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Fatty Acid Synthase Inhibitors from Geum japonicum THUNB. var. chinense
Abstract
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Bioassay‐guided fractionation of the MeOH extract of Geum japonicum Thunb. var. chinense using the fatty acid synthase inhibition assay led to the isolation of a new dimeric ellagitannin, gemin G ( 1 ), together with six known compounds, gemin A ( 2 ), casuarinin ( 3 ), pedunculagin ( 4 ), potentillin ( 5 ) , tellimagrandin II ( 6 ), and ellagic acid ( 7 ). Their structures were determined on the basis of spectroscopic analyses. Compounds 1 – 7 displayed strong inhibitory activities on fatty acid synthase with IC 50 values in the range of 0.21–41.4 μ M . Compounds 1 – 4 exhibited significant antioxidant activities higher than vitamin C in the ORAC assay. Compounds 1 and 2 also showed weak cytotoxic effects on BGC‐823 cell.
... var. chinense F. Bolle (Rosaceae), exhibit strong inhibitory activity against FAS with IC 50 values at the range of 0.21 to 41.4 μmol/L [31] . ...
... var. chinense F. Bolle (Rosaceae), exhibit strong inhibitory activity against FAS with IC 50 values at the range of 0.21 to 41.4 μmol/L [31] . ...
As the prevalence of obesity and related diseases continues to rise, obesity accompanied chronic inflammation becomesa non-neglect public health problem. Innovative treatment options and strategies for obesity-related chronic inflammation areurgently needed. Fatty acid synthase(FAS) is a multiple enzyme complex which has been recognized as a potential therapeutic targetfor obesity, inflammation, diabetes, non-alcohol fatty liver disease(NAFLD), and cancer. Research on FAS inhibitors has attractedincreasing attention in recent years. Several key inflammatory markers have been consistently associated with obesity, whichsuggests that a persistent inflammatory response is a potentially modifiable risk factor. In China, traditional Chinese medicines(TCMs) have been applied clinically to treat inflammation. Among them there are several TCMs with strong inhibitory effect onFAS. This brief review aims at summarizing literatures concerning the recognized role of FAS as a biomarker and therapeutic targetin obesity and related inflammation as well as providing evidence to support the anti-inflammation potential of TCMs with FASinhibitory activities. FAS has emerged as a crucial target in anti-obesity therapies, and FAS inhibition might contribute to thetreatment of inflammation.
... Geum japonicum, commonly known as Asian herb bennet, is used as a diuretic, astringent, antidizziness, and anti-headache agent in traditional Chinese medicine [6]. Previous studies have reported that G. japonicum crude extract and its active compounds such as triterpenoids have anticoagulant [7], antioxidant [8], anti-HIV [9], angiogenic [10], and vasorelaxant [11] activities. ...
Geum japonicum, commonly known as Asian herb bennet, has been used as a diuretic, astringent, anti-dizziness, and anti-headache agent in traditional medicine. Since the antidepressant-like effects of G. japonicum extract have not been well studied, we examined the antidepressant-like effects of G. japonicum extract using depressive‐like behavior induced in mice through daily injection of corticosterone (CORT). ICR mice (male, 8 weeks old) were treated with CORT (40 mg/kg, i.p.) and orally administered using oral gavage needles with G. japonicum extract (30, 100, and 300 mg/kg) for 4 weeks. Behavioral experiments were performed 1 h after administration. The control mice exhibited a significant increase in the immobility times in the tail suspension and forced swim tests as well as the step-through latency time in the passive avoidance test. Further, the control group showed a significant decrease in their sucrose consumption. However, treatment with G. japonicum extract at doses of 100 and 300 mg/kg significantly improved these depression-like behaviors without altering the locomotor activity. Moreover, treatment with G. japonicum extract significantly prevented the decrease in the expression of brain-derived neurotrophic factor (BDNF) in the hippocampus. In addition, G. japonicum extract had neuroprotective effects against CORT-induced neurotoxicity in SH-SY5Y cells. Our study indicates that G. japonicum extract exhibits antidepressant-like activity in CORT-induced depressive mice, which might be as a result of increased BDNF expression.
... It has been widely used because of its characteristics of both medicine and food. Accumulating clinical trials and basic research demonstrated that GJ extracts exhibited superior functions in various diseases, such as hyperlipaemia [32], hypertension [33], and cardiac infarction [34][35][36] as well as cerebral ischemia [37]. Previous researches have showed that the extracts of GJ could promote the supply of oxygen to the brain, reduce cerebral edema and reduce brain injury caused by cerebral ischemia. ...
Geum japonicum Thunb. var. chinense (GJ) is a type of wild vegetable found in China and other Asian countries; it has been reported that its extracts possess a neuroprotective effect against cerebral ischemia reperfusion (CIR) injury. The aim of this study is to explore the effect GJ extracts on transient focal CIR injury and neurons apoptosis and to clarify its possible underlying mechanisms in vivo . Our results indicated that pretreatment with GJ extracts significantly ameliorated the infarct volume, decreased neurological deficits, lessened neural cells apoptosis, downregulated GFAP activity level, and increased surviving neurons. Moreover, GJ extracts preadministration increased Bcl-2 levels and attenuated the increase in the expressions of Bax and it also lowered the cleaved caspase-3 activity in ischemic cortex tissues which was caused by CIR and increased the expression of PI3K and p-Akt. The above effects of high dose of GJ (GJ-H) group were much better than those of low dose of GJ (GJ-L), which indicated that GJ extracts may be helpful in the suppression of CIR injury with a dose-dependent manner.
... In addition, these natural sources lead to novel structural entities, which can be used directly or function as a precursor for the development of better and more effective molecules (Arif et al., 2009;Negri et al., 2014). The identification of promising molecules with antifungal properties can be streamlined through the screening of crude plant extract to aid the discovery process as the first step of investigation, followed by assays geared toward the identification of molecules responsible for the antifungal activity (Liu et al., 2009;Medeiros et al., 2011;Negri et al., 2014). Notably, this process has provided some evidence of the biological properties of plant extracts and their phytochemical compounds against dermatophytes ( Table 2). ...
Dermatophytes comprise pathogenic fungi that have a high affinity for the keratinized structures present in nails, skin, and hair, causing superficial infections known as dermatophytosis. A reasonable number of antifungal drugs currently exist on the pharmaceutical market to control mycoses; however, their cellular targets are restricted, and fungi may exhibit tolerance or resistance to these agents. For example, the stress caused by antifungal and cytotoxic drugs in sub-inhibitory concentrations promotes compensatory stress responses, with the over-expression of genes involved in cellular detoxification, drug efflux, and signaling pathways being among the various mechanisms that may contribute to drug tolerance. In addition, the ATP-binding cassette transporters in dermatophytes that are responsible for cellular efflux can act synergistically, allowing one to compensate for the absence of the other, revealing the complexity of drug tolerance phenomena. Moreover, mutations in genes coding for target enzymes could lead to substitutions in amino acids involved in the binding of antifungal agents, hindering their performance and leading to treatment failure. The relevance of each one of these mechanisms of resistance to fungal survival is hard to define, mainly because they can act simultaneously in the cell. However, an understanding of the molecular mechanisms involved in the resistance/tolerance processes, the identification of new antifungal targets, as well as the prospective of new antifungal compounds among natural or synthetic products, are expected to bring advances and new insights that facilitate the improvement or development of novel strategies for antifungal therapy.
