Pharmacokinetics of Gingerols, Shogaols, and Their Metabolites in Asthma Patients.

6-Gingerol and 6-shogaol are the most abundant gingerols and shogaols in ginger root and have been shown to reduce the asthmatic phenotype in murine models of asthma. Several studies have described the pharmacokinetics of gingerols and shogaols in humans following the oral ingestion of ginger, while little was known about the metabolism of these components in humans, particularly in patients with asthma. In this study, a dietary supplement of 1.0 g of ginger root extract was administered to asthma patients twice daily for 56 days and serum samples were drawn at 0.5-8 h on days 0, 28, and 56. The metabolic profiles of gingerols and shogaols in human plasma and the kinetic changes of gingerols, shogaols, and their metabolites in asthma patients collected on the three different visits were analyzed using liquid chromatography-mass spectrometry (LC-MS). Ketone reduction was the major metabolic pathway of both gingerols and shogaols. Gingerdiols were identified as the major metabolites of 6-, 8-, and 10-gingerols. M11 and M9 were identified as the double-bond reduction and both the double-bond and ketone reduction metabolites of 6-shogaol, respectively. Cysteine conjugation was another major metabolic pathway of 6-shogaol in asthma patients, and two cysteine-conjugated 6-shogaol, M1 and M2, were identified as the major metabolites of 6-shogaol. Furthermore, gingerols, shogaols, and their metabolites were quantitated in the human serum collected at different time points during each of the three visits using a very sensitive high-resolution LC-MS method. The results showed that one-third of 6-gingerol was metabolized to produce its reduction metabolites, 6-gingerdiols, and more than 90% of 6-shogaol was metabolized to its phase I and cysteine-conjugated metabolites, suggesting the importance of considering the contribution of these metabolites to the bioavailability and health beneficial effects of gingerols and shogaols. All gingerols, shogaols, and their metabolites reached their peak concentrations in less than 2 h, and their half-lives (t1/2) were from 0.6 to 2.4 h. Furthermore, long-term treatment of ginger supplements, especially after 56 days of treatment, increases the absorption of ginger compounds and their metabolites in asthma patients.

Ginger metabolites and metabolite-inspired synthetic products modulate intracellular calcium and relax airway smooth muscle.

Asthma affects millions of people worldwide and its prevalence is increasing. It is characterized by chronic airway inflammation, airway remodeling, and pathologic bronchoconstriction, and it poses a continuous treatment challenge with very few new therapeutics available. Thus, many asthmatics turn to plant-based complementary products, including ginger, for better symptom control, indicating an unmet need for novel therapies. Previously, we demonstrated that 6-shogaol (6S), the primary bioactive component of ginger, relaxes human airway smooth muscle (hASM) likely by inhibition of phosphodiesterases (PDEs) in the ß-adrenergic (cyclic nucleotide PDEs), and muscarinic (phospholipase C, PLC) receptor pathways. However, oral 6S is extensively metabolized and it is unknown if the resulting metabolites remain bioactive. Here, we screened all the known human metabolites of 6S and several metabolite-based synthetic derivatives to better understand their mechanism of action and structure-function relationships. We demonstrate that several metabolites and metabolite-based synthetic derivatives are able to prevent Gq-coupled stimulation of intracellular calcium [Ca2+]i and inositol trisphosphate (IP3) synthesis by inhibiting PLC, similar to the parent compound 6S. We also show that these compounds prevent recontraction of ASM after ß-agonist relaxation likely by inhibiting PDEs. Furthermore, they potentiate isoproterenol-induced relaxation. Importantly, moving beyond cell-based assays, metabolites also retain the functional ability to relax Gq-coupled-contractions in upper (human) and lower (murine) airways. The current study indicates that, although oral ginger may be metabolized rapidly, it retains physiological activity through its metabolites. Moreover, we are able to use naturally occurring metabolites as inspiration to develop novel therapeutics for brochoconstrictive diseases.

Dietary Genistein Reduces Methylglyoxal and Advanced Glycation End Product Accumulation in Obese Mice Treated with High-Fat Diet.

