Timosaponin AⅢ induces drug-metabolizing enzymes by activating constitutive androstane receptor (CAR) via dephosphorylation of the EGFR signaling pathway

The current study aimed to assess the effect of timosaponin AⅢ(T-AⅢ)on drug-metabolizing enzymes during anticancer therapy.The in vivo experiments were conducted on nude and ICR mice.Following a 24-day administration of T-AⅢ,the nude mice exhibited an induction of CYP2B10,MDR1,and CYP3A11 expression in the liver tissues.In the ICR mice,the expression levels of CYP2B10 and MDR1 increased after a three-day T-AⅢ administration.The in vitro assessments with HepG2 cells revealed that T-AⅢ induced the expression of CYP2B6,MDR1,and CYP3A4,along with constitutive androstane receptor(CAR)activation.Treatment with CAR siRNA reversed the T-AⅢ-induced increases in CYP2B6 and CYP3A4 expression.Furthermore,other CAR target genes also showed a significant increase in the expression.The up-regulation of murine CAR was observed in the liver tissues of both nude and ICR mice.Subsequent findings demonstrated that T-AⅢ activated CAR by inhibiting ERK1/2 phosphorylation,with this effect being partially reversed by the ERK activator t-BHQ.Inhibition of the ERK1/2 signaling pathway was also observed in vivo.Additionally,T-AⅢ inhibited the phosphorylation of EGFR at Tyr1173 and Tyr845,and suppressed EGF-induced phosphorylation of EGFR,ERK,and CAR.In the nude mice,T-AⅢ also inhibited EGFR phosphorylation.These results collectively indicate that T-AⅢ is a novel CAR activator through inhibition of the EGFR pathway.

Salvianolic acid B modulates the expression of drug-metabolizing enzymes in HepG2 cells

BACKGROUND: Enzymes involved in drug and xenobiotic metabolism have been considered to exist in two groups: phase I and phase II enzymes. Cytochrome P450 isoenzymes (CYPs) are the most important phase I enzymes in the metabolism of xenobiotics. The products of phase I metabolism are then acted upon by phase II enzymes, including glutathione S-transferases (GSTs). Herbs that inhibit CYPs such as CYP3A4 or that induce GSTs may have the potential to protect against chemical carcinogenesis since the mutagenic effects of carcinogens are often mediated through an excess of CYP-generated reactive intermediates. This study was designed to investigate the effects of salvianolic acid B (Sal B), a pure compound extracted from Radix Salviae Miltiorrhizae, a Chinese herb, on cell proliferation and CYP1A2 and CYP3A4 mRNA expression in the presence or absence of rifampicin, a potent inducer of CYPs and GST protein expression in HepG2 cells. METHODS: HepG2 cells were incubated with different concentrations of Sal B. Cell proliferation was determined by SYTOX-Green nucleic acid staining. CYP3A4 and CYP1A2 mRNA expression was assayed by real-time PCR. GST protein expression was analyzed by Western blotting. RESULTS: Low concentrations of Sal B (0-20 μmol/L) had no significant effects on cell proliferation, while higher concentrations (100-250 μmol/L) significantly inhibited proliferation in a concentration-dependent manner. Ten μmol/L Sal B, but not 1 μmol/L, down-regulated CYP3A4 and CYP1A2 mRNA expression after 24 hours of incubation, whereas both 1 and 10 μmol/L Sal B down-regulated CYP3A4mRNA expression after 96 hours of incubation; moreover, 1 and 10 μmol/L Sal B inhibited CYP3A4 mRNA expression induced by rifampicin. Both 1 μmol/L and 10 μmol/L Sal B increased GST expression. CONCLUSION: Sal B inhibits CYP3A4 and CYP1A2 mRNA expression and induces GST expression in HepG2 cells.