... chinense. In the referred study, EGCG, which has already been reported to be an inhibitor of FAS, exhibited an IC 50 value of 52.03 µM, while EA showed a higher inhibitory activity with an IC 50 value of 41.40 µM [28]. EAsupplemented rats did not show reductions in total body fat while their abdominal fat was reduced. ...
Background:
Naturally occurring polyphenols are the subject of increasing attention due to their potent antioxidant activity and their marked effects on the prevention of various oxidative stress-associated diseases such as cancer. Ellagic acid (EA) is an herbal polyphenol that is structurally a condensed dimer of gallic acid.
Methods:
This review aims to provide a comprehensive and updated overview on the biological activities of EA and potential therapeutic applications.
Results:
EA is found in fruits and nuts, either in the combined form with hexahydroxydiphenic acid or in the bound form (ellagitannins). EA exhibits many biological properties such as antioxidant, anti-diabetic, anticancer and apoptosis-inducing activities. These biological and pharmacological properties are relevant to the treatment of several human diseases.
Conclusion:
Owing to its multiple mechanisms of action, EA represents a potential therapeutic agent against human diseases particularly cancer.
... Gemin A and B, two ET from Geum japonicum Thunb., were found to exert mild cytotoxic effects on human BGC-823 gastric cancer cells [108]. ...
It is universally accepted that diets rich in fruit and vegetables lead to reduction in the risk of common forms of cancer and are useful in cancer prevention. Indeed edible vegetables and fruits contain a wide variety of phytochemicals with proven antioxidant, anti-carcinogenic, and chemopreventive activity; moreover, some of these phytochemicals also display direct antiproliferative activity towards tumor cells, with the additional advantage of high tolerability and low toxicity. The most important dietary phytochemicals are isothiocyanates, ellagitannins (ET), polyphenols, indoles, flavonoids, retinoids, tocopherols. Among this very wide panel of compounds, ET represent an important class of phytochemicals which are being increasingly investigated for their chemopreventive and anticancer activities. This article reviews the chemistry, the dietary sources, the pharmacokinetics, the evidence on chemopreventive efficacy and the anticancer activity of ET with regard to the most sensitive tumors, as well as the mechanisms underlying their clinically-valuable properties.
... In this work, we showed that EEF decreases FAS protein expression in a hepatocellular carcinoma cell line. Accordingly, Liu et al. (2009) reported that several ellagitannins were strong inhibitors of FAS activity. Taken together, ellagitannins might be potential anticancer molecules through the inhibition of FAS expression and activity. ...
The hepatocellular carcinoma, a primary malignancy of the liver, has a very poor prognosis and a lower survival rate. Moreover, the inefficacy of conventional therapies emphasizes the importance of discovering new bioactive compounds. Several studies clearly state that plant-derived polyphenols, namely ellagitannins, have several health benefits. Fragaria vesca leaves contain high amounts of polyphenols, being especially rich in ellagitannins. Therefore, this study aimed to characterize an ellagitannin-enriched fraction (EEF) from F. vesca leaves and to unveil the anticancer potential of this fraction on human hepatocellular carcinoma cells.
... Geum japonicum, which is abundant in China and commonly known as "Lanbuzheng", has been used as a herbal medicine in diuretics and astringents in traditional Chinese medicine [2]. It is also used for the treatment of dizziness and headache in some regions of China [3]. The previous phytochemical studies on the constituents of Geum japonicum THUNB. ...
This study aims to determine the best extraction conditions and find out the effects of solvent type
(ethanol, aceton, and ionic liquid (1-butyl-3-methylimidazolium bromide) [BMIM] Br), time (20–60 min), and
microwave power (200–600 w) on antioxidant activity and total tannins (TT) of Geum japonicum. The three
parameters, type solvents, extraction time and microwave power, were optimized using the Boxe Behnken design
(BBD) with a quadratic regression model built by using response surface methodology (RSM). The experiments
were carried out according to 17 runs with 3 variables and 3 levels for the optimization. The extracts were analyzed
by spectrophotometeric methods for the antioxidant and (TT). The optimal extraction conditions were determined as
follows: [BMIM]Br), microwave power 437.07 w, extraction time 36.89 min for the best antioxidant 92.24% and TT
2.44 mg GAE/g in these conditions. While the experimental maximum antioxidant was 91.5 ± 2.12 and TT was 2.72
± 2.34 mg GAE/g of the G. japonicum extract, which matched with the predicted values. Results showed that
[BMIM] [Br] solvent are more efficient in the extraction of antioxidant and TT compare with ethanol and aceton
solvents. This study confirmed that the [BMIM] [Br], time 36.89 min and power 437.07 w were the most efficient
for extraction of antioxidant and TT.
... Geum japonicum, which is abundant in China and commonly known as "Lanbuzheng", has been used as a herbal medicine in diuretics and astringents in traditional Chinese medicine [2]. It is also used for the treatment of dizziness and headache in some regions of China [3]. The previous phytochemical studies on the constituents of Geum japonicum THUNB. ...
This study aims to determine the best extraction conditions and find out the effects of solvent type (ethanol, aceton, and ionic liquid (1-butyl-3-methylimidazolium bromide) [BMIM] Br), time (20–60 min), and microwave power (200–600 w) on antioxidant activity and total tannins (TT) of Geum japonicum. The three parameters, type solvents, extraction time and microwave power, were optimized using the Boxe Behnken design (BBD) with a quadratic regression model built by using response surface methodology (RSM). The experiments were carried out according to 17 runs with 3 variables and 3 levels for the optimization. The extracts were analyzed by spectrophotometeric methods for the antioxidant and (TT). The optimal extraction conditions were determined as follows: [BMIM]Br), microwave power 437.07 w, extraction time 36.89 min for the best antioxidant 92.24% and TT 2.44 mg GAE/g in these conditions. While the experimental maximum antioxidant was 91.5 ± 2.12 and TT was 2.72 ± 2.34 mg GAE/g of the G. japonicum extract, which matched with the predicted values. Results showed that [BMIM] [Br] solvent are more efficient in the extraction of antioxidant and TT compare with ethanol and aceton solvents. This study confirmed that the [BMIM] [Br], time 36.89 min and power 437.07 w were the most efficient for extraction of antioxidant and TT.
... Other ETs may also have a potential effect on lipid metabolism and, consequently, in atherosclerosis development. For example, EA and some ETs present in the Chinese plant Geum japonicum (gemin-A and -B, casuarinin, pedunculagin, etc.) are able to inhibit the activity of fatty acid synthase (FASN) (Liu et al., 2009), an important lipogenic enzyme that catalyzes the synthesis of long-chain saturated fatty acids (Menendez et al., 2009). ETs like lagerstroemin, flosin B, stachyurin, etc. abundant in Lagerstroemia speciosa (L.) Pers. ...
