Biomedical subjects

C S Yang

Publications and source records attributed to C S Yang.

At least 73 records · Page 4Linked to original sources

PubMed2000

Oxidative damage in an esophageal adenocarcinoma model with rats.

Oxidative damage has long been related to carcinogenesis in human cancers and animal cancer models. Recently a rat esophageal adenocarcinoma (EAC) model was established in our laboratory by using esophagoduodenal anastomosis (EDA) plus iron supplementation. Our previous study suggested that iron supplementation enhanced inflammation and the production of reactive nitrogen species in the esophageal epithelium, which could contribute to esophageal adenocarcinogenesis. Here we further characterized oxidative damage in this model. We were particularly interested in how excess iron was deposited in the esophagus, and which cells were targeted by oxidative damage. Male Sprague-Dawley rats received iron supplementation (50 mg Fe/kg/month, i.p.) starting 4 weeks after EDA. The animals were killed at 11, 30 or 35 weeks after surgery. EAC appeared as early as week 11 after surgery, and increased over time, up to 60% at 35 weeks after surgery. All EACs were well-differentiated mucinous adenocarcinoma at the squamocolumnar junction. Iron deposition was found at the squamocolumnar junction and in the area with esophagitis. Esophageal iron overload could result from transient increase of blood iron after i.p. injection, and the overexpression of transferrin receptor in the premalignant columnar-lined esophagus (CLE) cells. Oxidative damage to DNA (8-hydroxy-2'-deoxyguanosine), protein (carbonyl content) and lipid (thiobarbituric acid reactive substance) in the esophagus was significantly higher than that of the non-operated control. CLE cells were believed to be the target cells of oxidative damage because they overexpressed heme oxygenase 1 and metallothionein, both known to be responsive to oxidative damage. We propose that oxidative damage plays an important role in the formation of EAC in the EDA model, and a similar situation may occur in humans with gastroesophageal reflux and iron over-nutrition.

8-Hydroxy-2'-Deoxyguanosine↗

PubMed2000

Molecular alterations of p73 in human esophageal squamous cell carcinomas: loss of heterozygosity occurs frequently; loss of imprinting and elevation of p73 expression may be related to defective p53.

p73 is structurally and functionally related to p53 and is possibly a tumor suppressor gene. Using 15 surgically resected frozen esophageal specimens containing both squamous cell carcinomas (ESCC) and neighboring normal epithelia, we studied p73 gene alterations and mRNA expression. Loss of heterozygosity of the p73 loci was found in nine of 14 informative cases (64%). A polymorphism at codon 173 (Thr) of p73 was identified (eight samples had ACC and seven had ACT), but mutation was not detected in tumor samples. Nine of the 15 ESCC samples (60%) displayed significantly elevated expression of p73 over the neighboring normal epithelium; of these nine samples, four displayed loss of imprinting (LOI) and one switched the expressed allele. Hypermethylation of exon 1 of the p73 gene was not detected, using the bisulfite modification method, in normal or tumor samples. Twelve of the 15 (80%) ESCC samples contained p53 defects, including missense mutation, non-frameshift small deletion or insertion, non-detectable transcripts and protein accumulation. The ESCC samples with p53 defects were significantly correlated with those which had elevated expression of p73 (Fisher's exact test, P < 0.05). The results suggest that increased expression of p73, including that by LOI, could be a partial compensatory mechanism for defective p53.

Carcinoma, Squamous Cell↗

PubMed2000

Effects of tea consumption on nutrition and health.

Beneficial health effects of tea have been demonstrated in animal experiments and some human studies. The two most extensively investigated diseases are cancer and heart disease. Although mechanisms of protective activity of tea against these diseases have been proposed, there are inconsistencies in the relationship between tea consumption and the risk of these diseases in humans. The bioavailability of active components is beginning to be understood, but further research is required to determine whether the results from animal studies are applicable to humans. Also discussed are the possible effects of tea in increasing thermogenesis and bone density as well as decreasing risk of cataracts and arthritis. The potential health benefits of tea consumption warrant further investigation.