Processing Effects on Selected Antioxidant Activities and Metabolizing Enzyme Inhibition of M. Koneigii (Curry Leaves) Extracts

Curry leaves, scientifically termed Murraya koenigii, are renowned in South Asian cuisine for their flavor enhancement and potential health benefits, including antioxidative, anti-inflammatory, and antidiabetic properties. This study aimed to evaluate the impact of thermal processing methods on curry leaves by analysing Total Phenolic Content (TPC), Total Flavonoid Content (TFC), antioxidant activity, and metabolizing enzyme inhibition. Fresh curry leaves were subjected to thermal treatments: Oven-dried at 60˚C and Air-dried at 25˚C for 2 weeks. Extracts were prepared using Ethanol and water solvents. Results indicated that Air-dried leaves exhibited significantly higher TPC (5132.65 mg GAE/100 g) and TFC (243.13 mg CE/100 g) compared to Fresh and Oven-dried leaves. Antioxidant assays show that oven-dried curry leaves at 60˚C displayed higher results in NORS, FRAP, and TEAC assays compared to Fresh and Air-dried leaves. Ethanol extracts showed better extraction of bioactive compounds than aqueous extracts. Moreover, Lipase inhibition activity was notably high, indicating potential health benefits. This study provides valuable insights into the effects of processing methods on curry leaf extracts, emphasizing the importance of solvent selection for optimal extraction of bioactive compounds.

Phenotype prediction of nonsynonymous single nucleotide polymorphisms in human phase II drug/xenobiotic metabolizing enzymes: perspectives on molecular evolution

Nonsynonymous single nucleotide polymorphisms (nsSNPs) in coding regions can lead to amino acid changes that might alter the protein’s function and account for susceptibility to disease and altered drug/xenobiotic response. Many nsSNPs have been found in genes encoding human phase II metabolizing enzymes; however, there is little known about the relationship between the genotype and phenotype of nsSNPs in these enzymes. We have identified 923 validated nsSNPs in 104 human phase II enzyme genes from the Ensembl genome database and the NCBI SNP database. Using PolyPhen, Panther, and SNAP algorithms, 44%?59% of nsSNPs in phase II enzyme genes were predicted to have functional impacts on protein function. Predictions largely agree with the available experimental annotations. 68% of deleterious nsSNPs were correctly predicted as damaging. This study also identified many amino acids that are likely to be functionally critical, but have not yet been studied experimentally. There was significant concordance between the predicted results of Panther and PolyPhen, and between SNAP non-neutral predictions and PolyPhen scores. Evolutionarily non-neutral (destabilizing) amino acid substitutions are thought to be the pathogenetic basis for the alteration of phase II enzyme activity and to be associated with disease susceptibility and drug/xenobiotic toxicity. Furthermore, the molecular evolutionary patterns of phase II enzymes were characterized with regards to the predicted deleterious nsSNPs.

Chrysoeriol ameliorates hyperglycemia by regulating the carbohydrate metabolic enzymes in streptozotocin-induced diabetic rats

The present study aimed to evaluate the effects of chrysoeriol from Cardiospermum halicacabum in streptozotocin induced Wistar rats.Thirty rats were categorized as control,diabetic control supplemented with 0,20 mg/kg chrysoeriol and 600μg/kg BW of glibenclamide for 45-day trial period.Our results indicated that the inclusion of chrysoeriol(20 mg/kg)showed a significant reduction in plasma glucose,hemoglobin and glycosylated hemoglobin level with a rising of plasma insulin sensitivity.Further,downregulated enzymes including glucose 6-phosphatase,fructose 1,6-bisphosphatase,and glycogen phosphorylase as well upregulated enzymes such as hexokinase,glucose-6-phosphate dehydrogenase,pyruvate kinase,and hepatic glycogen content.There was a diminish action found in liver glycogen synthase of tested rat with a rise in gamma-glutamyl transpeptidase,towards normal levels upon treatment with chrysoeriol.The histopathological study confirmed that renewal of the beta cells of pancreatic of chrysoeriol and glibenclamide treated rats.In addition,the molecular docking of chrysoeriol against glycolytic enzymes including hexokinase,glucose-6-phosphate dehydrogenase,pyruvate kinase,using Argus software shows chrysoeriol had greatest ligand binding energy as equivalent to glibenclamide,as a standard drug.Thus,chrysoeriol found to be non-toxic with potential regulation on glycemic control and upregulation of the carbohydrate metabolic enzymes.

