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Lung cancer is a multifactorial carcinoma with diverse heterogeneity. Genetic variations in drug-metabolizing enzymes may lead to defective detoxification and clearance of carcinogenic compounds. The high-order gene-gene interaction has been carried out between different genotypes of Phase II detoxification genes (NQO1, SULT1A1, NAT2, and EPHX1). Our results depict the genetic combination of SULT1A1 R213H with NAT2 × 5B L161L, SULT1A1 R213H with NAT2 × 5C K268R, EPHX1 H139R and NAT2 × 5B L161L exhibit a protective effect towards lung cancer risk. Further, the triple combinations of NQO1 P187S, EPHX1 Y113H, and EPHX1 H139R; NQO1 P187S, EPHX1 Y113H, and NAT2 × 6 R197Q; NQO1 P187S, EPHX1 Y113H, and NAT2 × 7 G286E; SULT1A1 R213H, EPHX1 H139R, and NAT2 × 7 G286E suggested a two-fold increased risk of lung cancer for subjects. Genetic polymorphisms of phase II detoxifying genes (NAT2, NQO1, EPHX1, SULT1A1) are prognostic markers for lung cancer. [ABSTRACT FROM AUTHOR]

Nuclear factor E2-related factor 2 (Nrf2) is fundamental to the maintenance of redox homeostasis within cells via the regulation of a series of phase II antioxidant enzymes. The unique olive-derived phenolic compound hydroxytyrosol (HT) is recognized as an Nrf2 activator, but knowledge of the HT derivative hydroxytyrosol acetate (HTac) on Nrf2 activation remains limited. In this study, we observed that an HT pretreatment could protect the cell viability, mitochondrial membrane potential, and redox homeostasis of ARPE-19 cells against a t-butyl hydroperoxide challenge at 50 μM. HTac exhibited similar benefits at 10 μM, indicating a more effective antioxidative capacity compared with HT. HTac consistently and more efficiently activated the expression of Nrf2-regulated phase II enzymes than HT. PI3K/Akt was the key pathway accounting for the beneficial effects of HTac in ARPE-19 cells. A further RNA-Seq analysis revealed that in addition to the consistent upregulation of phase II enzymes, the cells presented distinct expression profiles after HTac and HT treatments. This indicated that HTac could trigger a diverse cellular response despite its similar molecular structure to HT. The evidence in this study suggests that Nrf2 activation is the major cellular activity shared by HTac and HT, and HTac is more efficient at activating the Nrf2 system. This supports its potential future employment in various disease management strategies. [ABSTRACT FROM AUTHOR]

Objectives: Obesity is a complex multifactorial disease with recently increasing prevalence and incidence. Several studies have been conducted to explain the ethiology, pathophysiology, epidemiology, molecular and genetic mechanisms, and effective treatments of obesity. Glutathione S-transferase (GST) S1, GSTZ1, and GSTT1 are essential enzymes for oxidative stress and metabolism-related disorders. For this purpose, we aimed to reveal the role of GSTS1, GSTZ1, and GSTT1 in obesity. Methods: The gastric tissue samples were taken from the patients diagnosed with obesity who underwent bariatric surgery in Ankara Keçiören Training and Research Hospital General Surgery Clinic between 2017 and 2019. Immunostaining was performed on paraffin-embedded tissues to evaluate GSTS1, GSTZ1, and GSTT1 expressions. Laboratory data of the patients were recorded. All the results were analyzed statistically. Results: Weak GSTS1 expression was observed in 38.1% of tissues and moderate in 6.3%. 37.3% of the tissues presented weak GSTZ1 expression, and 11 (8.7%) displayed moderate. There were weak GSTT1 expressions in 7.1% of the tissues and moderate 0.8% of them. A positive and statistically significant correlation was observed between GSTS1 and GSTT1 expression levels ((r) = 0.028, p = 0.010; p < 0.05). There were no significant differences between expression levels and gender, age, comorbidities, and medication usage (p > 0.05). Conclusions: GSTs, in particular GSTS1, GSTT1, and GSTZ1, might contribute to molecular mechanisms and the progression of obesity. In our study, GSTS1, GSTT1, and GSTZ1 were found to be moderately expressed in gastric tissues taken from obese patients. However, new studies using more samples and advanced techniques are needed to elucidate the relationship. [ABSTRACT FROM AUTHOR]