Hydrolysable tannins are phenolic phytochemicals that show high antioxidant and free-radical scavenging activities. For this reason their potential effects preventing oxidative related diseases, such as cardiovascular diseases, have been largely studied. In vitro studies show that ellagitannins, at concentrations in the range 10-100 μM, show some relevant anti-atherogenic, anti-thrombotic, anti-inflammatory and anti-angiogenic effects, supporting the molecular mechanisms for the vascular health benefits. While there is good evidence supporting the vascular effects in vitro, the evidence on animal models or humans is much scarcer. The in vitro results often do not match the findings in the in vivo studies. This could be explained by the low bioavailability of the antioxidant ellagitannins and ellagic acid. The main ellagitannin metabolites circulating in plasma are ellagic acid microbiota metabolites known as urolithins, and they have lost their free-radical scavenging activity. They are present in plasma as glucuronide or sulphate conjugates, at concentrations in the nM range. Future studies should focus in the bioavailable metabolites, urolithins, and in the form (conjugated with glucuronic acid or sulphate) and concentrations (nM range) in which they are found in plasma. In this review we critically discuss the role of ellagitannins and ellagic acid on vascular health.
Cancer cells require a higher amount of energy in the form of fatty acids for their uncontrolled proliferation and growth. Fatty acid synthase (FASN) plays a crucial role in the synthesis of palmitate, which is involved in most of the critical malignant pathways. Hence, by targeting FASN, tumour growth can be controlled. By designing and developing FASN inhibitors with catalytic domain specificity, safe and potential anticancer drugs can be achieved. The article draws light towards the catalytic domains of FASN, their active site residues and interaction of some of the reported natural FASN inhibitors (resveratrol, lavandulyl flavonoids, catechins, stilbene derivatives, etc). The rationality (SAR) behind the variation in the activity of the reported natural FASN inhibitors (butyrolactones, polyphenolics, galloyl esters and thiolactomycins) has also been covered. Selective, safe and potentially active FASN inhibitors could be developed by: (i) having proper understanding of the function of all catalytic domains of FASN (ii) studying the upstream and downstream FASN regulators (iii) identifying cancer specific FASN biomarkers (that are non-essential/absent in the normal healthy cells) (iv) exploring the complete protein structure of FASN, e-screening of the compounds prior to synthesis and study their ADME properties (v) predicting the selectivity based on their strong affinity at the catalytic site of FASN.
Paradoxically, despite the progress in medicine, the prevalence of fungal infections is increasing from year to year. At the beginning of the third millennium, practical therapeutic options are still very limited. Currently, only eight classes of antifungal compounds are in clinical use, only four of which are used in the treatment of dermatomycoses. The intense search for the “Holy Grail” of antifungal therapy that has been going on since the second half of the 20th century faces serious obstacles arising from the eukaryotic model of fungal cell structure. In this paper, new groups of chemical compounds of mainly natural origin have been synthetically described, which due to their interesting antifungal activity, including pathogenic species of dermatophytes, may constitute new therapeutic options. Among compounds currently arousing great interest, compounds from the group of terpenoids, alkaloids, saponins, flavonoids and essential oils deserve attention. Many of these compounds are in clinical trials as potential antifungal agents, while others are in preclinical studies. Future research should focus on attempting to determine the applicability of the given substances in implementation for routine use and their effectiveness, toxicity and side effects.
1. Introduction. 2. General characteristics of dermatophytes in the therapeutic aspect. 3. New synthetic preparations with antifungal activity. 4. Natural antifungal preparations. 4.1. Terpenoids and essential oils. 4.2. Alkaloids. 4.3. Flavonoids. 4.4. Saponins. 4.5. Other chemical compounds 5. Summary
Background
Fatty acid synthase (FAS or FASN) is a vital enzyme which catalyzes the de novo synthesis of long chain fatty acids. A number of studies have recently been reported that FAS was combined targets for the discovery of anti-obesity and anti-cancer drugs. Great interest has been developed in finding novel FAS inhibitors, and result in more than 200 inhibitors being reported.
Methods
The reported research literature about the FAS inhibitors was collected and analyzed through major databases including Web of Science, and PubMed. Then the chemical stractures, FAS inhibitory activities, and structure-activity relationships (SAR) were summarized focused on all these reported FAS inhibitors.
Results
The 248 FAS inhibitors, which were reported during the past 20 years, could be divided into thiolactone, butyrolactone and butyrolactam, polyphenols, alkaloids, terpenoids, and other structures, in view of their structure characteristics. And the SAR of high inhibitory structures of each type was proposed in this paper.
Conclusion
A series of synthetic quinolinone derivatives show strongest inhibitory activity in the reported FAS inhibitors. Natural polyphenols, existing in food and herbs, show more adaptive in medicine exploration because of their safety and efficiency. Moreover, screening the FAS inhibitors from microorganism and marine natural products could be the hot research directions in the future.
Previous studies in humans have indicated that de novo lipogenesis contributes considerably to redundant lipid storage and steatosis in the liver of patients with nonalcoholic fatty liver disease (NAFLD), and...
Context Fatty acid synthase (FAS) is the only mammalian enzyme to catalyse the synthesis of fatty acid. The expression level of FAS is related to cancer progression, aggressiveness and metastasis. In recent years, research on natural FAS inhibitors with significant bioactivities and low side effects has increasingly become a new trend. Herein, we present recent research progress on natural fatty acid synthase inhibitors as potent therapeutic agents.
Objective This paper is a mini overview of the typical natural FAS inhibitors and their possible mechanism of action in the past 10 years (2004–2014).
Method The information was collected and compiled through major databases including Web of Science, PubMed, and CNKI.
Results Many natural products induce cancer cells apoptosis by inhibiting FAS expression, with fewer side effects than synthetic inhibitors.
Conclusion Natural FAS inhibitors are widely distributed in plants (especially in herbs and foods). Some natural products (mainly phenolics) possessing potent biological activities and stable structures are available as lead compounds to synthesise promising FAS inhibitors.
To establish the method for qualitative and quantitative determination of gallic acid in Herba Gei. Gallic acid content is determined by HPLC with Diamonsil C18 column as the stationary phase, under the conditions of methanol-0.1% phosphoric acid in water (10:90) mobile phase, 271 nm detection wavelength, and 40℃ column temperature. Peak area of gallic acid shows a good linearity with the injection volume within a 0.202~1.212 μg range, r=0.9997; average recovery is 99.26%, RSD 2.20%. Through quantitative determination of Herba Gei of different origins, the method established herein is confirmed to be simple, fast, sensitive, accurate, reliable and reproducible.
The present study was performed to investigate the potential effects of the unripened dried fruit of Rubus coreanus Miq., Rubi Fructus (RF), on hepatic steatosis and lipid metabolism in mice fed with a high‑fat diet (HFD) known to induce obesity and hyperlipidaemia. Rubi Fructus extract (RFex) fed mice demonstrated a reduced body weight and adipose tissue weight. RFex fed mice also demonstrated decreased aminotransferase levels, lipid contents [triglyceride (TG), total cholesterol (TC) and low‑density lipoprotein‑cholesterol (LDL‑C)], leptin content and increased high‑density lipoprotein‑cholesterol (HDL‑C) contents in the plasma. These effects were accompanied by a decreased expression of lipogenic genes, including sterol regulatory element binding protein‑1c, liver X receptor, fatty acid synthase (FAS), acetyl‑CoA carboxylase, cluster of differentiation 36, lipoprotein lipase and decreased lipogenic enzyme FAS and 3‑hydroxy‑3 methylglutamyl coenzyme reductase enzyme activities, while elevating carnitine palmitoyltrasferase‑1 activity. Based on these results, the present study hypothesized that the inhibitory effect on hepatic steatosis of RFex is the result of the suppression of lipid synthesis in mice fed with HFD, suggesting that RFex may be beneficial in preventing hepatic steatosis and liver lipotoxicity.
