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Keap1-nrf2 signaling_ a target for cancer prevention by sulforaphane

Keap1-nrf2 signaling_ a target for cancer prevention by sulforaphane
Keap1-nrf2 signaling_ a target for cancer prevention by sulforaphane

chemical carcinogenesis and other chronic degenerative diseases [4]. Sulforaphane is a potent inducer of Nrf2 signaling and blocks the formation of dimethylbenz[a]anthracene-evoked mammary tumors in rats as well as other tumor types in various animal models [5,6].In some instances, these protective effects are lost in Nrf2-disrupted mice [7,8]. In addition to increasing cellular capacity for detoxifying electrophiles and oxidants, sulforaphane has been shown to induce apoptosis, inhibit cell cycle progression and inhibit angiogenesis [9-11]. Collectively, these actions serve to impede tumor growth. However, not all of the molecular actions of sulforaphane are triggered at the same concentrations. For, example,activation of Nrf2 signaling occurs at substantially lower concentrations than does induction of apoptosis [2,12]. The overall potent and multimodal actions of sulforaphane makes it appealing to use in both preventive and therapeutic settings.Broccoli and other cruciferous vegetables (e.g., cabbage, kale, and Brussels sprouts),primary sources of sulforaphane, are widely consumed in many parts of the world.Epidemiological evidence from prospective cohort studies and retrospective case-control studies suggest that consumption of a diet rich in crucifers reduces the risk of several types of cancers as well as some chronic degenerative diseases [13,14]. There is growing evidence that the protective effects of crucifers against disease may be attributable largely to their content of glucosinolates (β-thioglucose N-hydroxysulfates) [15]. Glucosinolates in plant cells are hydrolyzed to bioactive isothiocyanates by the β-thioglucosidase myrosinase [15].Myrosinase is released from intracellular vesicles following crushing of the plant cells by chewing, food preparation or damage by insects. This hydrolysis is also mediated in a less predictable manner by β-thioglucosidases in the microflora of the human gut [16]. Young broccoli plants are an especially good source of glucosinolates, with levels 20-50 times those found in mature market-stage broccoli [17]. The principal glucosinolate contained in broccoli is glucoraphanin, which is hydrolyzed by myrosinase to sulforaphane (see Fig. 1).Human populations are continuously exposed to varying amounts of chemicals or manufacturing by-products that are carcinogenic in animal models; over 100 such compounds have been designated as human carcinogens by the International Agency for Research on Cancer [18] and the National Toxicology Program [19]. Exposures to these

exogenous agents occur through the environmental vectors of food, water and air. In some

cases the pathway to reducing cancer burden from these exposures is obvious – eliminate

exposures. However, in some instances, exposures are largely unavoidable, such as

exposures to aflatoxins and other mycotoxins in food, or require substantial behavioral

changes (e.g., smoking cessation) or economic investments (e.g., clean air in developing

megacities) that are exceedingly difficult to implement in individuals or populations. In

these settings, effective, tolerable, low cost and practical approaches to chemoprevention

with foods rich in glucosinolates serving as precursors for anticarcinogenic isothiocyanates,

such as glucoraphanin and its cognate isothiocyate sulforaphane in broccoli, may be

especially desirable.

This article highlights recent studies on the mechanisms of action of sulforaphane as an

inducer of Nrf2-regulated genes and their roles in attenuating or blocking carcinogenesis.

These studies, in turn, have supported the development and conduct of a series of clinical

trials in Qidong, China for the optimization of dose and formulation regimens seeking to

reduce body burdens of environmental carcinogens in residents of this region. In Qidong,

exposures to food-borne and air-borne toxins and carcinogens can be considerable.

Heptatocellular carcinoma can account for up to 10% of the adult deaths in some rural

townships there. Chronic infection with hepatitis B virus, coupled with exposure to

aflatoxins, likely contributes to this high risk of liver cancer [20]. As vaccination programs

and economic development take hold, risk factors for liver cancer are diminishing in

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Qidong; however, development is likely leading to increased exposures to air-borne

chemicals with uncertain but potentially adverse health outcomes.

Keap1-Nrf2 signaling

Environmental carcinogens typically undergo metabolic activation in target cells to form

reactive electrophiles that damage DNA. Several completed clinical trials have attempted to

reduce the burden of DNA damage imparted by environmental exposures to heterocyclic

amines [21], tobacco smoke [22] and aflatoxins [23-25]. The end points for these trials were

short-term biomarker modulations of carcinogen metabolism and/or DNA adducts and other

forms of DNA damage. In these studies, modulation of these biomarkers is presumptive

evidence for a cancer risk reduction, a concept that has been well validated in animal models

[26]. Multiple strategies for modifying the bioactivation and/or detoxication of

environmental carcinogens have been developed [4]. Disruption of Nrf2 signaling in mice

leads to increased sensitivity to carcinogenesis by environmental agents [7,27], increased

burden of carcinogen-DNA adducts in target tissues [28-30] and loss of chemopreventive

efficacy of anticarcinogens such as sulforaphane, oltipraz and CDDO-Im [7,27,30] and

highlight a critical role for this adaptive stress response pathway as a critical determinant of

susceptibility, and hence, a target for prevention.