Absorption↗

PubMed2000

Vitamin nutrition and gastroesophageal cancer.

Nitrosamines have been suspected in the etiology of esophageal/gastric cardia cancer in the high incidence area of Linxian of the Henan Province in northern China, but marginal deficiencies in riboflavin, vitamins A and C, and other micronutrients may also be involved. A joint U.S.-China nutritional intervention study with investigators from the Cancer Institute of the Chinese Academy of Medical Sciences and the U.S. National Cancer Institute tested the effects of the following four combinations of nutrients on 29,584 subjects in an eight-group design: 1) retinol and zinc; 2) riboflavin and niacin; 3) vitamin C and molybdenum; and 4) vitamin E, beta-carotene and selenium. Supplementation with Group 4 nutrients significantly decreased mortality rate from stomach cancer, primarily due to the decrease in deaths resulting from adenocarcinomas of the gastric cardia; it lowered the total mortality rate and showed signs of other beneficial effects. Another study of nutrition and gastric cancer in a high incidence area of Linqu of the Shangdong province in northern China (in collaboration with the Beijing Institute for Cancer Research and the U. S. National Institutes of Health) found significantly lower serum concentrations of vitamin C and beta-carotene among individuals with intestinal metaplasia; an intervention trial with vitamins C and E and selenium (combined) is ongoing in Linqu. Other studies are also elucidating the mechanisms for the pathogenesis of adenocarcinoma at the gastroesophageal junction with the use of a rat model. Such studies are expected to shed light on the etiology and prevention of gastroesophageal cancers in humans.

Adenocarcinoma↗

PubMed2000

Tea and tea polyphenols in cancer prevention.

The inhibitory action of tea (Camellia sinensis) and tea components against cancer formation has been demonstrated in different animal models involving different organ sites in many laboratories. The possible preventive activity of tea against cancer in humans, however, is not clear. A critical question is whether the information obtained from animal studies is applicable to humans because of possible species differences or the difference in the quantity of tea used in animal studies and that consumed by humans. This article will discuss the results from animal studies and possible cancer inhibitory mechanisms that might be applicable to human cancer prevention. To provide a basis for more quantitative analyses of the effect of tea on carcinogenesis, the levels of tea polyphenols in blood, urine and tissue samples have been analyzed, and the pharmacokinetic properties of tea polyphenols studied. Studies with cell lines have demonstrated that tea polyphenols affect signal transduction pathways, inhibit cell proliferation and induce apoptosis, but the effective concentrations are usually much higher than those observed in blood and tissues. More mechanistic studies in these areas will help us to understand the inhibitory action of tea against carcinogenesis and provide background for evaluating the effects of tea consumption on human carcinogenesis.

Animals↗

PubMed2000

Retinylidene proteins: structures and functions from archaea to humans.

Retinylidene proteins, containing seven membrane-embedded alpha-helices that form an internal pocket in which the chromophore retinal is bound, are ubiquitous in photoreceptor cells in eyes throughout the animal kingdom. They are also present in a diverse range of other organisms and locations, such as archaeal prokaryotes, unicellular eukaryotic microbes, the dermal tissue of frogs, the pineal glands of lizards and birds, the hypothalamus of toads, and the human brain. Their functions include light-driven ion transport and phototaxis signaling in microorganisms, and retinal isomerization and various types of photosignal transduction in higher animals. The aims of this review are to examine this group of photoactive proteins as a whole, to summarize our current understanding of structure/function relationships in the best-studied examples, and to report recent new developments.

Amino Acid Sequence↗

PubMed2000

Plasma and tissue levels of tea catechins in rats and mice during chronic consumption of green tea polyphenols.