Our previous study has found that dietary genistein could ameliorate high-fat diet (HFD)-induced obesity and especially lower methylglyoxal (MGO) and advanced glycation end product (AGE) accumulation in healthy mice exposed to genistein and HFD. However, it is still unclear whether dietary genistein intervention has a similar beneficial effect in obese mice. In this study, the mice were induced with obesity after being fed a HFD for nine weeks before being administered with two doses of genistein, 0.1% (G 0.1) and 0.2% (G 0.2), in the HFD for additional 19 weeks. After 19 week treatment, genistein supplementation reduced body and liver weights, plasma and liver MGO levels, and kidney AGE levels in mice. Mechanistically, genistein upregulated the expressions of glyoxalase I and II and aldose reductase to detoxify MGO, and genistein and its microbial metabolites, dihydrogenistein and 6'-hydroxy-O-demethylangolensin, were able to trap endogenous MGO via formation of MGO conjugates. Taken together, our results provide novel insights into the antiobesity and antiglycation roles of dietary genistein in obese subjects.

Translating In Vitro Acrolein-Trapping Capacities of Tea Polyphenol and Soy Genistein to In Vivo Situation is Mediated by the Bioavailability and Biotransformation of Individual Polyphenols.

SCOPE: Acrolein (ACR) is a highly toxic unsaturated aldehyde. Humans are both endogenously and exogenously exposed to ACR. Long-term exposure to ACR leads to various chronic diseases. Dietary polyphenols have been reported to be able to attenuate ACR-induced toxicity in vitro via formation of ACR-polyphenol conjugates. However, whether in vitro ACR-trapping abilities of polyphenols can be maintained under in vivo environments is still unknown. METHODS AND RESULTS: Two most commonly consumed dietary polyphenols, (-)-epigallocatechin-3-gallate (EGCG) from tea and genistein from soy, are evaluated for their anti-Acrolein behaviors both in vitro and in mice. Tea EGCG exerts a much higher capacity to capture ACR than soy genistein in vitro. But translation of in vitro anti-ACR activity into in vivo is mainly mediated by bioavailability and biotransformation of individual polyphenols. It is found that 1) both absorbed EGCG and genistein can trap endogenous ACR by forming mono-ACR adducts and eventually be excreted into mouse urine; 2) both absorbed EGCG and genistein can produce active metabolites, methyl-EGCG (MeEGCG) and orobol, to scavenge endogenous ACR; 3) both MeEGCG and non-absorbed EGCG show ability to trap ACR in the gut; 4) considerable amounts of microbial metabolites of genistein display enhanced anti-ACR capacity both in the body and in the gut, compared to genistein; and 5) biotransformation of genistein is able to boost its in vivo anti-ACR capacity, compared to EGCG. CONCLUSION: The findings demonstrate that in vivo anti-ACR ability of dietary polyphenols cannot be reflected solely based on their in vitro ability. The bioavailability and biotransformation of individual polyphenols, and especially the gut microbiome, contribute to in vivo anti-ACR ability of dietary polyphenols.

Induction of Apoptosis and Cell-Cycle Arrest in Human Colon-Cancer Cells by Whole-Grain Alkylresorcinols via Activation of the p53 Pathway.

Colon cancer, one of the leading causes of cancer-associated deaths, is the target of choice for nutrition-based-prevention approaches because of the direct and early contact between the active compounds and the cancerous tissues. We previously reported alkylresorcinols (ARs) as the major active components in wheat bran against human colon cancer. Here, we further investigate the anticancer mechanisms of action of ARs. Our mechanistic studies indicated that AR C15 and AR C17 exert their anticancer activities in colon-cancer cells by inducing apoptosis through PUMA upregulation and mitochondrial-pathway activation, inducing cell-cycle arrest through p21 upregulation, and inhibiting proteasome activity and Mdm2 expression. This cascade of distinct mechanisms was linked to the consequent activation and accumulation of p53. The results of treatment with p53 inhibitor further confirmed that the p53 pathway might play a very important role in AR-induced apoptosis in colon-cancer cells. Altogether these results show that AR C15 and AR C17 can specifically activate the mitochondrial pathway of apoptosis and cause cell-cycle arrest and that inhibition of p53 greatly reduces the activation of this pathway.

Interindividual Variability in Metabolism of [6]-Shogaol by Gut Microbiota.

[6]-Shogaol (6S), one of the major bioactive components in dry ginger, is attracting considerable attention because of its wide spectrum of biological activities, but its metabolic fate is still not fully understood. In the present study, the microbial metabolism of 6S was examined for the first time in in vitro batch fecal fermentation system and in mice. Two major microbial metabolites were detected and identified as 1-(4'-hydroxy-3'-methoxyphenyl)-decan-3-ol (M9) and 1-(4'-hydroxy-3'-methoxyphenyl)-decan-3-one (M11). Our results indicated that reductions of the double bond and the ketone group are the major metabolic pathways of 6S by the human gut microbiota. We also observed the interindividual variability in the metabolism of M11 to M9 by human gut microbiota. In addition, we demonstrated that the glucuronidated form of 6S and its metabolites could be rapidly deconjugated by human gut microbiota and in mice, which can be regarded as a reactive process taking place in the intestinal tract. To our knowledge, this is the first report involving the identification of the microbial metabolites of 6S in an in vitro fermentation system, and the first demonstration of the critical role of gut microbiota in producing the bioactive free form of 6S and its metabolites in the intestinal tract in mice.