The Keap1-Nrf2 signaling pathway provides a broad based cytoprotective response towards

disruption of cellular homeostasis by extrinsic and intrinsic stresses. The current model of

Keap1-Nrf2 interactions, as addressed in recent reviews [31,32], involves the Kelch domains

of a Keap1 homodimer functionally interacting with two different sites within the Neh2

domain of Nrf2, the ETGE, or high affinity ‘hinge’ site and the DLG, the lower affinity

‘latch’ site (see Fig. 2). Under normal cellular conditions, Tong et al [33] propose that Nrf2

first interacts with the Keap1 dimer through the ETGE hinge interaction, tethering Nrf2 to

the Keap1 homodimer, and subsequently the Cul3-Rbx1 complex which, following the

stable interaction of Nrf2 to Keap1 through the DLG latch motif, leads to the appropriate

orientation of proteins to facilitate the ubiquitination and subsequent proteasomal targeting

as well as destruction of Nrf2. Upon cellular stress or pharmacologic induction, the ability of

Keap1 to maintain both points of contact, the hinge and the latch, is thought to be disrupted

by the alteration of the tertiary or quaternary structure of the Keap1 homodimer,

accomplished via alterations of the many reactive cysteines within Keap1 through oxidation

or covalent modification [34,35]. The disruption of this efficient turnover of Nrf2 allows for

the accumulation of the protein and permits Nrf2 to translocate into the nucleus. Once within

the nucleus, Nrf2 forms heterodimers with small Maf proteins, and drives the transcription

of genes with a functional Antioxidant Response Element (ARE) within their promoters

[3,36]. These genes include, but are not limited to conjugation/detoxication proteins,

antioxidative enzymes, anti-inflammation proteins, the proteasome and cellular chaperones,

creating a general cytoprotective response following pathway activation [37]. Recently, the

response of Nrf2 has been broadened in scope, with studies documenting interactions

between Nrf2 and Notch signaling [38], p53/p21 [39], p62 based autophagy [40,41], aryl

hydrocarbon receptor signaling [42], NF-κB [43,44] and other processes [45]. These

interactions provide the means to elicit the broad-based cell survival responses that now

typify the pathway.Keap1 is targeted by sulforaphane

Sulforaphane is—or is amongst—the most potent naturally occurring inducers of Nrf2

signaling, exhibiting efficacy in the high nanomolar range in cell cultures. Its’ potency may

reflect in part a capacity to accumulate in cells as an interchangeable conjugate with

glutathione [46]. Keap1 is a cysteine-rich protein that serves as the sensor regulating

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activation of Nrf2 signaling by various chemical classes of anticarcinogens, all of which are

thiol regents [47]. Hong et al. [48] observed that sulforaphane modified multiple Keap1

domains, whereas the model electrophiles, but less potent pathway activators

dexamethasone mesylate and biotinylated iodoacetic acid, modified Keap1 preferentially in

the central linker domain [47]. Some of the differences between sulforaphane modification

patterns and those of other electrophiles probably reflect differences in electrophile

chemistry. Dexamethasone mesylate and biotinylated iodoacetic acid are SN2 type

electrophiles that alkylate by nucleophilic displacement of a leaving group. Thiols react with

sulforaphane by addition to the isothiocyanate carbon to yield thionoacyl adducts. The

acylation reaction occurs much more rapidly than does alkylation, although these adducts

are subjected to dissociation and rearrangement. A followup analysis by Hu et al [49] using

a modified sample preparation protocol has determined C151 to be one of four cysteine

residues preferentially modified by sulforaphane. These chemical mapping results are

consistent with in vivo observations reported by multiple investigators in which C151 has

also been determined to be the primary target for modification by sulforaphane [50,51]. In

cells in which cysteine 151 of Keap1 has been mutated to serine, nuclear accumulation and

subsequent induction of Nrf2 target genes by sulforaphane is severely abrogated.

As depicted in Fig. 2, the Nrf2 signaling pathway is activated in response to the modification

of Keap1 C151 by an increased amount of newly synthesized Nrf2 translocating to the

nucleus, a result of decreased Keap1-mediated Nrf2 ubiquitination, and subsequent

proteasomal degradation. This decrease in Nrf2 ubiquitination appears to arise from a

diminished interaction between Keap1 and Cul3 upon the modification of C151, as shown

by co-immunopreciptitation experiments in cells expressing mutant Keap1 (C151W) or

treated with sulforaphane [34].Gene expression changes evoked by sulforaphane in animal and human cells Extensive microarray-based studies have and continue to define the battery of Nrf2-regulated genes in the context of different species, tissues, cell types and responses to small

molecule activators of the pathway (reviewed in: [31,52]). These studies typically employ

both genetic and pharmacologic perturbations of pathway activity to define the nature and

range of induced or repressed genes. Several early studies focused on the comparative

effects of sulforaphane or vehicle treatment in Nrf2-disrupted or wild-type mice in small

intestine [53] and liver [54]. Patterns of elevated expression of Nrf2-regulated genes

reflected those seen with other inducers such as 1,2-dithiole-3-thione [55] or with genetic

upregulation via hepatic-specific disruption of Keap1 [56] in the liver. Families of genes

elevated in response to sulforaphane include electrophile detoxication enzymes, enzymes

involved in free radical metabolism, glutathione homeostasis, generation of reducing

equivalents and lipid metabolism, solute transporters, subunits of the 26S proteasome,

nucleotide excision repair proteins, and heat shock proteins. Bioavailability and Nrf2-