To understand the relationship between tea consumption and its biological effects, plasma and tissue levels of (-)-epigallocatechin-3-gallate (EGCG), (-)-epigallocatechin (EGC), and (-)-epicatechin (EC) were measured after rats and mice were given a 0.6% green tea polyphenol preparation as the drinking fluid for different periods of time. EGC and EC levels in rat plasma increased over time and reached peak values (3 times the Day 1 values) on Day 14. Then the plasma levels of tea catechins decreased, to Day 1 values on Day 28. The plasma concentrations of EGCG were much lower than those of EGC or EC. High levels of EGC and EC were found in urine, whereas high levels of EGCG were found in feces. The changes in the urinary and fecal excretions of tea catechins could not account for the above-described changes in the plasma levels. The amounts of catechins in different tissues reflected the ingestion, absorption, and excretion pattern. When the green tea polyphenol preparation was given to mice, the "increase-and-then-decrease" pattern of catechin levels was also observed in the plasma, lung, and liver; the EGCG levels were much higher than in the rats. The results suggest that consumption of tea by rodents could induce adaptive responses affecting blood and tissue levels of tea catechins with time and that investigation of a similar phenomenon in humans is warranted.

Adaptation, Biological↗

PubMed2000

Three new sesquiterpene lactones from the pericarps of Illicium merrillianum.

Structures of three new sesquiterpene lactones 1-3, isolated from the pericarps of Illicium merrillianum, have been assigned as 14-O-benzoylfloridanolide, 2,10-epoxy-3-dehydroxypseudoanisatin and 7-O-methylpseudomajucin on the basis of spectroscopic data and chemical transformation. The structure of 2, having an ether linkage between C-2 and C-10, has been confirmed by X-ray crystallographic analysis.

China↗

PubMed2000

Effect of organosulfur compounds from garlic and cruciferous vegetables on drug metabolism enzymes.

The frequent consumption of cruciferous vegetables and garlic is associated with several health benefits. These foods contain organosulfur compounds that are known to affect the biotransformation of xenobiotics, and therefore can influence the toxicity and carcinogenicity of environmental chemicals. In this article, we review the effects of isothiocyanates and diallyl sulfide on xenobiotic metabolism and the enzymes involved in the process. Isothiocyanates and diallyl sulfide can modulate the levels of phase I and phase II drug-metabolizing enzymes by affecting the transcriptional rates of their genes, the turnover rates of specific mRNAs or enzymes, or the enzyme activity. These compounds are not general enzyme inhibitors or inducers. They elicit selectivity in their mode of action. Elucidating the mechanisms involved in the alteration of drug-metabolizing enzymes by isothiocyanates and diallyl sulfide will increase our understanding of their possible effects on the biotransformation of drugs as well as the potential beneficial or detrimental effects of these organosulfur compounds.

Allyl Compounds↗

PubMed2000

Effects of vitamin E and selenium supplementation on esophageal adenocarcinogenesis in a surgical model with rats.

Two well-known antioxidative nutrients, vitamin E and selenium, were used in this study to investigate possible inhibitory action against the formation of esophageal adenocarcinoma (EAC) in rats. In this model, carcinogenesis is believed to be driven by oxidative stress. Male Sprague-Dawley rats (8 weeks old) were divided into four groups and received esophagoduodenal anastomosis (EDA) surgery plus iron supplementation (12 mg/kg/week). Vitamin E and selenium were supplemented in the diet in the forms of alpha-tocopheryl acetate (750 IU/kg) and sodium selenate (1.7 mg Se/kg), which were 10 times the regular amounts in the basic AIN93M diet. At 40 weeks after surgery, all the EDA groups had lower body weights than the non-operated control group. Iron nutrition (hemoglobin, total serum iron and transferrin saturation) was normal as a result of iron supplementation after EDA. Vitamin E supplementation maintained the normal plasma level of alpha-tocopherol in EDA rats, but not those of gamma-tocopherol and retinol. Selenium supplementation increased the serum and liver selenium contents of the EDA rats. Histopathological analysis showed that selenium supplementation increased the incidence of EAC and the tumor volume. The selenium level in the tumor is higher than that in the duodenum of the same animal. Vitamin E supplementation, however, inhibited carcinogenesis, especially in the selenium-supplemented group. We believe that vitamin E exerts its effect through its antioxidative properties, and a high dose of inorganic selenium may promote carcinogenesis by enhancing oxidative stress.