The chemical composition of the volatile oil extracted from the aerial parts of Brassica rapa cv. "yukina" was analyzed using GC-MS, GC-PFPD, and GC-O. A total of 50 compounds were identified. The most prominent constituents were (E)-1,5-heptadiene (40.27%), 3-methyl-3-butenenitrile (25.97%) and 3-phenylpropanenitrile (12.41%). With regard to aroma compounds, 12 compounds were identified by GC-O analysis. The main aroma-active compounds were dimethyl tetrasulfide (sulphury-cabbage, FD = 64), 3-phenylpropanenitrile (nutty, FD = 64), 3-methylindole (pungent, FD = 64), and methional (potato, FD = 32). The antioxidant activity of the aroma-active compounds of the oil was determined using an oxygen radical absorbance capacity (ORAC) assay using fluorescein as the fluorescent probe. The ORAC values were found to be 785 ± 67 trolox equivalents (μmol TE/g) for B. rapa cv. "yukina" oil. The results obtained showed that the volatile oil extracted from the aerial parts is a good dietary source of antioxidants.
The volatile oils from the Japanese wild edible plants of Diplazium squamigerum, Laportea macrostachya, and Vitis coignetiae were investigated by capillary gas chromatography and gas chromatography-mass spectrometry. The major components of D. squamigerum oil were linalool (28.7%), palmitic acid (13.9%), and α-terpineol (5.5%); of L. macrostachya oil were palmitic acid (14.1%), nonanal (9.2%), and linoleic acid (8.9%); and of V. coignetiae oil were nonanal (13.2%), geraniol (11.6%), and phenylacetaldehyde (8.5%). These oils were assayed to determine their antioxidant activity by the oxygen radical absorbance capacity assay using fluorescein as the fluorescent probe. The oxygen radical absorbance capacity values varied from 1255 ± 393 trolox equivalents (μmol TE/g) for D. squamigerum oil, from 514 ± 65 μmol TE/g for L. macrostachya oil, and from 911 ± 118 μmol TE/g for V. coignetiae oil. The difference in the antioxidant activities among D. squamigerum oil, L. macrostachya oil, and V. coignetiae oil were attributed to their different monoterpene alcohol contents and composition in the samples. These data provided evidence that the volatile oil from Japanese edible plants is a good dietary source of antioxidants.
The volatile oils from Japanese wild edible plant of Basella rubra, Erythronium japonicum and Wisteria brachybotrys were investigated by capillary GC and GC-MS. The major components of B. rubra oil were phytol (22.3%), palmitic acid (19.8%) and indol (14.0%), of E. japonicum oil were tulipaline A (42.8%), tricosane (12.3%) and 2-pentyl furan (5.7%), and of W. brachybotrys oil were benzyl cyanide (31.7%), palmitic acid (8.7%) and γ-(Z)-bisabolene (7.6%). These oils were assayed to determine their antioxidant activity by the oxygen radical absorbance capacity (ORAC) assay using fluorescein (FL) as fluorescent probe. The ORAC values varied as 937 ± 120 μmol TE/g for B. rubra oil, from 602 ± 76 μmol TE/g for E. japonicum oil, and from 1296 ± 163 μmol TE/g for W. brachybotrys oil. These data provided evidence that the volatile oil from Japanese edible plants as good dietary sources of antioxidants.
Two new resveratrol tetramers, cajyphenol A (1) and cajyphenol B (2), together with two known resveratrol dimers, quadrangularin A (3) and pallidol (4), and resveratrol (5) were isolated from the stems of Cayratia japonica (Thunb.) Gagn. Their structures were established by means of NMR (¹H,¹H-COSY, ¹H, ¹³C-HSQC, HMBC, and NOESY) and ESI-MS analyses. Compounds 1-5 showed fast-binding inhibitory activities on fatty acid synthase with the IC₅₀ values of 1.63±0.02, 1.49±0.03, 7.50±0.01, 11.1±0.01, and 10.2±0.01 μM, respectively. Compounds 1-5 also exhibited antioxidant activities in the ORAC assay.
Camellia pachyandra Hu. is a species in Camellia sect. Heterogenea (Theaceae), whose leaves have been used for making tea and consumed by the local people living in Yunnan province, China. This is the first investigation of the chemical constituents in the leaves of C. pachyandra, from which 22 phenolic compounds including nine hydrolyzable tannins (1-9), 11 flavonol glycosides (10-20), and two simple phenolics (21, 22) were isolated. It was noted that the leaves of the title plant contained no caffeine and no catechin, whereas hydrolyzable tannins were found to be the major constituents, of which the content of ellagitannin 5 reached to 3.7%. All the isolates were evaluated for their antioxidant activities by DPPH radical scavenging and tyrosinase inhibitory assays. Though the secondary metabolites without caffeine and catechins are different from the commonly consumed tea plants, the results suggested that the leaves of C. pachyandra, rich in hydrolyzable tannins as potent antioxidants, could be developed as an ideal resource for a natural beverage without caffeine.
Fatty acid synthase (FAS) is uniquely expressed at high levels in cancer cells and adipose tissue. The objectives of this study were to identify, purify and validate soy FAS inhibitory peptides and to predict their binding modes. Soy peptides were isolated from hydrolysates of purified β-conglycinin by co-immunoprecipitation and identified using LC-MS/MS. Three peptides, KNPQLR, EITPEKNPQLR and RKQEEDEDEEQQRE, inhibited FAS. The biological activity of these peptides was confirmed by their inhibitory activity against purified chicken FAS (IC50 = 79, 27 and 16 μm, respectively) and a high correlation (r = −0.7) with lipid accumulation in 3T3-L1 adipocytes. The FAS inhibitory potency of soy peptides also correlated with their molecular mass, pI value and the number of negatively charged and hydrophilic residues. Molecular modeling predicted that the large FAS inhibitory peptides (EITPEKNPQLR and RKQEEDEDEEQQRE) bond to the thioesterase domain of human FAS with lower interaction energies (−442 and −353 kcal·mol−1, respectively) than classical thioesterase inhibitors (Orlistat, −91 kcal·mol−1 and C75, −51 kcal·mol−1). Docking studies suggested that soy peptides blocked the active site through interactions within the catalytic triad, the interface cavity and the hydrophobic groove in the human FAS thioesterase domain. FAS thioesterase inhibitory activities displayed by the synthetic soy peptides EITPEKNPQLR and RKQEEDEDEEQQRE (IC50 = 10.1 ± 1.6 and 10.7 ± 4.4 μm, respectively) were higher than C75 (58.7 μm) but lower than Orlistat (0.9 μm). This is the first study to identify FAS inhibitory peptides from purified β-conglycinin hydrolysates and predict their binding modes at the molecular level, leading to their possible use as nutraceuticals.