Effects of different doses of glucose and fructose on central metabolic pathways and intercellular wireless communication networks in humans

Fructose and glucose are often widely used in food processing and may contribute to many metabolic diseases.To observe the effects of different doses of glucose and fructose on human metabolism and cellular communication,volunteers were given low,medium,and high doses of glucose and fructose.Serum cytokines,glucose,lactate,nicotinamide adenine dinucleotide(NADH)and metabolic enzymes were assayed,and central carbon metabolic pathway networks and cytokine communication networks were constructed.The results showed that the glucose and fructose groups basically maintained the trend of decreasing catabolism and increasing anabolism with increasing dose.Compared with glucose,low-dose fructose decreased catabolism and increased anabolism,significantly enhanced the expression of the inflammatory cytokine interferon-γ(IFN-γ),macrophage-derived chemokine(MDC),induced protein-10(IP-10),and eotaxin,and significantly reduced the activity of isocitrate dehydrogenase(ICDH)and pyruvate dehydrogenase complexes(PDHC).Both medium and high doses of fructose increase catabolism and anabolism,and there are more cytokines and enzymes with significant changes.Furthermore,multiple cytokines and enzymes show strong relevance to metabolic regulation by altering the transcription and expression of enzymes in central carbon metabolic pathways.Therefore,excessive intake of fructose should be reduced to avoid excessive inflammatory responses,allergic reactions and autoimmune diseases.

Effects of Terpinen-4-ol on Four Metabolic Enzymes and Polyphenol Oxidase (PPO) in Mythimna separta Walker

To study insecticidal mechanism of terpinen-4-ol, a main insecticidal composition in the essential oil of Sabina vulgaris, the 5th instar larvae of Mythimna separta, were investigated with terpinen-4-ol by topical application. The activities of phosphatase, glutathione S-transferase （GSTs）, cytochrome P450 （P450）, and polyphenol oxidase （PPO） of tested insects were determined in all poisoning stages, including exciting stage, convulsing stage, paralysis stage, and recover stage. The result showed that the activities of both acid phosphatase （ACP） and alkaline phosphatase （AKP） in treated insects were induced by terpinen-4-ol, but ACP was inhibited in paralysis stage. The activities of GSTs were inhibited in exciting stage, convulsing stage, and paralysis stage, but gradually recovered in recover stage. O-demethylase activity of cytochrome P450 was inhibited by terpinen-4-ol, and the inhibition rate in all poisoning stages were 26.27, 46.03, 80.24, and 90.22%, respectively. PPO activities were strongly inhibited by terpinen-4-ol both in vitro and in vivo. In conclusion, the activities of P450, GSTs, and PPO could have relation with toxicity of terpinen-4-ol against larvae of the Mythimna separta, but recover stage of the poisoning insects might be related to GSTs induced. As a new insecticide or synergist, terpinen- 4-ol has a potential value in field of insecticide resistance management.

Changes of Reactive Oxygen Species and Related Enzymes in Mitochondrial Respiration During Storage of Harvested Peach Fruits