dependent pharmacodynamic action of sulforaphane have been demonstrated in a number of

extrahepatic tissues [57,58]. More recent studies have evaluated the Nrf2 transcriptional

program in human cells [59,60]. Recently, Agyeman et al [61] analyzed the transcriptomic

and proteomic changes in human breast epithelial MCF10A cells following sulforaphane

treatment or Keap1 knockdown with siRNA using microarray and stabile isotopic labeling

with amino acids in culture, respectively. Strong concordance between the transcriptomic

and proteomic profiles was observed. As seen in other studies with human cells, induction of

aldo-keto reductase family members was most vigorous. Fig. 3 demonstrates that aldo-keto

reductases AKR1C1/2, AKR1C3 and AKR1B10, as well as the prototypic Nrf2-regulated

enzyme NQO1 are substantively induced by sulforaphane following treatment of primary

human mammary organoid cultures prepared from reduction mammaplasty specimens.

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Thus, an Nrf2 regulated response to sulforaphane in humans that recapitulates at least in part

that observed in rodent models is evident.

Clinical trials in Qidong with broccoli sprout preparations

Extensive work by Talalay and colleagues has characterized the pharmacokinetics and safety in humans of ingestion of sulforaphane-rich (SFR) or glucoraphaninrich (GRR) hot water extracts prepared from broccoli sprouts [16,62,63]. In many cases, freeze-dried standardized sprout extracts from specifically selected cultivars and seed sources grown in a prescribed manner were utilized to provide consistency of preparations across multiple studies. First and foremost, these studies have established the safety of these GRR and SFR preparations.Dose limiting factors center on taste, gastric irritation and flatulence. Second, they have demonstrated a linear uptake and elimination of sulforaphane following administration of a wide range of doses as a SFR beverage. Third, bioavailability of sulforaphane was substantially better when administered as a SFR versus a GRR beverage. This latter result points to a limited capacity for the microbial thioglucosidases of the human gut to catalyze the conversion of glucoraphanin to sulforaphane. Subsequently, dozens of clinical trials are underway or completed utilizing broccoli or broccoli sprout preparations, as indicated by a review of the https://www.wendangku.net/doc/109741804.html, website. Summarized below and in Table 1 are the key findings in a series of 4 clinical trials we have conducted in Qidong, China with broccoli sprout derived beverages. All trials were approved by Institutional Review Boards in the United States and China.In as much as these initial hospital-based studies with broccoli sprout beverages were conducted in Baltimore amongst Caucasian and African-American participants, our first initiative in Qidong sought to address whether and to what extent Chinese could convert,absorb and excrete sulforaphane following administration of a GRR beverage. In 2002,twelve volunteers from the village of He Zuo in Qidong refrained from eating cruciferous and other green vegetables over a 4-day period. Extensive dietary logs were maintained and daily home visits to witness food preparation confirmed the absence of these vegetables from the diet. On the evening of the 3rd day, each volunteer consumed a GRR beverage

containing 225 μmol glucoraphanin. Overnight, twelve-hour urine samples were collected

during the run-in and post-intervention phases of the study. Using a cyclocondensation assay

to measure sulforaphane and other isothiocyanate metabolites, average total excretion levels

of 0.23, 0.32, 0.26 and 12.17 μmol of isothiocyantes were detected in the overnight voids.

This greater than 40-fold increase reflects an excretion of sulforaphane metabolites as 5.4%

of the administered dose of sulforaphane (in the form of its precursor glucoraphanin).

In 2003, a beverage formed from hot water infusions of 3-day old broccoli sprouts grown on

site, containing defined concentrations of glucosinolates as the stable precursor of the

sulforaphane, was evaluated for its ability to alter the disposition of aflatoxin. Exposures to

aflatoxin, common in this community, likely arose from fungal contamination of their

dietary staples. In this clinical study, also conducted in He Zuo, 200 healthy adults drank

beverages containing either 400 or <3 μmole glucoraphanin nightly for 2 weeks. Urinary

levels of aflatoxin-N 7-guanine, formed from depurination of the primary hepatic DNA

adduct, were similar between the two intervention arms. A non-significant 9% decrease was

seen in participants randomized to receive glucoraphanin-rich (GRR) compared to placebo

beverage. However, measurement of urinary levels of sulforaphane metabolites indicated

striking interindividual differences in bioavailability. This outcome may reflect individual

differences in the rates of hydrolysis of glucoraphanin to sulforaphane by the intestinal

microflora of the study participants. Accounting for this variability, a significant inverse

association was observed for excretion of total sulforaphane metabolites and aflatoxin-N 7-

guanine adducts in the 100 individuals receiving broccoli sprout glucosinolates [25]. This

