenograft nude mice bearing SW620 cancer cells. The present study reveals that MH causes p21-mediated human colon cancer cell growth inhibition through suppression of NF-κB and indicates that this compound by itself or in combination with other anticancer agents could be useful for the treatment of cancer.

Anti-inflammatory and arthritic effects of thiacremonone, a novel sulfur compound isolated from garlic via inhibition of NF-kappaB.

INTRODUCTION: Sulfur compounds isolated from garlic exert anti-inflammatory properties. We recently isolated thiacremonone, a novel sulfur compound from garlic. Here, we investigated the anti-inflammatory and arthritis properties of thiacremonone through inhibition of NF-kappaB since NF-kappaB is known to be a target molecule of sulfur compounds and an implicated transcription factor regulating inflammatory response genes. METHODS: The anti-inflammatory and arthritis effects of thiacremone in in vivo were investigated in 12-O-tetradecanoylphorbol-13-acetate-induced ear edema, carrageenan and mycobacterium butyricum-induced inflammatory and arthritis models. Lipopolysaccharide-induced nitric oxide (NO) production was determined by Griess method. The DNA binding activity of NF-kappaB was investigated by electrophoretic mobility shift assay. NF-kappaB and inducible nitric oxide synthetase (iNOS) transcriptional activity was determined by luciferase assay. Expression of iNOS and cyclooxygenase-2 (COX-2) was determined by western blot. RESULTS: The results showed that topical application of thiacremonone (1 or 2 microg/ear) suppressed the 12-O-tetradecanoylphorbol-13-acetate-induced (1 microg/ear) ear edema. Thiacremonone (1-10 mg/kg) administered directly into the plantar surface of hind paw also suppressed the carrageenan (1.5 mg/paw) and mycobacterium butyricum (2 mg/paw)-induced inflammatory and arthritic responses as well as expression of iNOS and COX-2, in addition to NF-kappaB DNA-binding activity. In further in vitro study, thiacremonone (2.5-10 microg/ml) inhibited lipopolysaccharide (LPS, 1 microg/ml)-induced nitric oxide (NO) production, and NF-kappaB transcriptional and DNA binding activity in a dose dependent manner. The inhibition of NO by thiacremonone was consistent with the inhibitory effect on LPS-induced inducible nitric oxide synthase (iNOS) and COX-2 expression, as well as iNOS transcriptional activity. Moreover, thiacremonone inhibited LPS-induced p50 and p65 nuclear translocation, resulting in an inhibition of the DNA binding activity of the NF-kappaB. These inhibitory effects on NF-kappaB activity and NO generation were suppressed by reducing agents dithiothreitol (DTT) and glutathione, and were abrogated in p50 (C62S)-mutant cells, suggesting that the sulfhydryl group of NF-kappaB molecules may be a target of thiacremonone. CONCLUSIONS: The present results suggested that thiacremonone exerted its anti-inflammatory and anti-arthritic properties through the inhibition of NF-kappaB activation via interaction with the sulfhydryl group of NF-kappaB molecules, and thus could be a useful agent for the treatment of inflammatory and arthritic diseases.

l-Theanine, an amino acid in green tea, attenuates beta-amyloid-induced cognitive dysfunction and neurotoxicity: reduction in oxidative damage and inactivation of ERK/p38 kinase and NF-kappaB pathways.

Amyloid beta (Abeta)-induced neurotoxicity is a major pathological mechanism of Alzheimer disease (AD). In this study, we investigated the inhibitory effect of l-theanine, a component of green tea (Camellia sinensis), on Abeta(1-42)-induced neuronal cell death and memory impairment. Oral treatment of l-theanine (2 and 4 mg/kg) for 5 weeks in the drinking water of mice, followed by injection of Abeta(1-42) (2 microg/mouse, icv), significantly attenuated Abeta(1-42)-induced memory impairment. Furthermore, l-theanine reduced Abeta(1-42) levels and the accompanying Abeta(1-42)-induced neuronal cell death in the cortex and hippocampus of the brain. Moreover, l-theanine inhibited Abeta(1-42)-induced extracellular signal-regulated kinase (ERK) and p38 mitogen-activated protein kinase as well as the activity of nuclear factor kappaB (NF-kappaB). l-Theanine also significantly reduced oxidative protein and lipid damage and the elevation of glutathione levels in the brain. These data suggest that the positive effects of l-theanine on memory may be mediated by suppression of ERK/p38 and NF-kappaB as well as the reduction of macromolecular oxidative damage. Thus, l-theanine may be useful in the prevention and treatment of AD.

