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The dam break pattern of rock-fill dams is normally gradual failure. This kind of dam failure is caused by seepage piping or overtopping, in which dam crest overflow is more common. The dam breach expansion process shall depend comprehensively on the structure pattern, material property of dam, and damsite cross sectional topography. And the break duration has a significant impact on the magnitude of break flood and the counter-measures for excess-standard flood. Take the Karot Hydropower Project constructed on the Jhelum River in Pakistan as an example, the dam break mathematical model is set up to analyze the sensitivity of damsite discharge process, downstream highest flood water surface profile and flood peak appearance time to dam break duration. The results show that: with the increase of dam break duration, damsite peak discharge is decreased sharply, flood peak appearance time extends, on-way highest water levels below Karot dam are lowered significantly, and some settlement places below Karot dam can avoid being inundated until the break duration reaches a critical value. If encountering probable maximum flood, the dam break occurs when the reservoir water level reaches dam top EL, some measures can be taken to extend the break duration, so as to effectively reduce the loss of downstream flood. The research results will help to understand the relationship mechanism between rock-fill dam break flood and break duration and provide a scientific basis or some solutions for optimization design of dam and counter-measures of dam break flood.

Small noncoding microRNAs act as post-transcriptional regulators of gene expression involved in diverse biologic functions. Pregnane X receptor (PXR, NR1I2), a member of the superfamily of nuclear receptors, is a transcription factor governing the transport and biotransformation of various drugs and other chemicals. In the present study, we identified a specific microRNA (miR) involved in regulating the expression and functionality of human PXR (hPXR). According to bioinformatics analysis employing three commonly used algorithms (TargetScan, miRanda, and DIANA-microT-CDS), miR-18a-5p was predicted to be the top candidate microRNA regulator of hPXR. Consequently, this microRNA was selected for detailed experimental investigation. As shown in cell-based dual-luciferase reporter gene assays, functional interaction occurred between miR-18a-5p and the microRNA recognition element of miR-18a-5p in the 3'-untranslated region of hPXR mRNA. Transfection of LS180 human colorectal adenocarcinoma cells with an miR-18a-5p mimic decreased hPXR mRNA and protein expression, whereas transfection of LS180 cells with an miR-18a-5p inhibitor increased hPXR mRNA and protein expression. The decrease in hPXR expression by the miR-18a-5p mimic was associated with a reduction in the extent of hPXR target gene (CYP3A4) induction by rifampin and rilpivirine. Treatment of untransfected LS180 cells with either of these hPXR agonists decreased endogenous expression of miR-18a-5p, and this preceded the onset of CYP3A4 induction. In conclusion, miR-18a-5p is a negative regulator of hPXR expression and the hPXR agonists rifampin and rilpivirine are chemical suppressors of miR-18a-5p expression.

BACKGROUND Plasma concentrations of choline and its metabolites might serve as biomarkers for the health outcomes of several pathological states such as cardiovascular disease and cancer. However, information about the reliability of biomarkers of choline status is limited. We investigated biological variations in repeated measures of choline and metabolites in healthy adults to assess them as biomarkers. METHODS Blood samples were collected after an overnight fast at three-time points 12 days apart from 40 adults (mean age, 33 y; male, n = 21). A subset (n = 19; [male, n = 8]) provided one additional sample after a breakfast meal. Plasma free choline, betaine and dimethylglycine were measured using liquid chromatography-tandem mass spectrometry, and plasma phosphatidylcholine, sphingomyelin and lysophosphatidylcholine were measured using high-performance liquid chromatography. RESULTS The biological variations observed for choline and metabolites were ≤ 13% for adult fasting samples. This corresponded to intra-class correlations (ICC) that ranged from 0.593 to 0.770 for fasting values for choline and metabolites. A similar ICC range was also obtained between fasting and post-prandial states. Although most post-prandial concentrations of choline and metabolites were significantly higher (P