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preliminary study illustrated the potential use of an inexpensive, easily implemented, food-based method for secondary prevention in a population at high risk for aflatoxin exposures.One of several challenges in design of clinical chemoprevention trials is the selection of an adequate dose, type of formulation, and dose schedule of the intervention agent. A cross-over clinical trial was undertaken in He Zuo, Qidong in 2009 to compare the bioavailability and tolerability of sulforaphane from two broccoli sprout-derived beverages: one glucoraphanin-rich (GRR) and the other sulforaphane-rich (SFR) (see Fig. 1). Sulforaphane was generated from glucoraphanin contained in the GRR beverage by gut microflora or formed by treatment of GRR with myrosinase from daikon sprouts to provide a SFR beverage [64]. Bulk amounts of freeze-dried powders of GRR and SFR were prepared in a commercial facility to provide a consistent composition throughout the study. Fifty healthy,eligible participants were requested to refrain from crucifer vegetable consumption and randomized into two treatment arms. The study design was as follows: 5-day run-in period,7-day administration of beverages, 5-day washout period, and 7-day administration of the opposite intervention. Isotope dilution mass spectrometry was used to measure levels of glucoraphanin, sulforaphane, and sulforaphane thiol conjugates in urine samples collected daily throughout the study (see Fig. 1). Bioavailability, as measured by urinary excretion of sulforaphane and its metabolites, was substantially greater with the SFR (mean ~70%) than with GRR (mean ~5%) beverages. In addition, inter-individual variability in excretion was considerably lower with SFR than with GRR beverage. Elimination rates were considerably slower with GRR, allowing for achievement of steady-state dosing as opposed to bolus dosing with SFR [64].An emerging problem in this region of China is outdoor air pollution. Analysis of urine samples for levels of phenanthrene tetraol, a metabolite of the polycyclic aromatic hydrocarbon and pollutant phenanthrene, from samples collected in the 2003 Qidong study indicated levels 4-5 times higher than measured in urine samples collected from urban residents of Minneapolis – St. Paul, Minnesota at the same time [25]. Urinary levels of phenanthrene tetraol remained high in the 2009 Qidong samples [65]. Therefore, urinary excretion of the mercapturic acids of the air-borne toxins acrolein, crotonaldehyde, ethylene

oxide and benzene were also measured in urine samples from both pre- and post-

interventions using liquid chromatography tandem mass spectrometry. Statistically

significant increases of 20-50% in the levels of excretion of glutathione-derived conjugates

of acrolein, crotonaldehyde and benzene were seen in individuals receiving SFR, GRR or

both compared with their preintervention baseline values. No significant differences were

seen between the effects of SFR versus GRR. Intervention with broccoli sprouts may

enhance detoxication of airborne pollutants and attenuate their associated health risks [65].

Optimal dosing formulations in future studies might consider blends of sulforaphane and

glucoraphanin as SFR and GRR mixtures to achieve peak concentrations for activation of

some targets and prolonged inhibition of others implicated in the protective actions of

sulforaphane. With that view in mind, a placebo-controlled intervention in 291 participants

with a blend of 40 μmol SFR and 600 μmol GRR has been completed in early 2012 in Hu

He, Qidong. This study will assess the impact of the broccoli sprout beverage on internal

dose biomarkers of air pollution, and in particular, evaluate the sustainability of the

intervention over several months in terms of tolerability and efficacy. Although it is

apparent that the Keap1-Nrf2 pathway can be activated in humans over the short-term, it

remains to be determined whether or not the pathway becomes refractory to repeated

activation stimuli. Collectively, this series of clinical trials have defined paradigms for using

biomarkers of exposures to environmental carcinogens as intermediate endpoints in the

evaluation of agents for the prevention of chronic diseases. In particular, prevention trials of

whole foods or simple extracts offer prospects for reducing an expanding global burden of

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cancer effectively with minimal cost, in contrast to promising isolated phytochemicals or

pharmaceuticals [66].

Acknowledgments

This work has been supported by USPHS grants P01 ES006052, R01 CA93780, R01 CA94076, Breast SPORE P50

CA088843, Center grant ES003819 and Department of Defense W81XWH-08-1-0176 and the Prevent Cancer

Foundation.

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56. Yates MS, Tran QT, Dolan PM, et al. Genetic versus chemoprotective activation of Nrf2 signaling:overlapping yet distinct gene expression profiles between Keap1 knockout and triterpenoid-treated mice. Carcinogenesis. 2009; 30:1024–1031. [PubMed: 19386581]57. Cornblatt BS, Ye L, Dinkova-Kostova AT, et al. Preclinical and clinical evalutation of sulforaphane for chemoprevention in the breast. Carcinogenesis. 2007; 28:1485–1490. [PubMed:17347138]58. Clarke JD, Hsu A, Williams DE, et al. Metabolism and distribution of sulforaphane in Nrf2knockout and wild-type mice. Pharm Res. 2011; 28:3171–3179. [PubMed: 21681606]59. Devling TW, Lindsay CD, McLellan, et al. Utility of siRNA against Keap1 as a strategy to stimulate a cancer chemopreventive phenotype. Proc Natl Acad Sci USA. 2005; 102:7280–7285.[PubMed: 15883370]60. Jeong WS, Keum YS, Chen C, et al. differential expression and stability of endogenous nuclear factor E2-related factor 2 (Nrf2) by natural chempreventive compounds. J Biochem Mol Biol.2005; 38:167176.61. Agyeman AS, Chaerkaedy R, Shaw PG, et al. Transcriptomic and proteomic profiling of KEAP1disrupted and sulforaphane-treated human breast epithelial cells reveals common expression profiles. Breast Cancer Res Treat. 2012; 132:175–187. [PubMed: 21597922]62. Shapiro TA, Fahey JW, Dinkova-Kostova AT, et al. Safety, tolerance and metabolism of broccoli sprout glucosinolates and isothiocyanates: a clinical phase I study. Nutr Cancer. 2006; 55:53–62.[PubMed: 16965241]63. Ye L, Dinkova-kostova AT, Wade KL, et al. Quantitative determination of dithiolcarbamates in human plasma, serum, erythrocytes and urine: pharmacokinetics of broccoli sprout isothiocyanates in humans. Clin Chim Acta. 2002; 316:43–53. [PubMed: 11750273]64. Egner PA, Chen JG, Wang JB, et al. Bioavailability of sulforaphane from two broccoli sprout beverages: results of a short-term, cross-over clinical trial in Qidong, China. Cancer Prev Res.2011; 4:384–395.65. Kensler TW, Ng D, Carmella SG, et al. Modulation of the metabolism of airborne pollutants by glucoraphanin-rich and sulforaphane-rich broccoli sprout beverages in Qidong, China.Carcinogenesis. 2012; 33:101–107. [PubMed: 22045030]66. Fahey JW, Talalay P, Kensler TW. Notes from the field: “green” chemoprevention as frugal medicine. Cancer Prev Res. 2012; 5:179–188.