Structured digital abstract
Compared to normal human tissues, many common human cancers, including carcinoma of the colon, prostate, ovary, breast, and
endometrium, express high levels of fatty acid synthase (FAS, EC 2.3.1.85), the primary enzyme responsible for the synthesis of fatty acids. This differential expression of FAS between normal tissues
and cancer has led to the notion that FAS is a target for anticancer drug development. Recent studies with C75, an inhibitor
of fatty acid synthesis, have shown significant antitumor activity with concomitant inhibition of fatty acid synthesis in
tumor tissue and normal liver. Importantly, histopathological analysis of normal tissues after C75 treatment showed no adverse
effects on proliferating cellular compartments, such as bone marrow, gastrointestinal tract, skin, or lymphoid tissues. In
this study, we describe the de novo synthesis of C75 based on the known mechanism of action of cerulenin and the theoretical reaction intermediates of the β-ketoacyl
synthase moiety of FAS. In addition, we demonstrate that C75 is a synthetic, chemically stable inhibitor of FAS. C75 inhibits
purified mammalian FAS with characteristics of a slow-binding inhibitor and also inhibits fatty acid synthesis in human cancer
cells. Treatment of human breast cancer cells with [5-3H]C75 demonstrates that C75 reacts preferentially with FAS in whole cells. Therefore, we have shown that the primary mechanism
of the antitumor activity of C75 is likely mediated through its interaction with, and inhibition of, FAS. This development
will enable the in vivo study of FAS inhibition in human cancer and other metabolic diseases.
Fatty acid synthase (FAS; EC 2.3.1.85) was purified to near homogeneity from a human hepatoma cell line, HepG2. The HepG2 FAS has a specific activity of 600 nmol of NADPH oxidized per min per mg, which is about half that of chicken liver FAS. All the partial activities of human FAS are comparable to those of other animal FASs, except for the beta-ketoacyl synthase, whose significantly lower activity is attributable to the low 4'-phosphopantetheine content of HepG2 FAS. We cloned the human brain FAS cDNA. The cDNA sequence has an open reading frame of 7512 bp that encodes 2504 amino acids (M(r), 272,516). The amino acid sequence of the human FAS has 79% and 63% identity, respectively, with the sequences of the rat and chicken enzymes. Northern analysis revealed that human FAS mRNA was about 9.3 kb in size and that its level varied among human tissues, with brain, lung, and liver tissues showing prominent expression. The nucleotide sequence of a segment of the HepG2 FAS cDNA (bases 2327-3964) was identical to that of the cDNA from normal human liver and brain tissues, except for a 53-bp sequence (bases 3892-3944) that does not alter the reading frame. This altered sequence is also present in HepG2 genomic DNA. The origin and significance of this sequence variance in the HepG2 FAS gene are unclear, but the variance apparently does not contribute to the lower activity of HepG2 FAS.
One of the key limiting factors in the treatment of advanced stage human epithelial malignancies is the lack of selective molecular targets for antineoplastic therapy. A substantial subset of human ovarian, endometrial, breast, colorectal, and prostatic cancers exhibit increased endogenous fatty acid biosynthesis and overexpress certain enzymes in the pathway. Cell lines derived from these tumors use endogenously synthesized fatty acids for cellular functions, whereas normal cells and tissues appear to utilize dietary lipids preferentially. We have previously shown that the difference in fatty acid biosynthesis between cancer and normal cells is an exploitable target for metabolic inhibitors in vitro. Here, we report observations in vivo using the i.p. model of the multiply drug-resistant OVCAR-3 human ovarian carcinoma in nude mice which demonstrate that: (a) fatty acid synthase overexpression in OVCAR-3 is comparable to levels in primary human tumors assessed by immunohistochemistry; (b) fatty acid synthetic activity of OVCAR-3 is comparably elevated in vitro and in vivo and is 4 to >20-fold higher than normal murine tissues; (c) treatment with the specific fatty acid synthase inhibitor, cerulenin, markedly reduces tumor cell fatty acid biosynthesis in vivo; (d) fatty acid synthase inhibition produces regression of established ascites tumor; and (e) treatment with cerulenin causes reduction in ascites incidence, delay in onset of ascites, and significantly increased survival (P<0.04).
Pharmacological inhibitors of the anabolic enzyme, fatty acid synthase (FAS), including the natural product cerulenin and the novel compound c75, are selectively cytotoxic to cancer cells via induction of apoptosis, apparently related to the tumor cell phenotype of abnormally elevated fatty acid synthetic metabolism. As part of a larger effort to understand the immediate downstream effect of FAS inhibition that leads to apoptosis, the effects of these inhibitors on cell cycle progression were examined. Both FAS inhibitors produce rapid, profound inhibition of DNA replication and S phase progression in human cancer cells. The dose responses for fatty acid synthesis inhibition and DNA synthesis inhibition are similar. The kinetics of both effects are rapid, with fatty acid synthesis inhibition occurring within 30 min and DNA synthesis inhibition occurring within 90 min of drug exposure. Meanwhile, apoptotic changes are not detected until 6 h or later after inhibitor exposure. Fatty acid synthetic pathway activity and the magnitude of DNA synthesis inhibition by FAS inhibitors are increased in parallel by withdrawal of lipid-containing serum from the cultures. The mechanism of DNA synthesis inhibition by cerulenin is indirect, because expression of certain viral oncogenes rescues DNA synthesis/S phase progression in cerulenin-exposed cells. The data suggest a direct linkage at a regulatory level, between fatty acid synthesis and DNA synthesis in proliferating tumor cells.
Compared to normal human tissues, many common human cancers, including carcinoma of the colon, prostate, ovary, breast, and endometrium, express high levels of fatty acid synthase (FAS, EC ), the primary enzyme responsible for the synthesis of fatty acids. This differential expression of FAS between normal tissues and cancer has led to the notion that FAS is a target for anticancer drug development. Recent studies with C75, an inhibitor of fatty acid synthesis, have shown significant antitumor activity with concomitant inhibition of fatty acid synthesis in tumor tissue and normal liver. Importantly, histopathological analysis of normal tissues after C75 treatment showed no adverse effects on proliferating cellular compartments, such as bone marrow, gastrointestinal tract, skin, or lymphoid tissues. In this study, we describe the de novo synthesis of C75 based on the known mechanism of action of cerulenin and the theoretical reaction intermediates of the beta-ketoacyl synthase moiety of FAS. In addition, we demonstrate that C75 is a synthetic, chemically stable inhibitor of FAS. C75 inhibits purified mammalian FAS with characteristics of a slow-binding inhibitor and also inhibits fatty acid synthesis in human cancer cells. Treatment of human breast cancer cells with [5-(3)H]C75 demonstrates that C75 reacts preferentially with FAS in whole cells. Therefore, we have shown that the primary mechanism of the antitumor activity of C75 is likely mediated through its interaction with, and inhibition of, FAS. This development will enable the in vivo study of FAS inhibition in human cancer and other metabolic diseases.