Ezetimibe (EZE) is a selective cholesterol absorption inhibitor. Hepatic impairment significantly increases the systemic exposure of EZE and its main active phenolic glucuronide, EZE-Ph. Although changes in efflux transporter activity partly explain the changes in EZE-Ph pharmacokinetics, the causes of the changes to EZE and the effects of the administration route on EZE-Ph remain unclear. A carbon tetrachloride (CCl4)-induced hepatic failure rat model was combined with in vitro experiments to explore altered EZE and EZE-Ph disposition caused by hepatic impairment. The plasma exposure of EZE and EZE-Ph increased by 11.1- and 4.4-fold in CCl4-induced rats following an oral administration of 10 mg/kg EZE, and by 2.1- and 16.4-fold after an intravenous injection. The conversion of EZE to EZE-Ph decreased concentration-dependently in CCl4-induced rat liver S9 fractions, but no change was observed in the intestinal metabolism. EZE-Ph was a substrate for multiple efflux and uptake transporters, unlike EZE. In contrast to efflux transporters, no difference was seen in the hepatic uptake of EZE-Ph between control and CCl4-induced rats. However, bile acids that accumulated due to liver injury inhibited the uptake of EZE-Ph by organic anion transporting polypeptides (OATPs) (glycochenodeoxycholic acid and taurochenodeoxycholic acid had IC50 values of 15.1 and 7.94 μM in OATP1B3-overexpressed cells). In conclusion, the increased plasma exposure of the parent drug EZE during hepatic dysfunction was attributed to decreased hepatic glucuronide conjugation, whereas the increased exposure of the metabolite EZE-Ph was mainly related to transporter activity, particularly the inhibitory effects of bile acids on OATPs after oral administration. [ABSTRACT FROM AUTHOR]

Nuclear factor E2-related factor 2 (Nrf2) is fundamental to the maintenance of redox homeostasis within cells via the regulation of a series of phase II antioxidant enzymes. The unique olive-derived phenolic compound hydroxytyrosol (HT) is recognized as an Nrf2 activator, but knowledge of the HT derivative hydroxytyrosol acetate (HTac) on Nrf2 activation remains limited. In this study, we observed that an HT pretreatment could protect the cell viability, mitochondrial membrane potential, and redox homeostasis of ARPE-19 cells against a t-butyl hydroperoxide challenge at 50 μM. HTac exhibited similar benefits at 10 μM, indicating a more effective antioxidative capacity compared with HT. HTac consistently and more efficiently activated the expression of Nrf2-regulated phase II enzymes than HT. PI3K/Akt was the key pathway accounting for the beneficial effects of HTac in ARPE-19 cells. A further RNA-Seq analysis revealed that in addition to the consistent upregulation of phase II enzymes, the cells presented distinct expression profiles after HTac and HT treatments. This indicated that HTac could trigger a diverse cellular response despite its similar molecular structure to HT. The evidence in this study suggests that Nrf2 activation is the major cellular activity shared by HTac and HT, and HTac is more efficient at activating the Nrf2 system. This supports its potential future employment in various disease management strategies.