Absorption↗

PubMed2000

Inhibition of ultraviolet B-induced AP-1 activation by theaflavins from black tea.

Theaflavins are believed to be key active components in black tea for chemoprevention of cancer. However, the molecular mechanisms underlying the inhibitory effects of theaflavins are not clear. With the JB6 mouse epidermal cell line, we investigated the effects of theaflavins on ultraviolet (UV) B radiation-induced activator protein-1 (AP-1)-dependent transcriptional activation and compared them with (-)-epigallocatechin-3-gallate (EGCG), a major green tea polyphenol that has cancer chemopreventative activity. Theaflavins and EGCG inhibited UVB-induced AP-1 activation in a concentration-dependent manner. The inhibitory effects of theaflavins were stronger than those of EGCG. We found that theaflavins significantly inhibited activation of extracellular signal-regulated protein kinases and c-jun NH(2)-terminal kinases. Because the transcription factor AP-1 is important in the process of tumor promotion, the inhibitory effect of these polyphenols on AP-1 activation may further explain the anti-tumor promotion action of these tea constituents. Mol. Carcinog. 28:148-155, 2000.

Animals↗

PubMed2000

Inhibition of arsenite-induced apoptosis and AP-1 activity by epigallocatechin-3-gallate and theaflavins.

Arsenite-induced apoptosis appears to be important in its toxicity and its role in carcinogenesis. Green tea has been used as a traditional Chinese remedy for detoxification of arsenite-caused toxicity. In the present work, we found that tea polyphenols, EGCG and theaflavins, effectively blocked arsenite-induced apoptosis of JB6 cells and inhibited arsenite-induced AP-1 transcription activity and AP-1 DNA binding activity. EGCG and theaflavins potently inhibited arsenite-induced Erks activity, but not p38 kinase activity. PD 98059, an inhibitor of Erks, and DNM-JNK1 blocked arsenite-induced apoptosis, while SB202190, an inhibitor of p38 kinases, or DNM-p38 kinase did not. We conclude that Erks and JNKs may be involved in arsenite-induced apoptosis, and the inhibition of arsenite-induced apoptosis by EGCG and theaflavins may be mediated by a decreased phosphorylation of Erks and JNKs. Furthermore, these results provide a possible mechanism for the detoxification effect of tea on arsenite-induced toxicity.

Animals↗

PubMed1999

On-line derivatization for continuous and automatic monitoring of brain extracellular glutamate levels in anesthetized rats: a microdialysis study.

Glutamate is an important excitatory amino acid in central nervous system. We developed a method for in vivo, continuous and automatic monitoring of brain extracellular glutamate, as well as other amino acids in anesthetized rat. This method involves the use of microdialysis perfusion technique and a high-performance liquid chromatography system equipped with a fluorescence detector. The microdialysate (perfused at a flow-rate of 1 microl/min) was on-line derivatized with o-phthaldehyde (perfused at 2 microl/min) through a mixing tee prior to the injection onto the HPLC column. The efficiency of this on-line derivatization was equivalent to that performed with an off-line manner. The effect of cerebral ischemia (2 h) and reperfusion (2 h) in brain cortex of anesthetized rats was monitored using this method. In addition to glutamate, extracellular concentrations of other amino acids, such as aspartate, glutamine, glycine, taurine and gamma-aminobutyric acid, were also simultaneously monitored with this on-line method. Since monitoring of extracellular amino acids by microdialysis perfusion is intensively used in neuroscience investigations, this simple and convenient method would be useful in the future applications.

Anesthesia↗

PubMed1999

Metabolism of methyl tert-butyl ether and other gasoline ethers by human liver microsomes and heterologously expressed human cytochromes P450: identification of CYP2A6 as a major catalyst.