Choline has critical roles during periods of rapid growth and development, such as infancy. In human milk, choline is mostly present in water-soluble forms (free choline, phosphocholine, and glycerophosphocholine). It is thought that milk choline concentration is influenced by maternal choline intake, and the richest food sources for choline are of animal origin. Scarce information exists on milk choline from countries differing in animal-source food availability. In this secondary analysis of samples from previous trials, the concentrations of the water-soluble forms of choline were quantified by liquid chromatography-tandem mass spectrometry in mature milk samples collected from lactating women in Canada (n = 301) and in Cambodia (n = 67). None of the water-soluble forms of choline concentrations in milk differed between Canada and Cambodia. For all milk samples (n = 368), free choline, phosphocholine, glycerophosphocholine, and the sum of water-soluble forms of choline concentrations in milk were (mean (95%CI)) 151 (141, 160, 540 (519, 562), 411 (396, 427), and 1102 (1072, 1133) µmol/L, respectively. Theoretically, only 19% of infants would meet the current Adequate Intake (AI) for choline. Our findings suggest that the concentrations in milk of water-soluble forms of choline are similar in Canada and Cambodia, and that the concentration used to set the infant AI might be inaccurate.

In order to mitigate the flood disaster, an integrated structural flood control system, mainly incorporating levees, reservoirs, and flood diversion and detention zones, has been established in the JingJiang Reach of the Yangtze River by the efforts of Chinese government after several decades. The flood control effect of the integrated structural flood control system on mitigating the most catastrophic flood in history record which did occur in 1870 was assessed. According to the results, the used storage for flood control of the Three Gorges Reservoir is 18.4 billion m3 and the used storage for flood control of the other upstream reservoirs is 9.3 billion m3. The used flood storage of the Jingjiang Flood Diversion Zone is 5.4 billion m3 and the highest water level at Shashi Station is 45.00m. It shows that the flood control safety in the Jingjiang Reach is ensured to reach the achievement that controlling the highest water level at Shashi Station no more than 45.00m in the flood of 1870 to avoid the likely catastrophic flood disaster in the Jianghan plain and Dongting Lake plain along the Jingjiang Reach.

Choline, an essential dietary nutrient for humans, is required for the synthesis of the neurotransmitter, acetylcholine, the methyl group donor, betaine, and phospholipids; and therefore, choline is involved in a broad range of critical physiological functions across all stages of the life cycle. The current dietary recommendations for choline have been established as Adequate Intakes (AIs) for total choline; however, dietary choline is present in multiple different forms that are both water-soluble (e.g., free choline, phosphocholine, and glycerophosphocholine) and lipid-soluble (e.g., phosphatidylcholine and sphingomyelin). Interestingly, the different dietary choline forms consumed during infancy differ from those in adulthood. This can be explained by the primary food source, where the majority of choline present in human milk is in the water-soluble form, versus lipid-soluble forms for foods consumed later on. This review summarizes the current knowledge on dietary recommendations and assessment methods, and dietary choline intake from food sources across the life cycle.

Platelet-derived growth factor (PDGF)-, epidermal growth factor (EGF)- and insulin-like growth factor I (IGF-I)-stimulated cell proliferation in 3T3 cells was accompanied by increased abundance of labile intracellular pool of zinc (LIPZ). However, the origin and regulation of this cell proliferation-associated increase in the abundance of LIPZ are unknown. Cellular zinc homeostasis involves zinc transporters and metallothionein. The objectives of this study were to determine whether cell proliferation-associated increase in the abundance of LIPZ was a result of an increased zinc uptake and to assess the involvement of zinc transporters and metallothionein in this cell proliferation-associated increase in the abundance of LIPZ in 3T3 fibroblasts. Zinc transporters assessed included both zinc importer (Zip1) and zinc exporters (ZnT1, ZnT2 and ZnT4). Growth factors increased the abundance of LIPZ while total cellular zinc concentration remained unaffected, demonstrating that LIPZ was responsive to the increased needs for zinc during growth factor-stimulated cell proliferation. Growth factors also increased net zinc retention as indicated by higher 65zinc radioactivity and elevated mRNA levels of Zip1, ZnT1 and ZnT4. Although zinc is essential to cell proliferation, excessive cellular zinc accumulation causes cytotoxicity. Collectively, these observations suggest that increase in the abundance of LIPZ during growth factor-stimulated cell proliferation was due to increased net retention of extracellular zinc, which was apparently achieved through a coordinated up-regulation of the expression of transporters involved in both zinc influx and efflux to ensure adequate supply of zinc to sustain cell proliferation, yet to prevent potential zinc cytotoxicity in 3T3 cells.