Genetic polymorphism of drug-metabolising enzymes such as NQO1, SULT1A1, EPHX1, and NAT2 alters its activity which hampers the detoxification and disposal of chemotherapeutic compounds. Thus, in the present study, we have comprehensively investigated the associations between SNPs of the Phase II detoxifying genes and its relationship towards platinum-induced toxicity of lung cancer patients. NQO1 (609 C > T), SULT1A1 (Arg213 His), EPHX1 (Tyr113His, His139Arg), and NAT2 (481 C > T, 803 A > G, 590 G > A, 857 G > A) were evaluated in our study for their associated adverse events caused due to the administration of platinum-based chemotherapy to the lung cancer patients. For NQO1 609 C > T polymorphism, the TT genotype showed reduced risk of constipation (OR = 0.10, p = 0.04) and anorexia (OR = 0.15, p = 0.03). For SULT1A1 Arg213His, heterozygous genotype (Arg/His) (AOR = 0.38, p = 0.006) and combined genotype (Arg/His + His/His) were not associated with increased risk of nephrotoxicity (AOR = 0.38, p = 0.004). For NAT2, heterozygous (NAT2*4/*6) and combined genotypes (NAT2*4/*4+*4/*6) for NAT2*6 polymorphism exhibit 2.4 folds (p = 0.005), and two-folds (p = 0.01) increased risk of hematological toxicity. The heterozygous (AOR = 0.45, p = 0.004) and variant genotype (AOR = 0.39, p = 0.02) for NAT2*5C had decreased risk for hematological toxicity. The heterozygous genotype for NAT2*7 polymorphism showed two-fold increased risk for developing thrombocytopenia. This study provides association of NAT2 polymorphic variants in predicting haematological toxicity. [ABSTRACT FROM AUTHOR]

Laith N AL-Eitan,1,2 Doaa M Rababa’h,1 Nancy M Hakooz,3 Mansour A Alghamdi,4,5 Rana B Dajani6– 8 1Department of Applied Biological Sciences, Jordan University of Science and Technology, Irbid, Jordan; 2Department of Biotechnology and Genetic Engineering, Jordan University of Science and Technology, Irbid, Jordan; 3Department of Biopharmaceutics and Clinical Pharmacy, School of Pharmacy, University of Jordan, Amman, Jordan; 4Department of Anatomy, College of Medicine, King Khalid University, Abha, Saudi Arabia; 5Genomics and Personalized Medicine Unit, College of Medicine, King Khalid University, Abha, Saudi Arabia; 6Department of Biology and Biotechnology, Hashemite University, Zarqa, Jordan; 7Radcliffe Institute for Advanced Studies, Harvard University, Cambridge, MA, USA; 8Jepson School of Leadership, Richmond University, Richmond, VA, USACorrespondence: Laith N AL-EitanDepartment of Applied Biological Sciences, Jordan University of Science and Technology, PO Box 3030, Irbid 22110, JordanTel +962 -2 -7201000Fax +962-2-7201071Email lneitan@just.edu.joBackground: Profiling rare variants in isolated populations can significantly clarify and understand the development of a clinically relevant process. Therefore, leading to a better identifying novel targeted treatment.Objective: This study aimed to determine the allele frequencies of 56 single nucleotide polymorphisms (SNPs) within several important pharmacogenes.Methods: This study consisted of 166 unrelated subjects from a genetically isolated group (Chechen) who were living in Jordan. In this study, the distribution of the variants among Chechen was compared to other ethnic groups available at two databases (Genome 1000 and (ExAC)). The frequency of genotypes and alleles was calculated and tested using the chi-square test and the Hardy–Weinberg equilibrium equation (HWE).Results: Our results revealed that the distribution of allele frequencies within different pharmacogenes among Chechen showed different similarities with other populations. The CEU and TSI showed the highest resemblance with the Chechen population (75% similarity), in contrast to LWK which had the lowest similarity (30%).Conclusion: This study sheds light on clinically relevant SNPs to enhance medical research and apply pharmacogenomics in clinical settings.Keywords: pharmacogenomics, VIP polymorphism, Phase I enzymes, Phase II enzymes, metabolizing