With the escalation of obesity-related disease, there is great interest in defining the mechanisms that control appetite and
body weight. We have identified a link between anabolic energy metabolism and appetite control. Both systemic and intracerebroventricular
treatment of mice with fatty acid synthase (FAS) inhibitors (cerulenin and a synthetic compound C75) led to inhibition of
feeding and dramatic weight loss. C75 inhibited expression of the prophagic signal neuropeptide Y in the hypothalamus and
acted in a leptin-independent manner that appears to be mediated by malonyl–coenzyme A. Thus, FAS may represent an important
link in feeding regulation and may be a potential therapeutic target.
The Cotton effects around 235, 265 and 285 nm in the CD spectra of twenty hydrolysable tannins and related compounds were empirically correlated with the stereostructures of ellagitannins and gallotannins.
Chemical investigation of Euphorbia thymifolia has led to the isolation and characterization of a new hydrolysable tannin named isomallotinic acid, in addition to 15 known tannins. The structure of isomallotinic acid was established on the basis of spectroscopic and chemical evidence.
Three novel dimeric hydrolysable tannins, gemins A, B, and C, have been isolated from the leaves of Geum japonicum(Thunb.) and their structures, which have α- and β-glucose cores linking through a dehydrodigalloyl group, have been elucidated from spectral and chemical evidence
Three novel C-glucosidic ellagitannins, casuarinin, casauriin, and stachyurin, and two additional new ellagitannins, casuarictin and strictinin, were isolated from the leaves of Casuarina stricta, and their structures elucidated on the basis of chemical and spectral evidence. Pedunculagin and tellimagrandin I were also isolated, and the structure having (S)-4,4′,5,5′,6,6′-hexahydroxydiphenoyl groups was established for pedunculagin. These seven ellagitannins isolated from C. stricta have been found also in Stachyurus praecox.
The induction of interleukin-1 (IL-1) by agrimoniin, a tannin of Agrimonia pilosa Ledeb., in human peripheral blood mononuclear cells (PBMC) in vitro and in mouse adherent peritoneal exudate cells (PEC) in vivo was studied. A significant amount of IL-1 beta in the culture supernatant of the human PBMC stimulated with agrimoniin was detected with an enzyme-linked immunoadherent assay. Agrimoniin induced IL-1 beta secretion dose- and time-dependently. The adherent PEC from mice intraperitoneally injected with agrimoniin (10 mg/kg) also secreted IL-1 4 days later. These results suggest that agrimoniin, a plant tannin, is a novel cytokine inducer.
Fatty acid synthase of chicken liver is inactivated rapidly and irreversibly by incubation with chloroacetyl-CoA or with bromopyruvate. Inactivation by both reagents follows saturation kinetics, indicating the formation of an E ... I complex (dissociation constants of 0.36 microM for chloroacetyl-CoA and 31 microM for bromopyruvate) prior to alkylation. The limiting rate constants are 0.15 s-1 for bromopyruvate and 0.041 s-1 for chloroacetyl-CoA. Inactivation by both reagents is protected by NADPH and 200 mM KCl, and by saturating amounts of thioester substrates which reduced the limiting rate constants 6.5-30-fold. Active-site-directed reaction of chloroacetyl-CoA is supported by the ability of this compound to form a kinetically viable complex with the enzyme as competitive inhibitor of acetyl-CoA. Chloroacetyl-CoA interacts initially at the CoA binding pocket, since the nucleotide afforded competitive protection of inactivation and caused a large decrease in its affinity. Subsequently, the phosphopantetheine prosthetic group is alkylated. Evidence is presented to show that bromopyruvate competes with chloroacetyl-CoA for the same target site.
The relationships between structures, antitumor activities and interleukin-1 (IL-1) induction by fifteen tannins were studies. When tannins (10 mg/kg) were intraperitoneally injected into mice once, 4 days before intraperitoneal inoculation of S-180 cells, tellimagrandin II, rugosin A, hirtellin B, oenothein B and oenothein A, which have only tellimagrandins I or II units in their molecules, had significant antitumor activity. Although casuarictin and its related tannins were ineffective, agrimonin, which is a dimer, had a strong effect, as previously reported. On the other hand, monomeric ellagitannins such as tellimagrandins I and II, rugosin A and casuarictin also increased IL-1 beta production from human peripheral macrophages in vitro by 2-fold over the non-stimulated basal production and oligomeric ellagitannins with strong antitumor activity more potently stimulated the IL-1 beta induction. Other tannins having no antitumor activity induced less IL-beta. This study indicates that oligomeric ellagitannins, which consist of tellimagrandin I or II, casuarictin or their related structure units, have antitumor activity and induce IL-1 beta.
This review documents the changing perspectives on the function of fatty-acid synthase and fatty-acid synthesis in human tumor biology. With the recent discovery that human cancer cells express high levels of fatty-acid synthase and undergo significant endogenous fatty-acid synthesis, our understanding of the role of fatty acids in tumor biology is expanding. Once considered largely an anabolic-energy-storage pathway, fatty-acid synthesis is now associated with clinically aggressive tumor behavior and tumor-cell growth and survival and has become a novel target pathway for chemotherapy development. These findings will ultimately enhance our understanding of fatty acids in tumor biology and may provide new diagnostic and therapeutic moieties for patient care.
With the escalation of obesity-related disease, there is great interest in defining the mechanisms that control appetite and body weight. We have identified a link between anabolic energy metabolism and appetite control. Both systemic and intracerebroventricular treatment of mice with fatty acid synthase (FAS) inhibitors (cerulenin and a synthetic compound C75) led to inhibition of feeding and dramatic weight loss. C75 inhibited expression of the prophagic signal neuropeptide Y in the hypothalamus and acted in a leptin-independent manner that appears to be mediated by malonyl-coenzyme A. Thus, FAS may represent an important link in feeding regulation and may be a potential therapeutic target.
Correlation of elevated levels of the lipogenic enzyme, fatty acid synthase (FASE), with advanced stages of some cancers has drawn attention to this enzyme as a possible marker of poor prognosis. Because recent studies have shown that cancer cells are dependent on fatty acid synthetic activity and pharmacologic inhibitors of this enzyme are selectively cytotoxic to cancer cells, expression of FASE also may provide a potential target for intervention in the neoplastic process. To determine the potential usefulness of expression of FASE in the neoplastic process of the lung, we evaluated its pattern of expression immunohistochemically in archival specimens from 60 human lung specimens with squamous cell cancer (SCC) and associated "preneoplastic" lesions compared with its expression in the normal bronchial epithelium of 60 noncancer specimens. The expression of FASE was significantly higher in SCC associated uninvolved bronchial epithelium (mean = 0.40+/-0.03, median = 0.38) compared with its expression in the bronchial epithelium of noncancer specimens (mean = 0.18+/-0.02, median = 0.16) indicating its early expression. We also observed a statistically significant step-wise increase in FASE expression from SCC associated uninvolved bronchial epithelium (mean = 0.40+/-0.03, median = 0.38) to epithelial hyperplasia (0.58+/-0.04, median = 0.57) to SCC (1.53+/-0.06, median = 1.50). The results suggested that expression of FASE is an early event in the development and progression of SCC of the lung. The inhibition of fatty acid synthesis by inhibiting enzymatic function with metabolic analogues may be a useful strategy in the treatment of SCCs. The expression of FASE in early lesions such as SCC associated uninvolved bronchial epithelium and epithelial hyperplasia might also provide a potential means for intervention early in the neoplastic process in the lung or even preventing their malignant transformation to invasive carcinomas.