Zinc has been shown to be accumulated in N-methyl-N-nitrosourea (MNU)-induced rat mammary tumors. Zinc is required for cell proliferation and tumorigenesis is characterized by dysregulation of cell proliferation. An accumulation of zinc in mammary tumors perhaps indicates a reliance on zinc to sustain tumor growth. Limiting zinc supply by means such as reduced zinc intake should negatively modulate mammary tumorigenesis. Our objective was to determine the effects of zinc status on MNU-induced mammary tumorigenesis in sexually mature female rats. Twenty-one-day-old Sprague-Dawley rats were assigned to low-zinc (3 mg zinc/kg diet) or adequate-zinc (12 mg zinc/kg diet) ad libitum or pair-fed control group (n = 25-33 rats/ group). On day 50 of age, all rats were intraperitoneally injected with MNU (50 mg/kg body wt) to induce mammary tumorigenesis. Rats were further maintained on their assigned diet until 14 weeks post-MNU injection. Total food intake and overall body weight gain were lower in low-zinc rats than in adequate-zinc ad libitum control rats, but were similar to adequate-zinc pair-fed control rats. Plasma zinc concentration was lower in low-zinc rats than in adequate-zinc ad libitum and pair-fed control rats, confirming moderately low-zinc status in low-zinc rats. Tumor incidence (46 versus 84 and 80%; P < 0.05) and tumor multiplicity (0.8 versus 5.0 and 2.6 tumors/rat; P < 0.05) and tumor number (28 versus 123 and 66 tumors) were reduced in low-zinc rats compared with that in adequate-zinc ad libitum and pair-fed control rats, respectively. Tumor latency in low-zinc and adequate-zinc pair-fed control rats was not significantly different, but was longer than in adequate-zinc ad libitum control rats (P < 0.05), suggesting that reduced food intake associated with low-zinc intake prolonged tumor latency. Tumor burden and size were not affected by zinc intake. Overall, our observations showed that moderately low-zinc status suppressed MNU-induced rat mammary tumorigenesis.

The objectives of this study were (i) to investigate the modulating effects of zinc nutrition on histochemically reactive zinc in the rat intestine and liver and (ii) to assess the relationship between histochemically reactive zinc and metallothionein-bound zinc in these tissues under varying zinc nutrition. Male Wistar rats were fed a zinc-deficient (3 mg zinc/kg), adequate-zinc (30 mg zinc/kg, ad libitum or pair-fed), or zinc-supplemented (155 mg zinc/kg) diet for 2 or 6 weeks. Plasma N-(6-methoxy-8-quinolyl)-para-toluenesulfonamide-reactive zinc reflected dietary zinc intake. Abundance of the intestine histochemically reactive zinc was correlated with dietary zinc intake after 2 weeks of dietary treatment. Dietary zinc intake had no effect on the abundance of the intestine histochemically reactive zinc after 6 weeks of dietary treatment and the hepatic histochemically reactive zinc after both 2 and 6 weeks of dietary treatment. This lack of effect of dietary zinc intake on the abundance of histochemically reactive zinc was associated with a higher level of metallothionein. The molecular-mass distribution profile revealed that N-(6-methoxy-8-quinolyl)-para-toluenesulfonamide-reactive zinc and metallothionein-bound zinc represented two different, but interrelated, pools of zinc. Overall, these results suggested that the abundance of histochemically reactive zinc was homeostatically regulated, which was partially achieved through the regulation of metallothionein levels in rats.Key words: N-6-methoxy-para-toluenesulfonamide (TSQ), histochemically reactive zinc, plasma TSQ-reactive zinc, intestine, metallothionein, rats.

This article examines the evolution, development, and current status of community health nursing in the People's Republic of China. Although its origin in China went back as early as the 1920s, community health nursing in the contemporary American sense was a recent development after the 1980s. Specifically, the article reviews the delivery models and service areas of community health nursing and discusses its current challenges. Based on original government policy documents, first-hand field knowledge, and published literature in both English and Chinese, the article also provides an account of the latest developments and elaborates on the implications of these policies for future community health nursing development in China.