Ezetimibe (EZE) is a selective cholesterol absorption inhibitor. Hepatic impairment significantly increases the systemic exposure of EZE and its main active phenolic glucuronide, EZE-Ph. Although changes in efflux transporter activity partly explain the changes in EZE-Ph pharmacokinetics, the causes of the changes to EZE and the effects of the administration route on EZE-Ph remain unclear. A carbon tetrachloride (CCl4)-induced hepatic failure rat model was combined with in vitro experiments to explore altered EZE and EZE-Ph disposition caused by hepatic impairment. The plasma exposure of EZE and EZE-Ph increased by 11.1- and 4.4-fold in CCl4-induced rats following an oral administration of 10 mg/kg EZE, and by 2.1- and 16.4-fold after an intravenous injection. The conversion of EZE to EZE-Ph decreased concentration-dependently in CCl4-induced rat liver S9 fractions, but no change was observed in the intestinal metabolism. EZE-Ph was a substrate for multiple efflux and uptake transporters, unlike EZE. In contrast to efflux transporters, no difference was seen in the hepatic uptake of EZE-Ph between control and CCl4-induced rats. However, bile acids that accumulated due to liver injury inhibited the uptake of EZE-Ph by organic anion transporting polypeptides (OATPs) (glycochenodeoxycholic acid and taurochenodeoxycholic acid had IC50 values of 15.1 and 7.94 μM in OATP1B3-overexpressed cells). In conclusion, the increased plasma exposure of the parent drug EZE during hepatic dysfunction was attributed to decreased hepatic glucuronide conjugation, whereas the increased exposure of the metabolite EZE-Ph was mainly related to transporter activity, particularly the inhibitory effects of bile acids on OATPs after oral administration.

Copyright of Journal of Agro-Environment Science is the property of Journal of Agro-Environment Science Editorial Board and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

The European honey bee, Apis mellifera , serves as the principle managed pollinator species globally. In recent decades, honey bee populations have been facing serious health threats from combined biotic and abiotic stressors, including diseases, limited nutrition, and agrochemical exposure. Understanding the molecular mechanisms underlying xenobiotic adaptation of A. mellifera is critical, considering its extensive exposure to phytochemicals and agrochemicals present in the environment. In this study, we conducted a comprehensive structural and functional characterization of AmGSTD1, a delta class glutathione S-transferase (GST), to unravel its roles in agrochemical detoxification and antioxidative stress responses. We determined the 3-dimensional (3D) structure of a honey bee GST using protein crystallography for the first time, providing new insights into its molecular structure. Our investigations revealed that AmGSTD1 metabolizes model substrates, including 1-chloro-2,4-dinitrobenzene (CDNB), p -nitrophenyl acetate (PNA), phenylethyl isothiocyanate (PEITC), propyl isothiocyanate (PITC), and the oxidation byproduct 4-hydroxynonenal (HNE). Moreover, we discovered that AmGSTD1 exhibits binding affinity with the fluorophore 8-Anilinonaphthalene-1-sulfonic acid (ANS), which can be inhibited with various herbicides, fungicides, insecticides, and their metabolites. These findings highlight the potential contribution of AmGSTD1 in safeguarding honey bee health against various agrochemicals, while also mitigating oxidative stress resulting from exposure to these substances. [Display omitted] • The three-dimensional structure of AmGSTD1 was solved by X-ray crystallography. • G-site S34A and H-site F142A mutants exhibited the largest changes in kinetics. • Herbicides, fungicides, insecticides, and metabolites hindered AmGSTD1-ANS binding. • AmGSTD1 was highly expressed in the Malpighian tubules of both nurse and forager bees. [ABSTRACT FROM AUTHOR]

NF-E2-related factor 2 (Nrf2), the key transcription regulator of phase II enzymes, has been considered beneficial for neuronal protection. We previously designed a novel chalcone analog, 1-(2,3,4-trimethoxyphenyl)-2-(3,4,5-trimethoxyphenyl)-acrylketone (Tak), that could specifically activate Nrf2 in vitro. Here, we report that Tak confers significant hippocampal neuronal protection both in vitro and in vivo. Treatment with Tak has no significant toxicity on cultured neuronal cells. Instead, Tak increases cellular ATP production by increasing mitochondrial function and decreases the levels of reactive oxygen species by activating Nrf2-mediated phase II enzyme expression. Tak pretreatment prevents glutamate-induced excitotoxic neuronal death accompanied by suppressed mitochondrial respiration, increased superoxide production, and activation of apoptosis. Further investigation indicates that the protective effect of Tak is mediated by the Akt signaling pathway. Meanwhile, Tak administration in mice can sufficiently abrogate scopolamine-induced cognitive impairment via decreasing hippocampal oxidative stress. In addition, consistent benefits are also observed in an energy stress mouse model under a high-fat diet, as the administration of Tak remarkably increases Akt signaling-mediated antioxidative enzyme expression and prevents hippocampal neuronal apoptosis without significant effect on the mouse metabolic status. Overall, our study demonstrates that Tak protects cognitive function by Akt-mediated Nrf2 activation to maintain redox status both vivo and in vitro, suggesting that Tak is a promising pharmacological candidate for the treatment of oxidative neuronal diseases.