Many common human cancer tissues express high levels of fatty acid synthase (FAS), the primary enzyme for the synthesis of fatty acids, and the differential expression of FAS between normal and neoplastic tissues has led to the consideration of FAS as a target for anticancer therapy. To investigate the potential of targeting FAS for the treatment of pleural mesothelioma, we first determined whether FAS is overexpressed in human mesothelioma. By immunohistochemistry, we found 22 of 30 human mesothelioma tissue samples tested to express significantly increased levels of FAS compared with normal tissues, including mesothelium. To further explore FAS as a therapeutic target in mesothelioma, we established a nude mouse xenograft model for human mesothelioma using the H-Meso cell line. The i.p. xenografts of this cell line have high levels of FAS expression and fatty acid synthesis pathway activity and grow along mesothelial surfaces in a manner similar to the growth pattern of human mesothelioma. Growth of these tumor xenografts was essentially abolished in mice treated with weekly i.p. injections of C75, a synthetic, small molecule inhibitor of FAS, at levels that resulted in no significant systemic toxicity except for reversible weight loss. These results suggest that FAS may be an effective target for pharmacological therapy in a high proportion of human mesotheliomas.
Fatty acid synthase (FAS) is selectively expressed in certain human cancers, including carcinoma of the breast, prostate, colon, ovary, and endometrium, compared to normal human tissues and therefore is a putative tumor marker. In this study, we found FAS concentrations were elevated in cell culture supernatants during cell growth in two human breast cancer cell lines but not other cancer cell lines. A quantitative enzyme-linked immunosorbent assay and Western blot analysis were employed in this study. In addition, serum FAS levels were significantly higher in breast cancer patients with different clinical stages (Stage II: 0.59+/-0.09 units/l, Stage III: 0.79+/-0.13 units/l, and Stage IV: 1.39+/-0.35 units/l) compared with healthy subjects (0.27+/-0.02 units/l, P<0.05). Taken together, our data suggest that FAS expression may be a useful tumor marker for breast cancer and play a role in assessing cancer virulence.
An improved method of oxygen radical absorbance capacity (ORAC) assay has been developed and validated using fluorescein (3',6'-dihydroxyspiro[isobenzofuran-1[3H],9'[9H]-xanthen]-3-one) as the fluorescent probe. Our results demonstrate that fluorescein (FL) is superior to B-phycoerythrin. The oxidized FL products induced by peroxyl radical were identified by LC/MS, and the reaction mechanism was determined to follow a classic hydrogen atom transfer mechanism. In addition, methodological and mechanistic comparison of ORAC(FL) with other widely used methods was discussed. It is concluded that, unlike other popular methods, the improved ORAC(FL) assay provides a direct measure of hydrophilic chain-breaking antioxidant capacity against peroxyl radical.
We discover that epigallocatechin gallate (EGCG) from green tea is an inhibitor of fatty-acid synthase (FAS) from chicken liver. Its inhibition of FAS is composed of reversible fast-binding inhibition, through which 52 microM EGCG can inhibit 50% of the activity of FAS, and irreversible slow-binding inactivation following saturation kinetics with the dissociation constant of 0.352 mM and limiting rate constant of 0.0168 min(-1). The marked inhibition of ketoacyl reduction shows that the inhibition is related to beta-ketoacyl reductase of FAS. The observable protection of NADPH and competitive inhibition of NADPH for ketoacyl reduction indicate that EGCG may compete with NADPH for the same binding site. The synthetic inhibitor C75 does not show obvious fast-binding inhibition, but does exhibit irreversible slow-binding biphasic inactivation, which is demonstrated to be a second-order reaction. That the inactivation by C75 is protected by malonyl-CoA indicates C75 is similar to cerulenin in being a covalent inactivator of the beta-ketoacyl synthase.
The expression of fatty acid synthase (FAS), a key lipogenic enzyme and potential target for antineoplastic therapy, was analyzed in 87 frozen needle biopsies of prostate cancer using a highly sensitive immunohistochemical detection technique (Envision). In comparison to normal or benign, hyperplastic glandular structures, which were all negative for FAS staining, immunohistochemical signal was evident in 24/25 low grade prostatic epithelial neoplasia (PIN) lesions, in 26/26 high grade PIN lesions and in 82/87 invasive carcinomas. Staining intensity tended to increase from low grade to high grade PIN to invasive carcinoma. Cancers with a high FAS expression had an overall high proliferative index. No correlation was found between FAS expression and lipid accumulation. These findings indicate that increased FAS expression is one of the earliest and most common events in the development of prostate cancer, suggesting that FAS may be used as a general prostate cancer marker and that antineoplastic therapy based on FAS inhibition may be an option for chemoprevention or curative treatment for nearly all prostate cancers.
Most plant-derived polyphenols exhibit strong antioxidant potentials, established by various assay procedures. With pulse radiolysis experiments, absolute scavenging rate constants can be obtained with a variety of oxidizing radicals which allow further structure-activity correlations and, combined with EPR spectroscopy, detailed insight into the mechanisms governing these antioxidant reactions. The most striking difference occurs between regular flavonoids and both condensed and hydrolyzable tannins. The tannins are considered superior antioxidants as their eventual oxidation may lead to oligomerization via phenolic coupling and enlargement of the number of reactive sites, a reaction which has never been observed with the flavonoids themselves.
Fatty acid synthase (FAS), the key enzyme responsible for the synthesis of fatty acids, is weakly expressed in some normal human tissues. Recently, FAS has been demonstrated to be overexpressed in many non-neoplastic highly proliferative lesions and in aggressive carcinomas with poor outcome, including colon, breast and ovary carcinomas.
In order to evaluate the prognostic significance of FAS in human melanoma, we analysed by means of immunohistochemistry, using a monoclonal anti-FAS antibody, 77 primary melanomas and 30 nodal and cutaneous metastasis. Thirty nevi (15 dermal and 15 junctional nevi) were used as controls. All patients were followed-up for 5 years.
Thirty-four melanomas expressed strong FAS immunostaining; the remaining 43 cases showed weak expression or were negative. All cutaneous and nodal metastasis were strongly positive. All patients with metastases deceased during the follow up period. Control specimens expressed weak staining. None of these patients developed recurrence. Statistical analysis revealed significant association of FAS expression with Breslow thickness (p = 0.012). The intensity of FAS immunostaining was also predictive of prognosis (p = 0.049).
FAS is a reliable prognostic marker in human melanomas. FAS predictive strength is increased when associated with Breslow thickness. The observation of FAS in human melanomas may stratify patients for stricter follow-ups and suggest different therapeutic approaches.
Fatty Acid Synthase (FAS) and Human Erythrocyte Glucose Transporter 1 (GLUT1) are new markers involved in the biological activities of cancer cells. FAS is a multifunctional enzyme that synthesizes palmitate from acetyl-CoA and malonyl-CoA. GLUT1 is a transmembrane protein normally expressed in perineurium and erythrocytes. FAS and GLUT1 expression have been recently described in many aggressive tumors. We explored the immunohistochemical expression of FAS and GLUT1 in bladder carcinomas to reveal statistical associations with clinico-pathological features and recurrence.