Today, vanadium compounds are frequently included in nutritional supplements and are also being developed for therapeutic use in diabetes mellitus. Previously, tissue uptake of vanadium from bis(maltolato)oxovanadium(IV) (BMOV) was shown to be increased compared to its uptake from vanadyl sulfate (VS). Our primary objective was to test the hypothesis that complexation increases vanadium uptake and that this effect is independent of oxidation state. A secondary objective was to compare the effects of vanadium complexation and oxidation state on tissue iron, copper, and zinc. Wistar rats were fed either ammonium metavanadate (AMV), VS, or BMOV (1.2 mM each in the drinking water). Tissue uptake of V following 12 wk of BMOV or AMV was higher than that from VS (p0.05). BMOV led to decreased tissue Zn and increased bone Fe content. The same three compounds were compared in a cellular model of absorption (Caco-2 cells). Vanadium uptake from VS was higher than that from BMOV or AMV at 10 min, but from BMOV (250 microM only, 60 min), uptake was far greater than from AMV or VS. These results show that neither complexation nor oxidation state alone are adequate predictors of relative absorption, tissue accumulation, or trace element interactions.

Zinc distribution is apparently altered in breast cancer patients. It is unclear if this apparent zinc redistribution is a consequence of altered zinc nutrition or tissue-specific response to breast cancer. Our objectives were to assess effects of N-methyl-N-nitrosourea-treatment and N-methyl-N-nitrosourea-induced mammary tumorigenesis on body zinc-distribution profile in rats and to assess effects of dietary zinc intake on the body zinc-distribution profile during N-methyl-N-nitrosourea treatment and N-methyl-N-nitrosourea-induced mammary tumorigenesis in rats. Female Sprague-Dawley rats were assigned to zinc-deficient (3 mg/kg diet) or zinc-adequate (31 mg/kg diet) ad libitum or pair-fed group. Rats were sham treated or N-methyl-N-nitrosourea treated (50 mg/kg body weight; Experiment 1 or 40 mg/kg body weight; Experiment 2) (n = 6). In both experiments, the zinc concentration was significantly higher (6-19 times) in mammary tumor than in mammary gland. Tissue zinc concentration was essentially unaffected by N-methyl-N-nitrosourea treatment and tumor bearing, but was reduced by zinc deficiency in the bone, kidney, and liver. Overall, higher mammary tumor zinc concentration and absence of zinc redistribution during N-methyl-N-nitrosourea treatment and N-methyl-N-nitrosourea-induced mammary tumorigenesis, regardless of zinc intakes, indicates zinc accumulation in mammary tumors. Because zinc is essential for growth and cancer is characterized by uncontrolled growth, this zinc accumulation suggests an involvement of zinc in N-methyl-N-nitrosourea-induced rat mammary tumorigenesis.

The present study investigated the effect of dietary zinc deficiency during the developmental period on hepatic cytochrome P450 (CYP) expression in postpubertal male rats. Twenty-one-day-old weanling male Wistar rats were randomly assigned to one of the following dietary groups: zinc-adequate (31 mg zinc/kg diet); marginal zinc-deficient (3 mg zinc/kg diet); severe zinc-deficient (1 mg zinc/kg diet); or pair-fed control for either the marginal or severe zinc-deficient group. All rats were killed at 63 days of age. Compared with the corresponding pair-fed controls, marginal zinc deficiency decreased CYP2C11-mediated testosterone 2α- and 16α-hydroxylase activities by 43 and 42%, respectively, whereas severe zinc deficiency reduced each of these activities by approximately 60%. The decrease in CYP2C11 activity was accompanied by a reduction in CYP2C11 protein and mRNA levels, as assessed by immunoblot and reverse transcription-polymerase chain reaction (RT-PCR) assays, respectively. Additional RT-PCR analysis indicated that severe zinc deficiency decreased CYP3A2 and CYP3A18 mRNA levels by 49 and 43%, respectively, whereas it increased CYP2C12 (253%) and CYP3A9 (238%) mRNA expression. Plasma testosterone concentration was decreased by 67% in the marginal zinc-deficient group when compared with the corresponding pair-fed control group. By comparison, it was below the limit of quantification (0.2 ng/mL) in the severe zinc-deficient rats. Overall, these results indicate that dietary zinc deficiency during the developmental period feminized the hepatic gene expression of the sexually dimorphic CYP2C11, CYP3A2, CYP3A18, CYP2C12, and CYP3A9 in postpubertal male rats.