In this work an HPLC/hydrophilic interaction liquid chromatography (HILIC) system for intact glucosinolates was optimized using a weak anion exchange resin to remove carboxylic phenolics that absorbed at the same wavelength (229 nm) as glucosinolates, by selectively protonating contaminating phenolics with pKas from 2.98 to 4 while leaving the second OH of the sulfate of the thioglycosidic linkage (pKa = 1.92) ionized. Glucosinolates bound to the anion exchange resin, while the contaminating phenolics washed through. The extraction was performed in 2-ml snap top centrifuge tubes with 50 to 80 mg of fresh tissue in 0.3 ml of extractant. The corresponding spin tubes contained 20–22 mg of anion exchange resin and were loaded with 100 μl of extractant. A 48-well pressure plate was used to load, wash, and finally elute the glucosinolates without a centrifuge into autosampler vials. Seventeen glucosinolates found in common vegetables were separated in a 16-min isocratic run vs 50 min for the C18 gradient used in the desulfoglucosinolate method. The recovery of a spiked sample of phenethyl glucosinolate was greater than 90%, and the limit of detection (LOD) and limit of quantitation (LOQ) were 6.85 and 20.78 nmol respectively. The time from sample weighing to the end of the first chromatographic run was approximately 2 h. [ABSTRACT FROM AUTHOR]

Expression of a drug and xenobiotic metabolizing enzymes, cytochrome P450s (CYPs), and antioxidant enzymes can be modulated by various factors. The flavonoid rutin was investigated for its anti-carcinogen and protective effects as well as modulatory action on CYPs and phase II enzymes in human hepatocellular carcinoma cells. Rutin inhibited proliferation of HEPG2 cells in a dose-dependent manner with the IC50 value of 52.7 μmol L-1 and invasion of HEPG2 cells (21.6 %, p = 0.0018) and colony formation of those invaded cells (57.4 %, p < 0.0001). Rutin treatment also significantly increased early/late-stage apoptosis in HEPG2 cells (28.9 %, p < 0.001). Treatment by rutin significantly inhibited protein expressions of cytochrome P450-dependent CYP3A4 (75.3 %, p < 0.0001), elevated CYP1A1 enzymes (1.7-fold, p = 0.0084) and increased protein expressions of antioxidant and phase II reaction catalyzing enzymes, NQO1 (2.42-fold, p < 0.0001) and GSTP1 (2.03-fold, p < 0.0001). Besides, rutin treatment significantly inhibited mRNA expression of CYP3A4 (73.2 %, p=0.0014). Also, CYP1A1, NQO1 and GSTP1 mRNA expressions were significantly increased 2.77-fold (p = 0.029), 4.85- fold (p = 0.0051) and 9.84-fold (p < 0.0001), respectively.

The primary aim of this review is to summarize the current literature on the effects of acute exercise and regular exercise on nuclear factor erythroid 2-related factor 2 (Nrf2) activity and downstream targets of Nrf2 signaling. Nrf2 (encoded in humans by the NFE2L2 gene) is the master regulator of antioxidant defenses, a transcription factor that regulates expression of more than 200 cytoprotective genes. Increasing evidence indicates that Nrf2 signaling plays a key role in how oxidative stress mediates the beneficial effects of exercise. Episodic increases in oxidative stress induced through bouts of acute exercise stimulate Nrf2 activation and when applied repeatedly, as with regular exercise, leads to upregulation of endogenous antioxidant defenses and overall greater ability to counteract the damaging effects of oxidative stress. The evidence of Nrf2 activation in response to exercise across variety of tissues may be an important mechanism of how exercise exerts its well-known systemic effects that are not limited to skeletal muscle and myocardium. Additionally there are emerging data that results from animal studies translate to humans.