To reduce the production of carbon monoxide and other pollutants in motor vehicle exhaust, methyl tert-butyl ether (MTBE), ethyl tert-butyl ether (ETBE), and tert-amyl methyl ether (TAME) are added to gasoline as oxygenates for more complete combustion. Previously, we demonstrated that human liver is active in metabolizing MTBE to tert-butyl alcohol (TBA) and that cytochrome P450 (CYP) enzymes play a critical role in the metabolism of MTBE. The present study demonstrates that human liver is also active in the oxidative metabolism of ETBE and TAME. A large interindividual variation in metabolizing these gasoline ethers was observed in 15 human liver microsomal samples. The microsomal activities in metabolizing MTBE, ETBE, and TAME were highly correlated among each other (r, 0.91-0. 96), suggesting that these ethers are metabolized by the same enzyme(s). Correlation analysis of the ether-metabolizing activities with individual CYP enzyme activities in the liver microsomes showed that the highest degree of correlation was with human CYP2A6 (r, 0. 90-0.95), which is constitutively expressed in human livers and known to be polymorphic. CYP2A6 displayed the highest turnover number in metabolizing gasoline ethers among a battery of human CYP enzymes expressed in human B-lymphoblastoid cells. Kinetic studies on MTBE metabolism with three human liver microsomes exhibited apparent Km values that ranged from 28 to 89 microM and the V(max) values from 215 to 783 pmol/min/mg, with similar catalytic efficiency values (7.7 to 8.8 microl/min/mg protein). Metabolism of MTBE, ETBE, and TAME by human liver microsomes was inhibited by coumarin, a known substrate of human CYP2A6, in a concentration-dependent manner. Monoclonal antibody against human CYP2A6 caused a significant inhibition (75% to 95%) of the metabolism of MTBE, ETBE, and TAME in human liver microsomes. Taken together, these results clearly indicate that in human liver, CYP2A6 is the major enzyme responsible for the metabolism of MTBE, ETBE, and TAME.

Aryl Hydrocarbon Hydroxylases↗

PubMed1999

Inhibition of activator protein 1 activity and cell growth by purified green tea and black tea polyphenols in H-ras-transformed cells: structure-activity relationship and mechanisms involved.

ras gene mutation, which perpetually turns on the growth signal transduction pathway, occurs frequently in many cancer types. The mouse epidermal JB6 cell line has been transfected with a mutant H-ras gene to mimic carcinogenesis in vitro. These transformed cells (30.7b Ras 12) are able to grow in soft agar, exhibiting anchorage independence and high endogenous activator protein 1 (AP-1) activity, which can be detected by a stable AP-1 luciferase reporter. The present study investigated the ability of different pure green and black tea polyphenols to inhibit this ras signaling pathway. The major green tea polyphenols (catechins), (-)-epigallocatechin-3-gallate (EGCG), (-)-epigallocatechin, (-)-epicatechin-3-gallate, (-)-epicatechin, and their epimers, and black tea polyphenols, theaflavin, theaflavin-3-gallate, theaflavin-3'-gallate, and theaflavin-3,3'-digallate (TFdiG), were compared with respect to their ability to inhibit the growth of 30.7b Ras 12 cells and AP-1 activity. All of the tea polyphenols except (-)-epicatechin showed strong inhibition of cell growth and AP-1 activity. Among the catechins, both the galloyl structure on the B ring and the gallate moiety contributed to the growth inhibition and AP-1 activity; the galloyl structure appeared to have a stronger effect on the inhibitory action than the gallate moiety. The epimers of the catechins showed similar inhibitory effects on AP-1 activity. The addition of catalase to the incubation of the cells with EGCG or TFdiG did not prevent the inhibitory effect on AP-1 activity, suggesting that H2O2 does not play a significant role in the inhibition by tea polyphenols. Both EGCG and TFdiG inhibited the phosphorylation of p44/42 (extracellular signal-regulated kinase 1 and 2) and c-jun without affecting the levels of phosphorylated-c-jun-NH2-terminal kinase. TFdiG inhibited the phosphorylation of p38, but EGCG did not. EGCG lowered the level of c-jun, whereas TFdiG decreased the level of fra-1. These results suggest that tea polyphenols inhibited AP-1 activity and the mitogen-activated protein kinase pathway, which contributed to the growth inhibition; however, different mechanisms may be involved in the inhibition by catechins and theaflavins.