Numerous studies have shown that zinc nutrition influences the growth of several types of tumor. However, the influence of zinc nutrition on mammary tumorigenesis is not known. To study the effects of dietary zinc intake on N-methyl-N-nitrosourea (MNU)-induced mammary tumorigenesis, female Sprague-Dawley rats were fed an egg-white-based diet providing 3 (Z3), 12 (Z12), or 31 (Z31) mg zinc/kg diet ad libitum. In addition, two pair-fed controls, PFZ12 and PFZ31, were also included. Fourteen weeks after MNU injection, cumulative tumor incidence and total number of tumors were lower in Z3 rats than in Z12 and Z31 rats. Cumulative tumor incidence and total number of tumors were lower in Z3 rats than in PFZ12 rats, but were the same as in PFZ31 rats. Cumulative tumor incidence and total number of tumors were also lower in pair-fed controls than in their corresponding ad libitum controls, but were the same between the ad libitum controls. Overall, the results showed that the effect of marginal zinc deficiency on MNU-induced mammary tumorigenesis in rats was primarily the result of a reduced feed intake associated with marginal zinc deficiency rather than zinc per se.

The insulin-like growth factors (IGFs) are mitogenic polypeptides that have been linked to a variety of normal physiological processes as well as neoplasia. Overexpression of several components of the IGF system is associated with hepatocarcinogenesis in humans and rodents. In rat liver, diets rich in n-6 polyunsaturated fatty acid (PUFA) enhance the development of preneoplastic lesions and tumors. Therefore, the objective of this study was to determine the effect of these dietary fatty acids on the hepatic expression of the various components of the IGF system. The mRNA levels of IGF-1 and the type 1 receptor were not different in livers of rats fed a diet containing 20% corn oil (CO) compared with those fed 5% CO. Analysis of the IGF binding proteins revealed that insulin-like growth factor binding protein-1 (IGFBP-1) levels were altered by the amount and type of dietary fat. A 2.5-fold induction of IGFBP-1 mRNA occurred within 1 week after the animals were fed the 20% corn oil diet compared with those fed 5% CO and was further enhanced to over 6-fold after 1 month. Furthermore, IGFBP-1 protein was only detectable in the livers of animals fed the 20% CO diet. Induction of IGFBP-1 mRNA (4.5-fold) also occurred in rats fed a high-fat diet containing safflower (rich in n-6 PUFAs) compared with those fed a high-fat diet containing menhaden oil (rich in n-3 PUFAs). The induction of IGFBP-1 mRNA was independent of serum insulin levels and the development of insulin resistance. Since IGFBP-1 mRNA is upregulated in regenerating liver, we reasoned that the induction of IGFBP-1 mRNA may be associated with an increase in cell proliferation; however, no difference was observed in the hepatic labeling index of rats fed the 20% CO compared with the 5% CO diet. In summary, these studies show a striking induction by dietary n-6 PUFAs of hepatic IGFBP-1, a protein that has been implicated in liver cancer development.

The objective of this study was to investigate the effect of dietary zinc deficiency on free radical production in the rat liver homogenate and whole liver under acute oxidative stress in vitro and in vivo. Three-week-old male Wistar rats were given free access to either a zinc-adequate diet or a zinc-deficient diet for 3 weeks. A second control group, the pair-fed control, was also included. The oxidative stress was imposed in vitro by incubating whole-liver homogenate prepared from rats with CCl4, ethanol, or FeNTA. The same oxidants were used to impose oxidative stress in vivo. Incubation of liver homogenate with CCl4 or ethanol resulted in the detection of their free radical metabolites, a CCl3· radical (αN = 13.9 G, αβH = 1.9 G) and a 1-hydroxyethyl radical (αN = 15.1 G, αβH = 4.6 G), respectively. A free radical (αN = 14.9 G, αβH = in the whole-liver homogenate incubated with FeNTA. A CCl3· radical was detected in the livers of CCl4-challenged 4.8 G) was detected in the rats in vivo. However, no free radicals were detected in the livers of ethanol- or FeNTA-challenged rats regardless of dietary treatment. The production of free radicals both in vitro and in vivo was not affected by dietary zinc deficiency as indicated by electron spin resonance signals of α-phenyl-N-tert-butyl nitrone-spin adduct. It seems that dietary zinc-deficient rats are capable of coping with an increased free radical production in liver, both in vitro and in vivo, under acute oxidative stresses.