Bioactive compounds isolated from apple, tea, and ginger protect against dicarbonyl induced stress in cultured human retinal epithelial cells.

BACKGROUND: Methylglyoxal (MGO) is known to be a major precursor of advanced glycation end products (AGEs) which are linked to diabetes and its related complications. Naturally occurring bioactive compounds could play an important role in countering AGEs thereby minimizing the risk associated with their formation. METHODS: In this study, eight specific bioactive compounds isolated from apple, tea and ginger were evaluated for their AGEs scavenging activity using Human Retinal Pigment Epithelial (H-RPE) cells treated with MGO. RESULTS: Among the eight specific compounds evaluated, (-)-epigallocatechin 3-gallate (EGCG) from tea, phloretin in apple, and [6]-shogaol and [6]-gingerol from ginger were found to be most effective in preventing MGO-induced cytotoxicity in the epithelial cells. Investigation of possible underlying mechanisms suggests that that these compounds could act by modulating key regulative detoxifying enzymes via modifying nuclear factor-erythroid 2-related factor 2 (Nrf2) function. MGO-induced cytotoxicity led to increased levels of AGEs causing increase in Nε-(Carboxymethyl) lysine (CML) and glutathione (GSH) levels and over expression of receptor for advanced glycation end products (RAGE). Data also showed that translocation of Nrf2 from cytosol to nucleus was inhibited, which decreased the expression of detoxifying enzyme like heme oxygenase-1 (HO-1). The most potent bioactive compounds scavenged dicarbonyl compounds, inhibited AGEs formation and significantly reduced carbonyl stress by Nrf2 related pathway and restoration of HO-1 expression. CONCLUSIONS: These findings demonstrated the protective effect of bioactive compounds derived from food sources against MGO-induced carbonyl stress through activation of the Nrf2 related defense pathway, which is of significant importance for therapeutic interventions in complementary treatment/management of diabetes-related complications.

Natural ß-Dihydroagarofuran-Type Sesquiterpenoids as Cognition-Enhancing and Neuroprotective Agents from Medicinal Plants of the Genus Celastrus.

Alzheimer's disease (AD) is an irreversible, multifaceted, and progressive neurodegenerative disorder. Over the past 30 years, the search for anti-AD drugs has been primarily based on the cholinergic deficiency hypothesis and/or the ß-amyloid (Aß) cascade hypothesis. In this study, we report the identification of 16 new and 38 known ß-dihydroagarofuran-type sesquiterpenoids from Celastrus flagellaris and Celastrus angulatus. The ß-dihydroagarofuran-type sesquiterpenoids 58, 59, 61, and 63 significantly attenuated scopolamine-induced prolonged escape latency and increased number of errors compared with the control group. At 10 µM, 21 of the 62 tested ß-dihydroagarofuran-type sesquiterpenoids rescued Aß25-35-induced SH-SY5Y cells from viability reduction, which increased the cell viability from 64.6% for the model to more than 74.0%. The majority of the ß-dihydroagarofuran-type sesquiterpenoids with ester groups exhibited stronger activity than those with free hydroxy groups or without substituents at the same positions. These results identified a new chemical skeleton as drug lead for the investigation of novel therapeutic agents against AD.

Carnosic acid as a major bioactive component in rosemary extract ameliorates high-fat-diet-induced obesity and metabolic syndrome in mice.