Peach fruits [Prumus persica （L.） Batsch, cv. Yuhuasanhao] were used as materials to investigate the changes of reactive oxygen species （ROS） and related enzymes in mitochondria respiration during storage and then their influence on senescence of harvested Peach fruits was studied. The results showed that low temperature （5℃） strongly inhibited the reduction of firmness and the increase in respiration rate. During storage at ambient temperature （20℃）, ROS had a cumulative process while malondialdehye （MDA） content continued to increase in associated with enhanced membrane lipid peroxidation. Lipoxygenase （LOX） activity was strongly inhibited under the low temperature condition. The activities of succinic dehydrogenase （SDH）, cytochrome C oxidase （CCO）, and Ca^2＋-ATPase declined to a certain extent at ambient temperature, while they showed higher activities at low temperature, which may be related to lower membrane lipid peroxidation at low temperature. Higher Ca^2＋ content at ambient temperature may be responsible for impairment of mitochondrial function, thus, leading to fruit senescence. The results showed that under low temperature condition, the low accumulation of ROS and the low level of membrane lipid peroxidation could maintain the function of mitochondria that would help to delay the senescence of peach fruits. These suggested a close relationship existed between ROS metabolism and mitochondrial respiration. It can be inferred that the low temperature helps to delay senescence of peach fruits via suppression of ROS and related enzymes, maintain better homeostasis of Ca^2＋ in mitochondria and thus better mitochondrial functions.

Changes of Reactive Oxygen Species and Related Enzymes in Mitochondria Respiratory Metabolism During the Ripening of Peach Fruit

The fruits of peach cultivar Yuhua 3 were used as materials to investigate the changes of active oxygen and related enzymes in mitochondria respiratory metabolism during ripening of peach fruit, involving their influence on the proceeding of peach fruit senescence. The results showed that the large decrease in firmness occurred between maturity II and IV. The decrease in firmness coincided with an increase in respiratory intensity. Obvious peaks of respiratory intensity lagging to the rapid change of fruit firmness could be shown during peach ripening. Reactive oxygen species （ROS） had a cumulative process and positively correlated with respiratory intensity. During peach ripening, the content of Ca^2＋ increased, the activities of succinic dehydrogenase （SDH）, cytochrome C oxidase （CCO）, H＋-ATPase, and Ca^2＋-ATPase decreased varying in different degree at the later step of ripening. These suggested a close relationship existed between ROS metabolism and mitochondrial respiration, namely, both ROS metabolism and mitochondrial respiration probably played important roles in ripening and senescing of peach fruit.

Effects of Drought Stress on Key Enzymes of Carbon Metabolism, Photosynthetic Characteristics and Agronomic Traits of Soybean at the Flowering Stage under Different Soil Substrates

Soybean is an important legume food crop,and its seeds are rich in nutrients,providing humans and animals with edible oil and protein feed.However,soybean is sensitive to water requirements,and drought is an important factor limiting soybean yield and quality.This study used Heinong 84(drought resistant variety)and Hefeng 46(intermediate variety)as tested varieties planted in chernozem,albic,and black soils.The effects of drought stress on the activities of key enzymes in carbon metabolism and photosynthetic characteristics of soybean were studied during the flowering stage,most sensitive to water.(1)The activities of SS-1,6PGDH,and G6PDH enzymes in soybean leaves first increased and then decreased under drought stress.The enzyme activity was the highest under moderate drought stress and weakest in the blank group.(2)Drought stress increased Phi2,PhiNO,and Fm in soybean leaves and reached the highest value under severe drought;with the increase in drought stress,PhiNPQ and Fv/Fm of soybean leaves gradually decreased,reaching the lowest under severe drought.(3)With the increase in drought stress,F0 and Fs of soybean leaves showed a single peak curve,and the maximum was at moderate drought.(4)Correlation analysis showed that F0 was greatly affected by varieties and soil types;Fs,F0,and Fm soil varieties had a great influence,and chlorophyll fluorescence parameters were affected differently under drought stress with different drought degrees.(5)Drought stress changed the agronomic traits and yield of soybean.With the increase of drought degree,plant height,node number of main stem,effective pod number,100-seed weight and total yield decreased continuously.(6)Drought stress affected the dry matter accumulation of soybean.With the increase of drought degree,the dry matter accumulation gradually decreased.Among them,the leaf was most seriously affected by drought,and SD decreased by about 55%compared with CK.Under the condition of black soil,the dry matter accumulation of soybean was least affected by drought.