Green tea (-)-epigallocatechin-3-gallate inhibits beta-amyloid-induced cognitive dysfunction through modification of secretase activity via inhibition of ERK and NF-kappaB pathways in mice.

Alzheimer's disease (AD) is characterized by the extracellular deposition of beta-amyloid peptide (Abeta) in cerebral plaques. Abeta is derived from the beta-amyloid precursor protein (APP) by the enzymes alpha-, beta- and gamma-secretase. Compounds that enhance alpha-secretase, but inhibit beta- or gamma-secretase activity, have therapeutic potential in the treatment of AD. Green tea, or its major polyphenolic compound, has been shown to have neuroprotective effects. In this study, we investigated the possible effects of (-)-epigallocatechin-3-gallate (EGCG) on memory dysfunction caused by Abeta through the change of Abeta-induced secretase activities. Mice were pretreated with EGCG (1.5 or 3 mg/kg body weight in drinking water) for 3 wk before intracerebroventricular administration of 0.5 microg Abeta(1-42). EGCG dose-dependently reduced the Abeta(1-42)-induced memory dysfunction, which was evaluated using passive avoidance and water maze tests. Abeta(1-42) induced a decrease in brain alpha-secretase and increases in both brain beta- and gamma-secretase activities, which were reduced by EGCG. In the cortex and the hippocampus, expression of the metabolic products of the beta- and gamma-secretases from APP, C99, and Abeta also were dose-dependently suppressed by EGCG. Paralleled with the suppression of beta- and gamma-secretases by EGCG, we found that EGCG inhibited the activation of extracellular signal-regulated kinase and nuclear transcription factor-kappaB in the Abeta(1-42)-injected mouse brains. In addition, EGCG inhibited Abeta(1-42)-induced apoptotic neuronal cell death in the brain. To further test the ability of EGCG to affect memory, EGCG (3 mg/kg body weight) was administered in drinking water for 1 wk to genetically developed preseniline 2 (PS2) mutant AD mice. Compared with untreated mutant PS2 AD mice, treatment with EGCG enhanced memory function and brain alpha-secretase activity but reduced brain beta- and gamma-secretase activities as well as Abeta levels. Moreover, EGCG inhibited the fibrillization of Abeta in vitro with a half maximal inhibitory concentration of 7.5 mg/L. These studies suggest that EGCG may be a beneficial agent in the prevention of development or progression of AD.

Inhibition of cell growth and induction of apoptosis via inactivation of NF-kappaB by a sulfurcompound isolated from garlic in human colon cancer cells.

Compounds such as S-allylmercaptocysteine, diallyl disulfide, and S-trityl-L-cysteine isolated from garlic have been known to be effective in chemoprevention. Nuclear transcription factor-kappaB (NF-kappaB) has been known to be an implicated factor in apoptotic cell death of several cancer cells. In this study, we investigated whether a sulfurcompound (named thiacremonone) isolated from garlic could modulate NF-kappaB activity and thereby induce apoptotic cell death of colon cancer cells. Treatment with different concentrations (30 - 150 microg/ml) of thiacremonone for various periods (0 - 48 h) inhibited colon cancer cell (SW620 and HCT116) growth followed by induction of apoptosis in a dose-dependent manner. We also found that thiacremonone modulated tumor necrosis factor-alpha (TNF-alpha) and tetradeanoyl phorbol acetate (TPA)-induced NF-kappaB transcriptional and DNA binding activity. Moreover, thiacremonone suppressed NF-kappaB target anti-apoptotic genes (Bcl-2, cIAP1/2, and XIAP) and inflammatory genes (iNOS and COX-2), whereas it induced apoptotic genes (Bax, cleaved caspse-3, and cleaved PARP) expression. These results suggest that a novel sulfurocompound from garlic inhibited colon cancer cell growth through induction of apoptotic cell death by modulating of NF-kappaB.