In this study, we investigated the preventive effects of carnosic acid (CA) as a major bioactive component in rosemary extract (RE) on high-fat-diet-induced obesity and metabolic syndrome in mice. The mice were given a low-fat diet, a high-fat diet or a high-fat diet supplemented with either 0.14% or 0.28% (w/w) CA-enriched RE (containing 80% CA, RE#1L and RE#1H), or 0.5% (w/w) RE (containing 45% CA, RE#2), for a period of 16 weeks. There was the same CA content in the RE#1H and RE#2 diets and half of this amount in the RE#1L diet. The dietary RE supplementation significantly reduced body weight gain, percent of fat, plasma ALT, AST, glucose, insulin levels, liver weight, liver triglyceride, and free fatty acid levels in comparison with the mice fed with a HF diet without RE treatment. RE administration also decreased the levels of plasma and liver malondialdehyde, advanced glycation end products (AGEs), and the liver expression of receptor for AGE (RAGE) in comparison with those for mice of the HF group. Histological analyses of liver samples showed decreased lipid accumulation in hepatocytes in mice administrated with RE in comparison with that of HF-diet-fed mice. Meanwhile, RE administration enhanced fecal lipid excretion to inhibit lipid absorption and increased the liver GSH/GSSG ratio to perform antioxidant activity compared with HF group. Our results demonstrate that rosemary is a promising dietary agent to reduce the risk of obesity and metabolic syndrome.

Oxyphytosterols as active ingredients in wheat bran suppress human colon cancer cell growth: identification, chemical synthesis, and biological evaluation.

Consumption of whole grains has been reported to be associated with a lower risk of colorectal cancer. Recent studies illustrated that phytochemicals in wheat bran (WB) may protect against colorectal cancer. There is a growing interest in the phytosterol contents of foods as either intrinsic or added components due to their beneficial health effects. However, little is known whether phytosterols in WB contribute the observed chemopreventative activity of the grain. In the present study, we directly purified and identified four oxyphytosterols 1-4 from sterol-enriched fraction of WB, and also successfully synthesized five sterol oxides 5-8 and 13. Using these nine compounds as references, we outlined a comprehensive profile of steroids in WB using tandem liquid chromatography mass spectrometry with electrospray ionization (LC-ESI/MS(n), n = 2-3) techniques for the first time. Among them, three sterol oxides 13, 14, and 18 are novel compounds, and 14 compounds 3, 4, 6-11, 13, 14, 16, and 18-20 were reported in WB for the first time. Our results on the inhibitory effects of available sterol oxides 1-8 and 13 against the growth of human colon cancer cells HCT-116 and HT-29 showed that compounds 2-8 exerted significant antiproliferative effects, with oxysterol 8 being the most active one in both cells. We further demonstrated that four most active sterol oxides 5-8 could induce cell death through the apoptosis pathway. Our results showed that phytosterols, particularly oxyphytosterols, in WB possess significant antiproliferative properties, and thereby may greatly contribute the observed chemoprevention of the whole grain wheat.

Tea Flavanols Block Advanced Glycation of Lens Crystallins Induced by Dehydroascorbic Acid.

Growing evidence has shown that ascorbic acid (ASA) can contribute to protein glycation and the formation of advanced glycation end products (AGEs), especially in the lens. The mechanism by which ascorbic acid can cause protein glycation probably originates from its oxidized form, dehydroascorbic acid (DASA), which is a reactive dicarbonyl species. In the present study, we demonstrated for the first time that four tea flavanols, (-)-epigallocatechin 3-O-gallate (EGCG), (-)-epigallocatechin (EGC), (-)-epicatechin 3-O-gallate (ECG), and (-)-epicatechin (EC), could significantly trap DASA and consequently form 6C- or 8C-ascorbyl conjugates. Among these four flavanols, EGCG exerted the strongest trapping efficacy by capturing approximate 80% of DASA within 60 min. We successfully purified and identified seven 6C- or 8C-ascorbyl conjugates of flavanols from the chemical reaction between tea flavanols and DASA under slightly basic conditions. Of which, five ascorbyl conjugates, EGCGDASA-2, EGCDASA-2, ECGDASA-1, ECGDASA-2 and ECDASA-1, were recognized as novel compounds. The NMR data showed that positions 6 and 8 of the ring A of flavanols were the major active sites for trapping DASA. We further demonstrated that tea flavanols could effectively inhibit the formation of DASA-induced AGEs via trapping DASA in the bovine lens crystallin-DASA assay. In this assay, 8C-ascorbyl conjugates of flavanols were detected as the major adducts using LC-MS. This study suggests that daily consumption of beverages containing tea flavanols may prevent protein glycation in the lens induced by ascorbic acid and its oxidized products.

Effect of microfluidisation on antioxidant properties of corn bran.