The objective of this study was to investigate if the altered 2E1 drug metabolism capacity in rats is due to effects of dietary zinc deficiency on the expression of hepatic microsomal P450 2E1 in rats. Rats were given free access to either a zinc-adequate diet or a zinc-deficient diet for 3 weeks. A second control group, the pair-fed control, was also included. At the end of the feeding trial, each dietary group was further divided into the drug control and ethanol treatment group. Ethanol (EtOH, 8 mL/kg body weight, intubation) was given once a day for 3 consecutive days. Within the drug control group, zinc deficiency reduced total P450 concentration but had no effect on the level of NADPH-P450 reductase, 2E1 protein, and 2E1 mRNA. 2E1 activity, which was indicated by N-nitrosodimethylamine demethylase (NDMA), aniline hydroxylase (AH), and p-nitrophenol hydroxylase (NH) activity, was also not affected by dietary zinc deficiency. The NDMA demethylase activity and 2E1 mRNA level were higher in zinc pair-fed rats than in zinc-adequate rats. EtOH treatment induced total P450 concentration in zinc-adequate and zinc-deficient rats and NADPH-P450 reductase level in zinc-adequate rats. 2E1 activity was induced by EtOH, while the level of 2E1 protein and 2E1 mRNA was unchanged. In conclusion, the constitutive expression of hepatic microsomal 2E1 was not affected by zinc deficiency per se; however, the prolonged severe depression of feed intake caused by zinc deficiency increased the level of 2E1 mRNA in rats. An acute EtOH treatment markedly induced 2E1 activity without affecting the level of 2E1 protein and mRNA. (J. Nutr. Biochem. 5:308–313, 1994.)

This study was conducted to investigate whether the effects of zinc deficiency on the in vitro and in vivo drug metabolism in rats results from an altered expression of hepatic microsomal P450, particularly P450 2B (2B), in rats. Three-week-old, male Wistar rats were randomly assigned to three groups: a zinc-adequate ad libitum (ZnAL), zinc-adequate pair-fed (ZnPF), and zinc-deficient (ZnDF) group. After 3 weeks on the diet, each dietary group was further divided into drug control and phenobarbital (PB, 100 mg/kg, 3 days, ip) group. Within the drug control group, total microsomal P450 concentration was lower in both ZnPF and ZnDF than in ZnAL. Zinc deficiency resulted in a decreased aminopyrine N-demethylase (AD) activity expressed per milligram protein, with no effect on benzphetamine N-demethylase (BD) activity. The constitutive level of 2B protein and mRNA was not affected by dietary treatments. The level of NADPH–P450 reductase in ZnDF was significantly higher than in ZnAL and ZnPF. PB treatment significantly induced total microsomal P450 concentration, AD and BD activities expressed per milligram protein, 2B protein and mRNA levels, and NADPH–P450 reductase level in all dietary groups. In summary, the constitutive level of AD activity, but not BD activity, was decreased in dietary zinc deficient rats. The constitutive levels of 2B protein and mRNA were not affected by dietary zinc deficiency. PB-induced expression of 2B, both transcriptionally and translationally, and the induction of AD and BD activity by PB were not affected by zinc deficiency in rats. Severe feed restriction had no effect on the levels of both constitutively and inductively expressed AD and BD activities, 2B protein, and 2B mRNA.Key words: dietary zinc deficiency, 2B protein and mRNA, 2B activity, induction of 2B, phenobarbital.

With the increasing popularity of E-learning, the digital instructional resources in school become more and more diverse. Due to the lack of sharing platform, a series of problems appear such as low resource utilization. Through introducing the current situation of digital instructional resources sharing, this paper builds a sharing platform and analyses the module of it, to perfect the construction of the sharing platform of digital teaching resources, and improve the efficiency of e-learning.

It has been proposed that a biochemical function of Zn is maintenance of the membrane structure and function. Previous research has shown that dietary Zn deficiency causes a leakage of H 2 O 2 from the NADPH-dependent P450 enzyme system. Microsomal membranes isolated from Zn-deficient rats are more susceptible to lipid peroxidation. The objectives of this study were to investigate the effects of dietary Zn deficiency on the function and stability of liver microsomal P450 in rats and to study the possible mechanisms involved. In rats fed the Zn-deficient diet, the concentration of total liver microsomal protein was unchanged, but P450 concentration and aminopyrine demethylase activity were significantly decreased compared with rats fed the Zn-adequate diet pair-fed or ad libitum . The decrease in P450 concentration was not accompanied by the appearance of P420. The decrease in enzyme activity was also reflected by impaired drug metabolism in vivo as indicated by increased pentobarbital-induced sleeping time, but a statistically significant difference was found only between the ZnDF and the ZnAL groups. However, membrane lipid peroxidation, as indicated by MDA concentration, was not affected by the dietary treatments. To understand the mechanism by which Zn deficiency causes reduced function and stability of P450, the results obtained from the microsomal membranes isolated from Zn-deficient rats were compared with the results obtained from the microsomal membranes treated with protein denaturants or free radical generating systems in vitro , or microsomal membranes isolated from rats challenged with CC1 4 , or FeNTA in vivo . It is concluded that severe dietary Zn deficiency in rats caused a functional and structural impairment of liver microsomal P450 via a free radical medicated-like mechanism.