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Fig. 1.

Glucoraphanin in broccoli is converted to sulforaphane either by plant myrosinases, or if the

plant myrosinases have been denatured by cooking, by bacterial myrosinases in the human

colon. Sulforaphane is passively absorbed and rapidly conjugated with glutathione by

glutathione S-transferases (GSTs), then metabolized sequentially by γ-glutamyl-

transpeptidase (GTP), cysteinyl-glycinease (GCase) and N-acetyltransferase (NAT). The

conjugates are actively transported into the systemic circulation where the merapturic acid

and its precursors are urinary excretion products. Deconjugation may also occur to yield the

parent isothiocyanate, sulforaphane. The mercapturic acid and cysteine conjugate forms are

the major urinary metabolites of sulforaphane [64]. For the beverages used in the Qidong

interventions enumerated in Table I, sulforaphane was generated enterically from

glucoraphanin through the action of thioglucosidases in the gut microflora (glucoraphanin-

rich, GRR); or pre-released by treatment of aqueous broccoli sprout extract with myrosinase

from the daikon plant Raphanus sativus (sulforaphane-rich, SFR)

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Fig. 2.

Scheme of Keap1-Nrf2 interactions. Under homeostatic conditions, Nrf2 is bound by Keap1

through the “hinge” ETGE) and “latch” (DLG) domains of Nrf2. Upon association, Nrf2 is

ubiquitinated by the Cul2/Rbx1/E2 ubiquitin ligaase complex, marking it for proteasomal

degradation. Induction of Nrf2 signaling by sulforaphane through thiocarbamylation at Cys

151may lead to disruption of the Cul3 association with Keap1 and abrogation of Nrf2

ubiquitination. Newly synthesized Nrf2 thereby escapes proteasomal degradation and

translocates to the nucleus where it accumulates and activates the transcription of its target

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Fig. 3.Induction of Nrf2 target genes NQO1 and aldo-keto reductases (AKRs) following treatment of primary cultures of human mammosphere cultures. Western blots were conducted on cell isolates 48 h after treatment with 15 μM sulforaphane (SFN).

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Table 1

Summary of Clinical Intervention Trials with Broccoli Sprouts in Qidong

Agent Dose and

Schedule

Size

(duration)

Biomarker

Modulation

References

Broccoli

Sprout

GRR

?225 μmol GRR12

(1 day)

Bioavailability study

only: ~5% administered

GR recovered in urine

as SF metabolites

unpublished

Broccoli

Sprout

GRR

?Placebo, q.d.

?400 μmol GRR

200

(14 days)

9% decrease in urinary

excretion of AFB-N7-

gua DNA adducts at 10

days; 10% decrease in

pollutant PheT excretion

[25]

Broccoli

Sprout

GRR ?

SFR

Cross-

over

?Run-in → GRR (800 μ mol) → wash-out → SFR (150

μmol)

?Run-in → SFR → wash-out → GRR

50

(24 days)

Glucoraphanin and

sulforaphane elimination

pharmacokinetics;

20-50% increases in

urinary excretion of

mercapturic acid (NAC)

conjugates of air pollutants:

acrolein, ethylene

oxide, crotonaldehyde,

benzene

[64,65]

Broccoli

Sprout

GRR +

SFR

Blend

?Placebo

?GRR (600 μmol) + SFR (40 μmol)

291

(12 weeks)