The microfluidisation process was used to reduce the particle size and loosen the tight microstructure of corn bran. This process significantly increased corn bran's antioxidant activity exhibited through a surface reaction phenomenon and the extractability of phenolic compounds after alkaline and acid hydrolysis. For corn bran microfluidised through an 87 µm interaction chamber for 5 passes, the two most largely increased phenolic acids released after alkaline hydrolysis were p-coumaric acid (51.1%) and ferulic acid (45.1%). On the other hand, high shear stress during microfluidisation caused partial dispersion or dissolution of free phenolic compounds in water which was lost after the process. It was also found that bran residues after alkaline and acid hydrolysis still exhibited strong antioxidant activity via a surface reaction phenomenon, probably indicating the conventional method based on solvent extraction and relatively mild alkaline and/or acid hydrolysis underestimates the total phenolic content and antioxidant activity of corn bran.

Identification and pharmacokinetics of novel alkylresorcinol metabolites in human urine, new candidate biomarkers for whole-grain wheat and rye intake.

Biomarkers of dietary intake are prominent tools in nutritional research. The alkylresorcinol metabolites 3,5-dihydroxybenzoic acid (3,5-DHBA) and 3-(3,5-dihydroxyphenyl)propanoic acid (3,5-DHPPA) have been proposed as exposure biomarkers of whole-grain (WG) wheat and rye intake. However, the profile of alkylresorcinol metabolites is not fully understood. The aim of this study was to investigate the metabolism of alkylresorcinols in mice and in humans, while further determining urinary pharmacokinetics of the novel alkylresorcinol metabolites to explore their potential as biomarkers of WG wheat intake. Utilization of the liquid chromatography-mass spectrometry approach resulted in 10 alkylresorcinol metabolites identified in mice and in humans, including 3 phenolic acids and 7 of their phase II conjugates. Among them, 2 novel metabolites were discovered: 5-(3,5-dihydroxyphenyl)pentanoic acid (3,5-DHPPTA) and 2-(3,5-dihydroxybenzamido)acetic acid (3,5-DHBA glycine). The structures of these 2 metabolites were confirmed by comparing with authentic standards synthesized in-house. In the pharmacokinetic study, a group of 12 volunteers consumed a polyphenolic-restricted diet for 4 d before ingesting WG wheat bread containing 61 mg of alkylresorcinols. Urine samples were collected for 32 h, and alkylresorcinol metabolites were quantified with HPLC-coulometric electrode array detection. The mean urinary excretion rates and mean apparent half-life of 3,5-DHPPTA, 3,5-DHBA glycine, 3,5-DHBA, and 3,5-DHPPA at each time point were determined. Our results suggest that 3,5-DHPPTA and 3,5-DHBA glycine may be used in combination with 3,5-DHBA and 3,5-DHPPA as potential biomarkers to increase the accuracy of recording WG wheat and rye intake in epidemiologic studies. Further validation of 3,5-DHPPTA and 3,5-DHBA glycine as potential biomarkers is warranted.

Metabolism of ginger component [6]-shogaol in liver microsomes from mouse, rat, dog, monkey, and human.

SCOPE: There are limited data on the metabolism of [6]-shogaol (6S), a major bioactive component of ginger. This study demonstrates metabolism of 6S in liver microsomes from mouse, rat, dog, monkey, and human. METHODS AND RESULTS: The in vitro metabolism of 6S was compared among five species using liver microsomes from mouse, rat, dog, monkey, and human. Following incubations with 6S, three major reductive metabolites 1-(4'-hydroxy-3'-methoxyphenyl)-4-decen-3-ol (M6), 1-(4'-hydroxy-3'-methoxyphenyl)-decan-3-ol (M9), and 1-(4'-hydroxy-3'-methoxyphenyl)-decan-3-one (M11), as well as two new oxidative metabolites (1E,4E)-1-(4'-hydroxy-3'-methoxyphenyl)-deca-1,4-dien-3-one (M14) and (E)-1-(4'-hydroxy-3'-methoxyphenyl)-dec-1-en-3-one (M15) were found in all species. The kinetic parameters of M6 in liver microsomes from each respective species were quantified using Michaelis-Menten theory. A broad CYP-450 inhibitor, 1-aminobenzotriazole, precluded the formation of oxidative metabolites, M14 and M15, and 18ß-glycyrrhetinic acid, an aldo-keto reductase inhibitor, eradicated the formation of the reductive metabolites M6, M9, and M11 in all species. Metabolites M14 and M15 were tested for cancer cell growth inhibition and induction of apoptosis and both showed substantial activity, with M14 displaying greater potency than 6S. CONCLUSION: We conclude that 6S is metabolized extensively in mammalian species mouse, rat, dog, monkey, and human, and that there are significant interspecies differences to consider when planning preclinical trials toward 6S chemoprevention.