Age-related Metabolic Effects of Acetaldehyde on Rats With Reference to Detoxification Enzymes and Sulfhydryl Groups

Induced-acetaldehyde toxic effects on gluatathione [GSH] metabolism and sulfhydryl (SH) groups in liver and in brain of female albino rats with reference to age was studied.The total -SH groups were decreased whereas the specific activities of glutathione-S-transferase [GST] and glutathione peroxidase [GP0] were increased in acetaldehyde treated rats. However, the specific activity levels of glutathione reductase [GR] and Γ-glutamylcysteine synthetase [Γ-GCS] were decreased. In general, acetaldehyde indueed changes in the specific activities of the enzymes that increase with increasing age

Advances in Research of Mechanism of Herb-Drug Interactions

With the concurrent consumption of herbal medicines and conventional drugs,herb-drug interactions(HDIs)have become the most important clinical consequence of this practice.A general overview and the significance of pharmacokinetic and pharmacodynamic HDIs are provided,detailing basic mechanism,especially the metabolic enzymes and drug transporters,such as CYP450 and P-gp.

The positive function of selenium supplementation on reducing nitrate accumulation in hydroponic lettuce(Lactuca sativa L.)

High nitrate(NO3-) in vegetables, especially in leaf vegetables poses threaten to human health. Selenium(Se) is an important element for maintaining human health, and exogenous Se application during vegetable and crop production is an effective way to prevent Se deficiency in human bodies. Exogenous Se shows positive function on plant growth and nutrition uptake under abiotic and/or biotic stresses. However, the influence of exogenous Se on NO3-accumulation in hydroponic vegetables is still not clear. In the present study, hydroponic lettuce plants were subjected to six different concentrations(0, 0.1, 0.5, 5, 10 and 50 μmol L–1) of Se as Na2 Se O3. The effects of Se on NO3-content, plant growth, and photosynthetic capacity of lettuce(Lactuca sativa L.) were investigated. The results showed that exogenous Se positively decreased NO3-content and this effect was concentration-dependent. The lowest NO3-content was obtained under 0.5 μmol L–1 Se treatment. The application of Se enhanced photosynthetic capacity by increasing the photosynthesis rate(Pn), stomatal conductance(Cs) and the transpiration efficiency(Tr) of lettuce. The transportation and assimilation of NO3-and activities of nitrogen metabolism enzymes in lettuce were also analysed. The NO3-efflux in the lettuce roots was markedly increased, but the efflux of NO3-from the root to the shoot was decreased after treated with exogenous Se. Moreover, Se application stimulated NO3-assimilation by enhancing nitrate reductase(NR), nitrite reductase(Ni R), glutamine synthetase(GS) and glutamate synthase enzyme(GOGAT) activities. These results provide direct evidence that exogenous Se shows positive function on decreasing NO3-accumulation via regulating the transport and enhancing activities of nitrogen metabolism enzyme in lettuce. We suggested that 0.5 μmol L–1 Se can be used to reduce NO3-content and increase hydroponic lettuce yield.

Selenium distribution and nitrate metabolism in hydroponic lettuce(Lactuca sativa L.): Effects of selenium forms and light spectra