Biomarker analyses in

progress: primary endpoints

are urinary bi-

omarkers of food- and

air-borne toxins and

pollutants

unpublished

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        定义无序列表 23.定义列表的开始标记是
        24.定义表格的标记是标记,定义行的开始,,定义表格的行,用在
        定义行中的单元格 25.网页中设置滚动字幕的标记是标记 26.网页中版权声明符号标记是© 27.定义框架集的HTML标记是 28.框架集标记定义在标记之间。(F) 29.标记中用来定义滚动条的属性是scrolling 30.标记用来定义表单域 31.表单的提交方式有post和get 两种 32.关键字和描述信息定义在标记之间。 33. 标记定义页面标题,搜索引擎包括页面的信息,除标题以外的其他内容对访问者是不可见的。 34.标记必须用<> 括起来,标记一般成对出现。标记的属性带有特定的值,属性值包含在直引号中 35.网页文件标题标记 36.设置网页背景颜色通过在<body>标记中添加属性bgcolor实现 37.Xml语言Extensible Markup Language是指可扩展标记语言 38.XML是一种数据存储语言,XML标记用来描述文本的结构,而不是用于描述如何显示文本。 39.XML文件扩展名为”.xml” 40.XML文档主要由两部分组成:序言和文档元素,序言包括声明版本号、处理指令等。文档元素指出了文档 的逻辑结构,并且包含了文档的信息内容。一个典型的元素有起始标记、元素内容和结束标记。 41.CDATA节中的所有字符都会被当作元素中字符数据的常量部分,而不是XML标记。 42.将XML文档在浏览器中按特定的格式显示出来,需要css样式文件或者xsl样式文件告诉浏览器如何显示。 二、填空 1.body标记中Link属性定义未被访问过的链接颜色;alink属性定义链接激活状态的链接颜色;vlink属性定义 已被访问过链接的颜色 2.target属性用来定义链接打开窗口,当属性值为blank是定义链接在新窗口中打开。 3.<ol>定义有序列表,<ul>定义无序列表 4.定义表格的标记是<table>标记,<tr>定义行的开始,<td>定义行中的单元格 5.网页中设置滚动字幕的标记是<marquee>标记</p><h2>(完整版)初中音乐青春舞曲教案【三篇】</h2><p>初中音乐青春舞曲教案【三篇】 学唱歌曲《青春舞曲》,使学生能够把握歌曲的情绪、节奏,体会歌 曲的旋律特点。###小编整理了初中音乐青春舞曲教案【三篇】,希望 对你有协助! 青春舞曲教案一 一、教学理念: 根据新课程标准的指导思想,在音乐教学过程当中,把学生对音乐的 感受和参与放在重要的位置,充分利用现代化教学手段,提升课堂教 学效果,使学生在轻松愉快的学习气氛中体验美、感受美创造美,激 发学生的兴趣,提升学生的审美水平。在《青春舞曲》一课的教学中,主要是感受、体验新疆民歌的风格特点,让学生在学习过程中相互合作,充分发挥自主学习的水平、团结合作水平和创新水平。在表现歌 曲的多形式创作练习和参与音乐实践活动中,培养学生热爱民族音乐 的情感。 二、教学准备: 钢琴、CD碟片、小型打击乐器(手鼓、串铃等)、投影仪、音响设备等。 三、教学目标: 知识与技能:学会演唱歌曲,并能用活泼、有弹性的声音演唱《青春 舞曲》。准确把握歌曲的情绪,体会歌曲的旋律特点。 四、过程与方法: 1、尝试在聆听、模唱、讨论、创新中学习歌曲;通过音乐活动,调 动学生的积极参与,培养学生节奏感和创造力,训练协调性,加深对 歌曲风格的理解。</p><p>2、了解维吾尔族音乐特点,并可结合维吾尔族服装、乐器、舞蹈动作,体会音乐与舞蹈的结合。 五、情感态度与价值观: 通过学习维吾尔族歌曲《青春舞曲》及其相关知识,培养学生喜欢并 热爱我国的民族音乐,懂得青春易逝的道理,要珍惜大好时光,努力 学习。 六、教材分析: 这是一首G大调、4/4拍、单乐段的歌曲,短小精练,一气呵成,旋律活泼流畅,节奏具有鲜明的舞蹈性。感受体验维吾尔族民歌的风格特点, 七、教学重、难点: 1、重点:在听、唱、跳、等音乐活动中体验和表现歌曲的情绪。并 能用自然的声音准确地演唱《青春舞曲》。 2、难点:掌握维吾尔族民歌特点,能准确掌握歌曲节奏型,充分发 挥学生的创新水平及团结合作意识。并激发学生对“青春”的更深层 次的理解。 八、教学过程: (一)导入新课:1、以自己身上特有的民族特色来和学生实行讨论,抓住学生对少数民族的兴趣来导入新课。 (二)音画同步、提升兴趣 出示图片民族信仰,服饰,小吃,土特产,2、新疆的人们都能歌善舞,每逢喜庆、丰收时节,他们都用歌舞来表达自己的喜悦心情。另外新 疆这个民族有这独特的民族乐器(出示图片介绍新疆独特乐器)新疆 的音乐这么动听,新疆的舞蹈这么优美,让我们乘着去新疆的列车, 去学习一首新疆歌曲吧!</p><h2>监控系统安装流程(视频监控安装教程)</h2><p>监控安装指导与注意事项 A、线路安装与选材 1、电源线:要选“阻燃”电缆,皮结实,在省成本前提下,尽量用粗点的,以减少电源的衰减。 2、视频线:SYV75-3线传输在300米内,75-5线传输500米内,75-7的线可传输800米;超过500米距离,就要考虑采用“光缆”。另外,要注意“同轴电缆”的质量。 3、控制线:一般选用“带屏蔽”2*1.0的线缆,RVVP2*1.0。 