Metabolism of [6]-shogaol in mice and in cancer cells.

Ginger has received extensive attention because of its antioxidant, anti-inflammatory, and antitumor activities. However, the metabolic fate of its major components is still unclear. In the present study, the metabolism of [6]-shogaol, one of the major active components in ginger, was examined for the first time in mice and in cancer cells. Thirteen metabolites were detected and identified, seven of which were purified from fecal samples collected from [6]-shogaol-treated mice. Their structures were elucidated as 1-(4'-hydroxy-3'-methoxyphenyl)-4-decen-3-ol (M6), 5-methoxy-1-(4'-hydroxy-3'-methoxyphenyl)-decan-3-one (M7), 3',4'-dihydroxyphenyl-decan-3-one (M8), 1-(4'-hydroxy-3'-methoxyphenyl)-decan-3-ol (M9), 5-methylthio-1-(4'-hydroxy-3'-methoxyphenyl)-decan-3-one (M10), 1-(4'-hydroxy-3'-methoxyphenyl)-decan-3-one (M11), and 5-methylthio-1-(4'-hydroxy-3'-methoxyphenyl)-decan-3-ol (M12) on the basis of detailed analysis of their (1)H, (13)C, and two-dimensional NMR data. The rest of the metabolites were identified as 5-cysteinyl-M6 (M1), 5-cysteinyl-[6]-shogaol (M2), 5-cysteinylglycinyl-M6 (M3), 5-N-acetylcysteinyl-M6 (M4), 5-N-acetylcysteinyl-[6]-shogaol (M5), and 5-glutathiol-[6]-shogaol (M13) by analysis of the MS(n) (n = 1-3) spectra and comparison to authentic standards. Among the metabolites, M1 through M5, M10, M12, and M13 were identified as the thiol conjugates of [6]-shogaol and its metabolite M6. M9 and M11 were identified as the major metabolites in four different cancer cell lines (HCT-116, HT-29, H-1299, and CL-13), and M13 was detected as a major metabolite in HCT-116 human colon cancer cells. We further showed that M9 and M11 are bioactive compounds that can inhibit cancer cell growth and induce apoptosis in human cancer cells. Our results suggest that 1) [6]-shogaol is extensively metabolized in these two models, 2) its metabolites are bioactive compounds, and 3) the mercapturic acid pathway is one of the major biotransformation pathways of [6]-shogaol.

Cytotoxic dihydroagarofuranoid sesquiterpenes from the seeds of Celastrus orbiculatus.

A chemical study on the seeds of Celastrus orbiculatus has led to the isolation of nine new (1- 9) and 13 known dihydro-beta-agarofuran derivatives. The identification and structural elucidation of the new compounds were based on spectroscopic data analysis, and the absolute configurations of compounds 1- 6, 8-10, and 16, as well as derivatives 2a and 6a, were determined by CD studies or by chemical methods. All compounds isolated were evaluated for cytotoxic activity against HL-60 human leukemia cells.

Anti-Helicobacter pylori and thrombin inhibitory components from Chinese dragon's blood, Dracaena cochinchinensis.

Chemical studies on the constituents of Dracaena cochinchinensis led to the discovery of eight new flavonoid derivatives ( 1- 8) along with 14 known compounds ( 9- 22). The identification and structural elucidation of these isolates were based on spectral analyses. All isolates were tested for antibacterial activities against Helicobacter pylori (ATCC43504) and thrombin inhibitory effects. As a result, new flavonoid derivatives 6 and 7 and (2 S)-4',7-dihydroxy-8-methylflavan ( 11) were found to be most efficacious against H. pylori (ATCC43504) with MIC values of 29.5, 29.5, and 31.3 microM, respectively, and the seven new flavonoid derivatives ( 1- 7) and one known biflavonoid ( 9) were observed to exhibit moderate thrombin inhibitory activity.

Two new compounds from Cleidion brevipetiolatum.

Two new compounds, 4-ethoxycarbonyloxy-3,3',4'-trimethoxy-ellagic acid (1) and 4-E-propenyl-phenol-1-O-beta-D-rutinoside (2), together with four known compounds, 3,3',4'-trimethoxy-ellagic acid (3), 3,3'-dimethoxy-ellagic acid (4), 3,3',4'-trimethoxy-ellagic acid-4-O-beta-D-glucopyranoside (5) and 3'-methoxy-ellagic acid-4-O-alpha-L-rhamnopyranoside (6), were isolated from the whole plant of Cleidion brevipetiolatum. Their structures were elucidated from spectral evidences.