Lipopolysaccharide (LPS) triggers a global activation of Inflammatory responses leading to liver injury in humans. Zinc pretreatment has been shown to prevent LPS-induced hepatic necrosis. In North America, suboptimal zinc status is more common than once realized. However, the effect of inadequate zinc nutrition on the host's susceptibility to LPS-induced liver injury is not known. The objective of this study was to determine whether marginal zinc deficiency would render rats more susceptible to LPS-induced liver injury. Weanling Sprague-Dawley rats were assigned to one of three dietary treatment groups: marginally low zinc ad libitum (Z3; 3 mg zinc/kg diet), adequate zinc ad libitum (Z30; 30 mg zinc/kg diet), or adequate zinc pair-fed (Z30P) group. After 6 weeks, each dietary treatment group was further divided into LPS-control (saline) groups (C-Z3, C-Z30P, C-Z30) and LPS-treatment (1 mg/kg body weight, intraperitoneal, 8 hrs) groups (LPS-Z3, LPS-Z30P, LPS-Z30). LPS reduced the serum zinc concentration and increased the liver zinc concentration regardless of dietary zinc intake. Serum alanine aminotransferase level was higher in the LPS-Z3 rats than in the LPS-Z30P and LPS-Z30 rats. LPS also induced hepatocyte necrosis and neutrophil infiltration into the liver sinusoids. This LPS-induced liver damage was more severe in the LPS-Z3 rats than in the LPS-Z30P and LPS-Z30 rats. Together these findings have demonstrated that marginal zinc deficiency increased the susceptibility to LPS-induced liver injury in rats. These results indicate that patients with sepsis who have suboptimal zinc nutrition status may be at higher risk of developing greater liver damage.

Increasing evidence shows that labile intracellular zinc is metabolically important. Depletion of labile intracellular zinc using chelators suppresses DNA synthesis. In this study, we tested the hypothesis that labile intracellular zinc could be modulated via varying zinc nutrition. This could result in an altered availability of labile intracellular zinc, which, in turn, could influence zinc-dependent cellular events involved in cell proliferation and ultimately suppress growth. Labile intracellular zinc was detected by using N-(6-methoxy-8-quinolyl)-para-toluenesulfonamide (TSQ), a membrane-permeable fluorescence probe. After 48 h culture in a zinc-depleted medium, labile intracellular zinc in 3T3 cells was diminished along with a suppressed DNA synthesis and cell proliferation. In contrast, supplementation of zinc to the zinc-depleted medium increased the labile intracellular zinc and promoted DNA synthesis and cell proliferation. Furthermore, growth factor-dependent stimulation of DNA synthesis and cell proliferation was also accompanied by increased labile intracellular zinc. Together, our data showed an association between the labile intracellular zinc, detected using TSQ, and 3T3 cell growth, suggesting that labile intracellular zinc could be an important cellular link between zinc nutrition and growth.

Diets containing high levels of fat enhance the formation of methylnitrosourea (MNU)-induced mammary gland adenocarcinomas in rats, while administration of the antiestrogen tamoxifen decreases the incidence of these tumors. It is not known, however, at what stage during tumor development the fat or tamoxifen exert their effects. Here we have used a PCR/liquid hybridization and gel retardation assay to determine the effects of dietary fat and tamoxifen on the growth rate of cells harboring an Ha-ras oncogene in the mammary glands of rats at various times following MNU administration. Glands from animals on a high-fat diet had significantly higher mutant cell fractions than those on a low-fat diet at both 30 and 75 days following MNU treatment. In contrast, there was no difference between the mutant cell fractions of tamoxifen-treated animals and controls at either 30 or 70 days. These results suggest that dietary fat promotes tumor formation early in carcinogenesis by stimulating the growth of cells harboring Ha-ras mutations, while tamoxifen delays the appearance of tumors either by acting as a tumoristatic or tumoricidal agent, or by acting to eliminate or retard the growth of preneoplastic cells just prior to the emergence of tumors.