Abstract Mechanisms responsible for diesel exhaust particle (DEP)-induced toxicity in respiratory disorders are poorly understood, recent experimental and controlled exposure studies suggested that oxidative stress might be involved. To investigate the time-course effects DEP on nuclear factor erythroid 2-related factor 2 (Nrf2), a key regulator in cellular adaptive antioxidant response, mice were intratracheal instilled with 100 μg DEP/mouse and sacrificed after 30 min, 6 h, 12 h, 24 h, 48 h, and 72 h. We measured reactive oxygen species (ROS) as well as Nrf2 and antioxidant enzymes such as superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GSH-Px) and phase II enzymes including heme oxygenase-1 (HO-1), NAD(P)H:quinone oxidoreductase-1 (NQO1), glutamate–cysteine ligase catalytic subunit (GCLC), glutamate–cysteine ligase modifier subunit (GCLM) in the lungs. Additionally, histopathological changes were examined. At 6 h, ROS peaked, most of the enzymes were activated, and the histology showed the lungs were damaged. At 12 h, ROS returned to normal level and CAT activity decreased, while protein expression of Nrf2, HO-1, NQO1, GCLC, and GCLM increased, and the lungs were recovering from damage. After 24 h, ROS started to decrease and Nrf2 showed a decreasing trend at both gene and protein levels, while the lung damage had been entirely restored. These results suggested that a single exposure to DEP induce transient oxidative stress in the lungs, with time-dependent effects on Nrf2 and antioxidant enzymes and phase II enzymes. Graphical abstract Unlabelled Image Highlights • Single exposure to DEP induced a transient oxidative stress in lung. • Nrf2 were activated in response of oxidative stress caused by DEP. • Antioxidant enzymes and phase II enzymes revealed time course effects after DEP exposure. [ABSTRACT FROM AUTHOR]

Impairment of retinal pigment epithelial (RPE) cells is considered a key contributor to the development of age-related macular degeneration. Apoptosis-related protein 3 (APR3) was recently discovered after treatment with all-trans retinoic acid, a pivotal molecule in RPE cells. However, the function of APR3 remains poorly understood. In the present study, we found that APR3 could interact with nuclear factor (erythroid-derived 2)-like 2, which is a regulator of phase II enzymes, and that knockdown of APR3 promoted nuclear factor (erythroid-derived 2)-like 2 nuclear translocation and activated expression of phase II enzymes, which was accompanied by improved redox status and mitochondrial activity. Overexpression of APR3 revealed its mitochondrial localization and induced a robust production of reactive oxygen species that was accompanied by impaired mitochondrial oxygen consumption, complex activity, and lower ATP content, resulting in significant changes in mitochondrial structure, which may contribute to cell apoptosis. High doses of all-trans retinoic acid treatment were found to significantly induce APR3 expression, increase reactive oxygen species levels, and decrease ATP content, which were abolished by knockdown of APR3. These results indicate that APR3 plays a vital role in regulating redox status and mitochondrial activity and thus suggest APR3 might be a potential novel target for study of treatment of age-related macular degeneration. [ABSTRACT FROM AUTHOR]

Health benefits associated with consumption of cruciferous vegetables have received considerable attention with a hitherto focus on the role and bioactivity of glucosinolate degradation products. We investigated the in vivo metabolism of intact glucosinolates by following their fate in digesta and in the endogenous metabolism in pigs. This is the first study to show an intact glucosinolate, sinalbin, being absorbed and transformed to a sinalbin metabolite in the liver by glucuronidation expectedly performed by liver phase II enzymes with subsequent excretion to the urine. From LC–MS/MS data we propose a structure of the sinalbin metabolite as containing two 4-oxybenzyl groups. Sinalbin and the metabolite were detected in plasma from the hepatic vein with a ratio of metabolite to sinalbin of approximately 12:1 after 2–4 hours. Induction of liver phase II enzymes by intact glucosinolates indicates that these also themselves are bioactive compounds with potential health risks or beneficial effects.