A deficiency in selenium(Se) in the human diet is a worldwide problem. The intake of Se-rich vegetables can be a safe way to combat Se deficiency for humans. However, most leafy vegetables can accumulate a high content of nitrates, which poses a potential threat to human health. Light is an important environmental factor that regulates the uptake and distribution of mineral elements and nitrogen metabolism in plants. However, the effects of Se forms and light conditions, especially light spectra, on the uptake and translocation of Se and on nitrate reduction are poorly understood. In this study, lettuce(Lactuca sativa L.) was treated with exogenous Se applied as selenate(10 mmol L^-1) and selenite(0.5 mmol L^-1) and grown under five different light spectra: fluorescent light(FL), monochromatic red LED light(R), monochromatic blue LED light(B), and mixed red and blue LED light with a red to blue light ratio at 4(R/B=4), 8(R/B=8), and 12(R/B=12), respectively. The effects of light spectra and Se forms on plant growth, photosynthetic performance, Se accumulation and nitrate reduction were investigated. The results showed that the light spectra and Se forms had significant interactions for plant growth, foliar Se accumulation and nitrate reduction. The Se concentration and nitrate content in the leaves were negatively correlated with the percentage of red light from the light sources. Compared to Se applied as selenite, exogenous Se applied as selenate was more effective in reducing nitrate via promoting nitrate reductase and glutamate synthase activities. The lowest nitrate content and highest plant biomass were observed under R/B=8 for both the selenate and selenite treatments. The significant effect of the light spectra on the root concentration factor and translocation factor of Se resulted in marked variations in the Se concentrations in the roots and leaves. Compared with FL, red and blue LED light led to significant decreases in the foliar Se concentration. The results from this study suggest that the light spectra can contribute to Se distribution and accumulation to produce vegetables with better food quality.

Meta-analysis of ADH1B and ALDH2 polymorphisms and esophageal cancer risk in China

AIM: To evaluate whether alcohol dehydrogenase-1B (ADH1B) His47Arg and aldehyde dehydrogenase-2 (ALDH2) Glu487Lys polymorphism is involved in the esophageal squamous cell carcinoma (ESCC) risk in Chinese Han population. METHODS: Seven studies of ADH1B and ALDH2 genotypes in Chinese Han population in 1450 cases and 2459 controls were included for meta-analysis. Stratified analyses were carried out to determine the genealcohol and gene-gene interaction with ESCC risk. Potential sources of heterogeneity between studies were explored, and publication bias was also evaluated. RESULTS: Individuals with ADH1B arginine (Arg)/Arg genotype showed 3.95-fold increased ESCC risk in the recessive genetic model [Arg/Arg vs Arg/histidine (His) + His/His: odds ratio (OR) = 3.95, 95% confidence in- terval (CI): 2.76-5.67]. Signif icant association was found in the dominant model for ALDH2 lysine (Lys) allele [glutamate (Glu)/Lys + Lys/Lys vs Glu/Glu: OR = 2.00,95% CI: 1.54-2.61]. Compared with the non-alcoholics, Arg/Arg (OR = 25.20, 95% CI: 10.87-53.44) and Glu/ Lys + Lys/Lys (OR = 21.47, 95% CI: 6.44-71.59) were found to interact with alcohol drinking to increase the ESCC risk. ADH1B Arg+ and ALDH2 Lys+ had a higher risk for ESCC (OR = 7.09, 95% CI: 2.16-23.33). CONCLUSION: The genetic variations of ADH1B His47Arg and ALDH2 Glu487Lys are susceptible loci for ESCC in Chinese Han population and interact substantially with alcohol consumption. The individuals carrying both risky genotypes have a higher baseline risk of ESCC.

The effects of phenolic acid on nitrogen metabolism in Populus 3 euramericana ‘Neva’

The declines in soil fertility and productivity in continuously cropped poplar plantations axe related to phenolic acid accumulation in the soil. Nitrogen is a vital life element for poplar and whether the accumulation of phenolic acid could influence nitrogen metabolism in poplar and thereby hinder continuous cropping is not clear. In this study, poplar cuttings of Populus × euramericana ‘Neva＇ were potted in vermiculite, and phenolic acids at three concentrations （032, 0.5X and 1.0X） were added according to the actual content （1.0X） in the soil of a second-generation poplar plantation. Each treatment had eight replicates. We measured gas exchange parameters and the activities of key enzymes related to nitrogen metabolism in the leaves. Leaf photosynthetic parameters varied with the concentration of phenolic acids. The net photosynthetic rate （PN） significantly decreased with increasing phenolic acid concentration, and non-stomatal factors might have been the primary limitation for PN- The activities of nitrate reductase （NR）, glutamine synthetase （GS） and glutamate synthase （GOGAT）, as well as the contents of nitrate nitrogen, ammonium nitrogen, and total nitrogen in the leaves decreased with increasing phenolic acid concentration. This was significantly and positively related to PN （P 〈 0.05）. The low concentration of phe- nolic acids mainly affected the transformation process of NO3- to NO2-, while the high concentration of phenolic acids affected both processes, where NO3- was transferred to NO2- and NH4＋ was transferred to glutamine （Gln）. Overall, phenolic acid had significant inhibitory effects on the photosynthetic productivity of Populus x euramericana ＇Neva＇. This was probably due to its influence on the activities of nitrogen assimilation enzymes, which reduced the amount of amino acids that were translated into protein and enzymes. Improving the absorption and utilization of nitrogen by plants could help to overcome the problems caused by continuous cropping.