4、穿线管:一般用“PVC管”即可,要“埋地、防爆”的工程,要选“镀锌”钢管。 B、控制设备安装 1、控制台与机柜:安装应平稳牢固,高度适当,便于操作维护。机柜架的背面、侧面,离墙距离,考虑到便于维修。 2、控制显示设备:安装应便于操作、牢靠,监视器应避免“外来光”直射,设备应有“通风散热”措施。 3、设置线槽线孔:机柜内所有线缆,依位置,设备电缆槽和进线孔,捆扎整齐、编号、标志。</p><p>4、设备散热通风:控制设备的工作环境,要在空调室内,并要清洁,设备间要留的空间,可加装风扇通风。 5、检测对地电压:监控室内,电源的火线、零线、地线,按照规范连接。检测量各设备“外壳”和“视频电缆”对地电压,电压越高,越易造成“摄像机”的损坏,避免“带电拔插”视频线。 C、摄像机的安装 1、监控安装高度:室内摄像机的安装高度以2.5~5米,为宜,室外以3.5~10米为宜;电梯内安装在其顶部。 2. 防雷绝缘:强电磁干扰下,摄像机安装,应与地绝缘;室外安装,要采取防雷措施。 3、选好BNC:BNC头非常关键,差的BNC头,会让你生不如死,一点都不夸张。 4、红外高度:红外线灯安装高度,不超过4米,上下俯角20度为佳,太高或太过,会使反射率低。 5、红外注意:红外灯避免直射光源、避免照射“全黑物、空旷处、水”等,容易吸收红外光,使红外效果大大减弱。 6、云台安装:要牢固,转动时无晃动,检查“云台的转动范围”,是否正常,解码器安装在云台附近。</p><h2>网页设计期末复习试题</h2><p>网页设计复习 选择题答案:ABDAC CABCB BACDC CBACA BBDAD CCBBC ACAAC BDDDA DCACB CACDB CACDB DCBAB 如果有同学发现答案有误请大家在群里指出一下 一. 单项选择题 1、HTML 指的是。 A.超文本标记语言(Hyper Text Markup Language) B.家庭工具标记语言(Home Tool Markup Language) C.超链接和文本标记语言(Hyperlinks and Text Markup Language) 2、Web 标准的制定者是万维网联盟(W3C)。 A. 微软(Microsoft) B.万维网联盟(W3C) C.网景公司(Netscape) 3、在下列的 HTML 中,哪个是最大的标题。 A. <h6> B. <head> C. <heading> D. <h1> 4、在下列的 HTML 中,哪个可以插入折行。 A.<br> B.<lb> C.<break> 5、在下列的 HTML 中,哪个可以添加背景颜色。 A.<body color="yellow"> B.<background>yellow</background> C.<body bgcolor="yellow"> 6、产生粗体字的 HTML 标签是。 A.<bold> B.<bb> C.<b> D.<bld> 7、产生斜体字的 HTML 标签是。 A.<i> B.<italics> C.<ii> 8、在下列的 HTML 中,可以产生超链接? A.<a url="https://www.wendangku.net/doc/109741804.html,">https://www.wendangku.net/doc/109741804.html,</a> B.<a href="https://www.wendangku.net/doc/109741804.html,">W3School</a> C.<a>https://www.wendangku.net/doc/109741804.html,</a> D.<a name="https://www.wendangku.net/doc/109741804.html,">https://www.wendangku.net/doc/109741804.html,</a> 9、能够制作电子邮件链接。 A.<a href="xxx@yyy"> B.<mail href="xxx@yyy"> C.<a href="mailto:xxx@yyy"> D.<mail>xxx@yyy</mail> 10、可以在新窗口打开链接。 A.<a href="url" new> B.<a href="url" target="_blank"> C.<a href="url" target="new"> 11、以下选项中,全部都是表格标签。 A.<table><head><tfoot> B.<table><tr><td> C.<table><tr><tt> D.<thead><body><tr> 12、可以使单元格中的内容进行左对齐的正确 HTML 标签是。 A.<td align="left"> B.<td valign="left"></p><h2>a标签target属性详解</h2><p>a标签target属性详解 HTML 标签的target 属性 HTML 标签 定义和用法 标签的target 属性规定在何处打开链接文档。 如果在一个标签内包含一个target 属性,浏览器将会载 入和显示用这个标签的href 属性命名的、名称与这个目标吻合的框架或者窗口中的文档。如果这个指定名称或id 的框架或者窗口不存在,浏览器将打开一个新的窗口,给这个窗口一个指定的标记,然后将新的文档载入那个窗口。从此以后,超链接文档就可以指向这个新的窗 口。 打开新窗口 被指向的超链接使得创建高效的浏览工具变得很容易。