Olive oil, the primary source of dietary fat in the Mediterranean diet, is reported to have benefits on bone health, mechanisms of which remain obscure. Here we investigated the protective effects of hydroxytyrosol (HT), a major polyphenol in olive on preosteoblast toxicity induced by acrolein, the major component of cigarette smoke. Acrolein at 75 µM, induced significant oxidative stress which was attributed to the inhibition of Nrf2 nuclear translocation and suppression of phase II enzymes. And HT could efficiently promote Phase II enzymes activation and prevent the decrease of antioxidative enzymes, protect the autophagy pathway and maintain the normal level of mitochondrial complexes. These results indicated that cigarettes smoking could damage preosteoblast cells by inducing oxidative stress and mitochondrial dysfunction. While through activation of Keap1/Nrf2 pathway, olive component HT could contribute to cellular protection and potential bone health.

Several genetic variants have been identified that cause variation among different populations and even within individuals of a similar descent. This leads to interindividual variations in the optimal dose of the drug that is required to sustain the treatment efficiency. In this study, 56 single nucleotide polymorphisms (SNPs) within several pharmacogenes were analyzed in 128 unrelated subjects from a genetically isolated group of Circassian people living in Jordan. We also compared these variant distributions to other ethnic groups that are available at two databases (Genome 1000 and eXAC). Our results revealed that the distribution of allele frequencies within genes among Circassians in Jordan showed similarities and disparities when compared to other populations. This study provides a powerful base for clinically relevant SNPs to enhance medical research and future pharmacogenomic studies. Rare variants detected in isolated populations can significantly guide to novel loci involved in the development of clinically relevant traits.

Copyright of Shipin Kexue/ Food Science is the property of Food Science Editorial Department and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Asbestos exposure triggers inflammatory processes associated with oxidative stress and tissue damage linked to malignancy. LGM2605 is the synthetic lignan secoisolariciresinol diglucoside (SDG) with free radical scavenging, antioxidant, and anti-inflammatory properties in diverse inflammatory cell and mouse models, including exposure to asbestos fibers. Nuclear factor-E2 related factor 2 (Nrf2) activation and boosting of endogenous tissue defenses were associated with the protective action of LGM2605 from asbestos-induced cellular damage. To elucidate the role of Nrf2 induction by LGM2605 in protection from asbestos-induced cellular damage, we evaluated LGM2605 in asbestos-exposed macrophages from wild-type (WT) and Nrf2 disrupted (Nrf2-/-) mice. Cells were pretreated with LGM2605 (50 μM and 100 μM) and exposed to asbestos fibers (20 μg/cm²) and evaluated 8 h and 24 h later for inflammasome activation, secreted cytokine levels (interleukin-1β (IL-1β), interleukin-18 (IL-18), interleukin-6 (IL-6), and tumor necrosis factor alpha (TNFα)), cytotoxicity and cell death, nitrosative stress, and Nrf2-regulated enzyme levels. Asbestos exposure induced robust oxidative and nitrosative stress, cell death and cytotoxicity, which were equally mitigated by LGM2605. Inflammasome activation was significantly attenuated in Nrf2-/- macrophages compared to WT, and the protective action of LGM2605 was seen only in WT cells. In conclusion, in a cell model of asbestos-induced toxicity, LGM2605 acts via protective mechanisms that may not involve Nrf2 activation. [ABSTRACT FROM AUTHOR]

Radiation therapy for the treatment of thoracic malignancies has improved significantly by directing of the proton beam in higher doses on the targeted tumor while normal tissues around the tumor receive much lower doses. Nevertheless, exposure of normal tissues to protons is known to pose a substantial risk in long-term survivors, as confirmed by our work in space-relevant exposures of murine lungs to proton radiation. Thus, radioprotective strategies are being sought. We established that LGM2605 is a potent protector from radiation-induced lung toxicity and aimed in the current study to extend the initial findings of space-relevant, proton radiation-associated late lung damage in mice by looking at acute changes in human lung. We used an ex vivo model of organ culture where tissue slices of donor living human lung were kept in culture and exposed to proton radiation. We exposed donor human lung precision-cut lung sections (huPCLS), pretreated with LGM2605, to 4 Gy proton radiation and evaluated them 30 min and 24 h later for gene expression changes relevant to inflammation, oxidative stress, and cell cycle arrest, and determined radiation-induced senescence, inflammation, and oxidative tissue damage. We identified an LGM2605-mediated reduction of proton radiation-induced cellular senescence and associated cell cycle changes, an associated proinflammatory phenotype, and associated oxidative tissue damage. This is a first report on the effects of proton radiation and of the radioprotective properties of LGM2605 on human lung. [ABSTRACT FROM AUTHOR]