DNA polymorphism and risk of esophageal squamous cell carcinoma in a population of North Xinjiang,China

AIM:To investigate the role of metabolic enzyme and DNA repair genes in susceptibility of esophageal squamous cell carcinoma(ESCC). METHODS:A case-control study was designed with 454 samples from 128 ESCC patients and 326 gender, age and ethnicity-matched control subjects.Genotypes of 69 single nucleotide polymorphisms(SNPs)of metabolic enzyme(aldehyde dehydrogenase-2,ALDH2; alcohol dehydrogenase-1 B,ADHB1;Cytochrome P450 2A6,CYP2A6)and DNA repair capacity genes(excision repair cross complementing group 1,ERCC1; O 6-methylguanine DNA methyltransferase,MGMT; xeroderma pigmentosum group A,XPA;xeroderma pigmentosum group A,XPD)were determined by the Sequenom MassARRAY system,and results were analyzed using unconditional logistic regression adjusted for age,gender. RESULTS:There was no association between the variation in the ERCC1,XPA,ADHB1 genes and ESCC risk.Increased risk of ESCC was suggested in ALDH2 for frequency of presence C allele of SNP [Rs886205:1.626(1.158-2.284)],XPD for C allele [Rs50872:1.482(1.058-2.074)],and MGMT for A allele[Rs11016897:1.666(1.245-2.228)].Five variants of MGMT were associated with a protective effect on ESCC carcinogenesis,including C allele [Rs7069143:0.698(0.518-0.939)],C allele[Rs3793909: 0.6 5 3(0.4 2 9-0.9 9 5)],A a l l e l e[R s 1 2 7 7 1 8 8 2: 0.719(0.524-0.986)],C allele[Rs551491:0.707 (0.529-0.945)],and A allele[Rs7071825:0.618 (0.506-0.910)].At the genotype level,increased risk of ESCC carcinogenesis was found in homozygous carriers of the ALDH2 Rs886205[CC vs TT,odds ratios(OR): 3.116,95%CI:1.179-8.234],MGMT Rs11016879(AA vs GG,OR:3.112,95%CI:1.565-6.181),Rs12771882 (AA vs GG,OR:2.442,95%CI:1.204-4.595),and heterozygotes carriers of the ALDH2 Rs886205 (CT vs TT,OR:3.930,95%CI:1.470-10.504), MGMT Rs11016879(AG vs GG,OR:3.933,95%CI: 2.216-6.982)and Rs7075748(CT vs CC,OR:1.949, 95%CI:1.134-3.350),respectively.Three variants were associated with a protective effect on ESCC carcinogenesis,carriers of the MGMT Rs11016878(AG vs AA,OR:0.388,95%CI:0.180-0.836),Rs7069143(CT vs CC,OR:0.478,95%CI:0.303-0.754)and Rs7071825(GG vs AA,OR:0.493,95%CI:0.266-0.915). Increased risk of ESCC metastasis was indicated in MGMT for frequency of presence C allele[Rs7068306: 2.204(1.244-3.906)],A allele[Rs10734088:1.968 (1.111-3.484)]and C allele[Rs4751115:2.178(1.251-3.791)].Two variants in frequency of presence C allele of CYP2A6[Rs8192720:0.290(0.099-0.855)] and A allele of MGMT[Rs2053139:0.511(0.289-0.903)] were associated with a protective effect on ESCC progression.Increased risk of ESCC metastasis was found in heterozygote carriers of the MGMT Rs7068306 (CG vs CC,OR:4.706,95%CI:1.872-11.833).CONCLUSION:Polymorphic variation in ALDH2,XPD and MGMT genes may be of importance for ESCC susceptibility.Polymorphic variation in CYP2A6 and MGMT are associated with ESCC metastasis.