例如,一个简单的内容文档的列表,可以将文档重定向到一个单独的窗口: Table of Contents target="view_window">Preface</p><p>target="view_window">Chapter 1 target="view_window">Chapter 2 target="view_window">Chapter 3亲自试一试 当用户第一次选择内容列表中的某个链接时,浏览器将打开一个新的窗口,将它标记为 "view_window",然后在其中显示希望显示的文档内容。如果用户从这个内容列表中选择另一个链接,且这个 "view_window" 仍处于打开状态,浏览器就会再次将选定的文档载入那个窗口,取代刚才的那些文档。 在整个过程中,这个包含了内容列表的窗口是用户可以访问的。通过单击窗口中的一个连接,可使另一个窗口的内容发生变化。 在框架中打开窗口 不用打开一个完整的浏览器窗口,使用target 更通常的方法是在一个显示中将超链接内容定向到一个或者多个框 架中。可以将这个内容列表放入一个带有两个框架的文档的其中一个框架中,并用这个相邻的框架来显示选定的文档: name="view_frame"></p><h2>歌唱《青春舞曲》</h2><p>【课型】歌唱课型 【课题】《青春舞曲》 【教材】上海教育出版社六年级《音乐》教材第一学期第四单元“民族花苑” 【主要教学内容】 1、复习乐曲《马车夫之歌》 2、学唱歌曲《青春舞曲》 【教学任务分析】 1、教材简析 《青春舞曲》是王洛宾根据维吾尔族民歌创编的歌曲。这首歌的歌词用富于哲理的生活现实告诉年轻人:有些事物可以去而复返,有些事物却是一去不复返的。而人的青春正像那鸟儿一样,飞去后即不再回头。这首歌为4/4拍,结构为单乐段结构后缀补充段。歌曲旋律采用重复、变化重复及衍化动机的手法写成。整个歌曲给人以亲切、活泼、充满青春活力的感受。 2、学情分析 六年级的学生经过小学音乐的基础学习,已有了初步的审美能力、浅显音 乐知识与基本的技能,同时对周围事物有了一定的认识,对音乐作品也有了初步的感性认识。但重要的还是要培养他们对音乐的兴趣和热情,注重音乐课基本常规、欣赏音乐和演唱的习惯。同时,教学中应积极引领学生参加各项音乐实践活动,以提高学生的感知、表现、鉴赏、创造等审美能力。 【育人立意】 以人文为主线,以“音乐审美”为核心,以提高学生音乐实践能力为基点,以充分调动学生学习积极性为评价宗旨。中学的音乐教育是在学生已有的小学音乐学习的基础上进行的,中学则应加以巩固和提高,继续拓展学生的音乐视野,加强对生活的感受和理解能力。通过学生参与教学活动的愉悦学习,激发学生的主动探究意识,加深对音乐内涵的理解,更大地调动学生学习积极性和求知欲。 【教学目标】 1、学会用自然圆润的声音,轻松活泼的情绪演唱歌曲《青春舞曲》。正确把 握歌曲的音乐情绪和风格,体会歌曲的旋律特点。</p><p>2、尝试在聆听、模唱、律动中学习歌曲,体验歌曲的音乐情绪,加深对歌 曲 风格的理解。通过各种音乐活动,调动学生的积极参与,培养学生节奏感和创造力,训练协调性。 3、通过学习维吾尔族歌曲《青春舞曲》及其相关知识,培养学生喜欢并热 爱我国的民族音乐。懂得青春易逝的道理,启发学生珍惜光阴,努力学习。 【教学重难点】 教学重点:在听、唱、跳等音乐活动中体验和表现歌曲的情绪,并能用自然圆润的声音演唱歌曲。 教学难点:掌握维吾尔族民歌特点,能准确掌握歌曲节奏型。运用速度、力度的知识对歌曲进行处理,丰富歌曲的表现力。 【教学过程】 一、复习民歌《马车夫之歌》 1、复习民歌《马车夫之歌》。 2、复习巩固切分节奏型。 3、随着音乐节拍,用手鼓为乐曲伴奏,模唱乐曲旋律。 二、新授歌曲《青春舞曲》 (一)人文介绍,维吾尔族风情、文化艺术铺垫 1、维吾尔族简介 2、艺术文化介绍 (二)初听全曲,整体感受 1、教师设问:这首歌曲的音乐情绪是什么?节奏特点怎样? 2、教师设问:演唱形式是怎样的? 3、《青春舞曲》歌曲背景介绍。 (三)学唱歌曲,实践练习 1、学习歌曲中的节奏 1)教师讲授附点音符(十六分、八分)、后十六分音符的读法。 2)引导学生正确掌握附点十六分音符节奏型。 3)掌握全曲正确节奏型。 2、进一步熟悉旋律</p><h2>Dreamweaver里标签及属性详解</h2><p>《》 Dreamweaver里标签及属性的详细解释 Dreamweaver标签库可以帮助我们轻松的找到所需的标签,并根据列出的属性参数使用它,常用的HTML标签和属性解释, 请搜索"常用的HTML标签和属性". 基本结构标签: <HTML>,表示该文件为HTML文件 <HEAD>,包含文件的标题,使用的脚本,样式定义等 <TITLE>---,包含文件的标题,标题出现在浏览器标题栏中 ,的结束标志 ,放置浏览器中显示信息的所有标志和属性,其中内容在浏览器中显示. ,的结束标志 ,的结束标志 其它主要标签,以下所有标志用在中: ,链接标志,"…"为链接的文件地址 ,显示图片标志,"…"为图片的地址
        ,换行标志

        ,分段标志 ,采用黑体字 ,采用斜体字


        ,水平画线
        ,定义表格,HTML中重要的标志
        中 ,定义表格的单元格,用在中 ,字体样式标志 属性: 属性是用来修饰标志的,属性放在开始标志内. 例:属性bgcolor="BLACK"表示背景色为黑色. 引用属性的例子: 表示页面背景色为黑色; 表示表格背景色为黑色. 常用属性: 对齐属性,范围属性: ALIGN=LEFT,左对齐(缺省值),WIDTH=象素值或百分比,对象宽度. ALIGN=CENTER,居中,HEIGHT=象素值或百分比,对象高度. ALIGN=RIGHT,右对齐. 色彩属性:

        《青春舞曲》五年级

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