Thirty-one node- and distant metastasis-negative transitional cell carcinomas from patients with a five-year follow-up were evaluated for FAS and GLUT1 expression.
Univariate analysis showed that low-grade, pTa stage and FAS-negative expression were associated with indolent tumors. Multivariate analysis showed that FAS expression (p = 0.006) and pT1-2 stage tumors (p = 0.001) were independent predictors of recurrence.
Endogenous fatty acids are an exploitable storage of energy for aggressive human bladder carcinomas. Glucose uptake is not required by bladder tumors.
Methods are described for the extraction and analysis of hydrophilic and lipophilic antioxidants, using modifications of the oxygen radical absorbing capacity (ORAC(FL)) procedure. These methods provide, for the first time, the ability to obtain a measure of "total antioxidant capacity" in the protein free plasma, using the same peroxyl radical generator for both lipophilic and hydrophilic antioxidants. Separation of the lipophilic and hydrophilic antioxidant fractions from plasma was accomplished by extracting with hexane after adding water and ethanol to the plasma (hexane/plasma/ethanol/water, 4:1:2:1, v/v). Lipophilic and hydrophilic antioxidants were efficiently partitioned between hexane and aqueous solvents. Conditions for controlling temperature effects and decreasing assay variability using fluorescein as the fluorescent probe were validated in different laboratories. Incubation (37 degrees C for at least 30 min) of the buffer to which AAPH was dissolved was critical in decreasing assay variability. Lipophilic antioxidants represented 33.1 +/- 1.5 and 38.2 +/- 1.9% of the total antioxidant capacity of the protein free plasma in two independent studies of 6 and 10 subjects, respectively. Methods are described for application of the assay techniques to other types of biological and food samples.
Two new sulfated steroidal pentaglycosides (asterosaponins), novaeguinosides I (2) and II (3), along with the known regularoside B (1) were isolated from the starfish Culcita novaeguineae. Their structures were elucidated by extensive NMR techniques as well as chemical evidence. The new asterosaponins showed marginal in vitro cytotoxicity against two human tumor cell lines.
Continuing studies on the total synthesis of ellagitannin plant metabolites have led to the preparation of the dimeric antitumor compound, coriariin A, as well as designed structural analogues. In related investigations, the synthesis of a 2,4-hexahydroxydiphenoyl (HHDP)-bearing glucopyranose structure has been achieved. This species is related to the geraniin family of ellagitannins, and its subsequent chemistry is suggestive of a mechanistic rationale for the observation that the HHDP units within (3,6-bridged)2,4-HHDP-containing ellagitannins invariably are oxidized further in vivo. Companion studies designed to assay the immunomodulatory properties of coriariin A and analogues have led to the thesis that tumor necrosis factor alpha (TNFalpha) serves as a mediator of this ellagitannin's tumor remissive activity. Furthermore, certain tannins and tannin analogues appear to act in an immunosuppressive capacity with peripheral blood monocytes that were exposed to the bacterially derived septic shock inducing agent lipid A.
Diosgenin-3-O-alpha-L-rhamnopyranosyl-(1 --> 4)-beta-D-glucopyranoside (DRG) is a well-known pentacyclic triterpene glycoside newly isolated from the rhizomes of Dioscorea futschauensis R. Kunth (Dioscoreaceae) by our group. In the present work, the inhibitory effect of DRG on the cell proliferation of human cancer cell lines was examined to reveal for the first time that DRG shows stronger anticancer activity than that of the positive control cisplatin. DRG inhibited the proliferation of human cancer cells, A431, A2780, A549, K562, and HCT-15, with IC50 (micromol L(-1)) values of 9.33 +/- 0.22, 18.7 +/- 0.16, 9.98 +/- 0.38, 6.44 +/- 0.10, and 5.86 +/- 0.14 respectively. It was then found, by morphological observation, "DNA ladder" detection and flow cytometric analysis, that DRG exerts its anticancer effect through inducing apoptosis on HCT-15 cells. Furthermore, it has been demonstrated that DRG triggers a mitochondria-controlled apoptotic pathway to induce apoptosis on HCT-15 cells, which involves the reduction of the mitochondrial potential (deltapsim), the release of cytochrome c from mitochondria into the cytosol, and the down-regulation of the ratio of Bcl-2/Bax expression level. The present results reasonably suggest that regulating the balance of Bcl-2/Bax expression level plays a key role in the DRG-induced apoptosis. Such findings provide novel knowledge to elucidate the biological properties of DRG, even though DRG was discovered early in the late 1960s. These results suggest that DRG may be a good candidate as a chemotherapeutic agent to treat human colon carcinoma.
The antioxidant and hepatoprotective actions of Terminalia catappa L. collected from Okinawa Island were evaluated in vitro and in vivo using leaves extract and isolated antioxidants. A water extract of the leaves of T. catappa showed a strong radical scavenging action for 1,1-diphenyl-2-picrylhydrazyl and superoxide (O(2)(.-)) anion. Chebulagic acid and corilagin were isolated as the active components from T. catappa. Both antioxidants showed a strong scavenging action for O(2)(.-) and peroxyl radicals and also inhibited reactive oxygen species production from leukocytes stimulated by phorbol-12-myristate acetate. Galactosamine (GalN, 600 mg/kg, s.c.,) and lipopolysaccharide (LPS, 0.5 microg/kg, i.p.)-induced hepatotoxicity of rats as seen by an elevation of serum alanine aminotransferase, aspartate aminotransferase and glutathione S-transferase (GST) activities was significantly reduced when the herb extract or corilagin was given intraperitoneally to rats prior to GalN/LPS treatment. Increase of free radical formation and lipid peroxidation in mitochondria caused by GalN/LPS treatment were also decreased by pretreatment with the herb/corilagin. In addition, apoptotic events such as DNA fragmentation and the increase in caspase-3 activity in the liver observed with GalN/LPS treatment were prevented by the pretreatment with the herb/corilagin. These results show that the extract of T. catappa and its antioxidant, corilagin are protective against GalN/LPS-induced liver injury through suppression of oxidative stress and apoptosis.
It has been reported that inhibition of fatty-acid synthase (FAS) is selectively cytotoxic to human cancer cells. Considerable interest has developed in identifying novel inhibitors of this enzyme complex. Our previous work showed that green tea (-)-epigallocatechin gallate can inhibit FAS in vitro. To elucidate the structure-activity relationship of the inhibitory effects of tea polyphenols, we investigated the inhibition kinetics of the major catechins and analogues. Ungallated catechins from green tea do not show obvious inhibition compared with gallated catechins. Another gallated catechin, (-)-epicatechin gallate, was also found as a potent inhibitor of FAS and its inhibition characteristics are similar to (-)-epigallocatechin gallate. Furthermore, the analogues of galloyl moiety without the catechin skeleton such as propyl gallate also showed obvious slow-binding inhibition, whereas the green tea ungallated catechin not. Atomic orbital energy analyses suggest that the positive charge is more distinctly distributed on the carbon atom of ester bond of galloyl moiety of gallate catechins, and that gallated forms are more susceptible for a nucleophilic attack than other catechins. Here we identify the galloyl moiety of green tea catechins as critical in the inactivation of the ketoacyl reductase activity of FAS for the first time.
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Received December 18, 2007