Coping with extremes:lowered myocardial phosphofructokinase activities and glucose content but increased fatty acids content in highland Eurasian Tree Sparrows

Background:Efficient and selective utilization of metabolic substrates is one of the key strategies in high-altitude animals to cope with hypoxia and hypothermia.Previous findings have shown that the energy substrate utilization of highland animals varies with evolutionary history and phylogeny.The heart is a proxy for the cardiopulmonary system,and the metabolic substrate utilization in the myocardium is also under the strong selective pressure of chronically hypoxic and hypothermic environments.However,little information is available on the physiological adjustments in relation to metabolic substrate utilization in the myocardium for coping with high-altitude environments.Methods:We compared the metabolic enzyme activities,including hexokinase(HK),phosphofructokinase(PFK),pyruvate kinase(PK),citrate synthase(CS),carnitine palmitoyl transferase 1(CPT-1),lactic dehydrogenase(LDH),and creatine kinase(CK),and metabolic substrate contents including glucose(Glu),triglyceride(TG),and free fatty acid(FFA)in the myocardium of a typical human commensal species,Eurasian Tree Sparrows(Passer montanus)between the Qinghai-Tibet Plateau(the QTP,3230 m)and low altitude population(Shijiazhuang,80 m),and between sexes.Results:Among the seven metabolic enzymes and three substrates investigated,we identified no significant differences in PK,CPT-1,HK,CS,LDH,and CK activities and TG content of the myocardium between high and low altitude populations.However,the QTP sparrows had significantly lower Glu content and PFK activities but higher FFA content relative to their lowland counterparts.In addition,male sparrows had higher myocardial HK and CS activities relative to females,independent of altitude.Conclusions:Our results showed that the QTP sparrows elevated fatty acid utilization rather than glucose preference in the myocardium relative to lowland counterpart,which contributes to uncovering both the physiological adjustments for adapting to the extreme conditions of the QTP,intraspecifically.

Hydroxylation and sulfation of sex steroid hormones in inflammatory liver

Sex steroids, also known as gonadal steroids, are oxidized with hydroxylation by cytochrome P450,glucuronidation by UDP-glucuronosyltransferase, sulfation by sulfotransferase, and O-methylation by catechol Omethyltransferase. Thus, it is important to determine the process by which inflammation influences metabolism of gonadal hormones. Therefore, we investigated the mechanism of metabolic enzymes against high physiologic inflammatory response in vivo to study their biochemical properties in liver diseases. In this study, C57BL/6N mice were induced with hepatic inflammation by diethylnitrosamine(DEN) exposure. We observed upregulation of Cyp19a1, Hsd17b1, Cyplal, Sult1e1 in the DEN-treated livers compared to the control-treated livers using real time PCR. Moreover, the increased Cyp19a1 and Hsd17b1 levels support the possibility that estrogen biosynthesis from androgens are accumulated during inflammatory liver diseases. Furthermore, the increased levels of Cyp1a1 and Cyp1b1 in the hydroxylation of estrogen facilitated the conversion of estrogen to 2-or 4-hydroxyestrogen,respectively. In addition, the substantial increase in the Sultlel enzyme levels could lead to sulfate conjugation of hydroxyestrogen. The present information supports the concept that inflammatory response can sequester sulfate conjugates from the endogenous steroid hormones and may suppress binding of sex steroid hormones to their receptors in the whole body.