Animals↗

PubMed1999

Acetone catabolism by cytochrome P450 2E1: studies with CYP2E1-null mice.

Previous experiments in vitro have suggested that cytochrome P450 2E1 (CYP2E1) is involved in acetone catabolism by converting acetone to acetol and then to methylglyoxal, both intermediates in the gluconeogenic pathway. In the present study, CYP2E1-null mice were used to demonstrate the role of CYP2E1 in acetone catabolism in vivo. The blood acetone level in male CYP2E1-null mice was 3.3 +/- 0.9 microg/mL, which was similar to levels of their sex- and age-matched parental lineage strains C57BL/6N (2.3 +/- 0.2 microg/mL) and 129/Sv (3.5 +/- 0.3 microg/mL) mice (both are CYP2E1 wild-type). After fasting for 48 hr, the blood acetone levels in the CYP2E1 wild-type mice were increased by 2.5- to 4.4-fold, but that in the CYP2E1-null mice increased 28-fold. These results clearly demonstrate that CYP2E1 plays a vital role in the catabolism of acetone under fasting conditions.

Acetone↗

PubMed1999

Dorsal facial area of cat medulla; 5-HT2 action on glutamate release in regulating common carotid blood flow.

Serotonin (5-HT) may inhibit glutamate release in the dorsal facial area (DFA) of the medulla and decrease common carotid arterial (CCA) blood flow. We attempted to clarify which subtype(s) of 5-HT receptor was involved. A microdialysis probe was inserted in DFA. The concentration of glutamate in dialysates were determined by chromatography. Glutamate concentration was dose-dependently decreased by perfusion of 5-HT or DOI, a 5-HT2 agonist, but not by 5-CT, a 5-HT1 agonist. The 5-HT-induced decrease in glutamate was reversed by co-perfusion of ketanserin, a 5-HT2 antagonist, but not by propranolol, a 5-HT1 antagonist. CCA blood flow was decreased when 5-HT or DOI was perfused, and was reversed by co-perfusing ketanserin. In conclusion, 5-HT may inhibit glutamate release via 5-HT2 receptor in DFA, resulting in the reduction of CCA blood flow.

Animals↗

PubMed1999

The alpha-helical domain of Galphat determines specific interaction with regulator of G protein signaling 9.

RGS proteins (regulators of G protein signaling) are potent accelerators of the intrinsic GTPase activity of G protein alpha subunits (GAPs), thus controlling the response kinetics of a variety of cell signaling processes. Most RGS domains that have been studied have relatively little GTPase activating specificity especially for G proteins within the Gi subfamily. Retinal RGS9 is unique in its ability to act synergistically with a downstream effector cGMP phosphodiesterase to stimulate the GTPase activity of the alpha subunit of transducin, Galphat. Here we report another unique property of RGS9: high specificity for Galphat. The core (RGS) domain of RGS9 (RGS9) stimulates Galphat GTPase activity by 10-fold and Galphai1 GTPase activity by only 2-fold at a concentration of 10 microM. Using chimeric Galphat/Galphai1 subunits we demonstrated that the alpha-helical domain of Galphat imparts this specificity. The functional effects of RGS9 were well correlated with its affinity for activated Galpha subunits as measured by a change in fluorescence of a mutant Galphat (Chi6b) selectively labeled at Cys-210. Kd values for RGS9 complexes with Galphat and Galphai1 calculated from the direct binding and competition experiments were 185 nM and 2 microM, respectively. The gamma subunit of phosphodiesterase increases the GAP activity of RGS9. We demonstrate that this is because of the ability of Pgamma to increase the affinity of RGS9 for Galphat. A distinct, nonoverlapping pattern of RGS and Pgamma interaction with Galphat suggests a unique mechanism of effector-mediated GAP function of the RGS9.

3',5'-Cyclic-GMP Phosphodiesterases↗