Updated measurements of charged particle fluxes during the transit from Earth to Mars as well as on site measurements by Curiosity of Martian surface radiation fluxes identified potential health hazards associated with radiation exposure for human space missions. Designing mitigation strategies of radiation risks to astronauts is critical. We investigated radiation-induced endothelial cell damage and its mitigation by LGM2605, a radioprotector with antioxidant and free radical scavenging properties. We used an in vitro model of lung vascular networks (flow-adapted endothelial cells; FAECs), exposed to gamma rays, low/higher linear energy transfer (LET) protons (3–4 or 8–10 keV/µm, respectively), and mixed field radiation sources (gamma and protons), given at mission-relevant doses (0.25 gray (Gy)–1 Gy). We evaluated endothelial inflammatory phenotype, NLRP3 inflammasome activation, and oxidative cell injury. LGM2605 (100 µM) was added 30 min post radiation exposure and gene expression changes evaluated 24 h later. Radiation induced a robust increase in mRNA levels of antioxidant enzymes post 0.25 Gy and 0.5 Gy gamma radiation, which was significantly decreased by LGM2605. Intercellular cell adhesion molecule-1 (ICAM-1) and NOD-like receptor protein 3 (NLRP3) induction by individual or mixed-field exposures were also significantly blunted by LGM2605. We conclude that LGM2605 is a likely candidate to reduce tissue damage from space-relevant radiation exposure.

Background. The first line anti-tubercular (anti-TB) treatment normally involves isoniazid, rifampicin, pyrazinamide, and ethambutol. Clearance of these drugs depends on the activity of several enzymes such as N-acetyl transferase 2, cytochrome P450 oxidase and glutathione S-transferase (GST). Some of these enzymes are highly polymorphic leading to significant inter-individual variation in their activity thereby increasing the risk of drug induced hepatotoxicity (DIH).Aim. To investigate the possible association of anti-TB DIH with genetic polymorphism of GST genes in Western Indian population.Material and methods. A prospective case-control study was undertaken on patients who received anti-TB treatment. Cases (n = 50) were distinguished from controls (n = 246) based on occurrence of DIH during anti-tubercular treatment. A multiplex polymerase chain reaction was employed to identify homozygous null mutation at GSTM1 and GSTT1 loci.Results. Homozygous null mutation in GSTM1 gene alone or in both GSTM1 and T1 genes was found to be significantly associated with anti-TB DIH at p < 0.02 and p < 0.007, respectively, in our study population.Conclusions. This is the first study to report GSTM1 null and combined GSTM1 and T1 null genotypes to be risk factors of anti-TB DIH in Western Indian population. Screening of patients for these genotypes prior to anti-TB regimen would provide better control of hepatotoxicity.

Cruciferous and apiaceous vegetables may be chemopreventive due to their ability to modulate carcinogen-metabolizing enzymes but whether the effects on such enzymes are sustained over time is unknown. To examine the short- and long-term effects of the vegetables, rats were fed one of four diets for 7, 30, or 60 d: AIN-93G, CRU (21% cruciferous vegetables-fresh broccoli, green cabbage, watercress), API (9% apiaceous vegetables - fresh parsnips, celery), or API + CRU (10.5% CRU + 4.5% API). Although CRU increased activity and protein expression of cytochrome P450 (CYP) 1A1 and CYP1A2 after 7 d, only activity was sustained after 30 and 60 d. There was a trend towards an interaction between the length of feeding period and CRU for CYP1A1 activity; activity increased with greater time of feeding. API increased CYP1A2 activity but decreased sulfotransferase 1A1 activity after 7 d, although not at later times. Altogether, increased CYP1A activity by CRU was maintained with long term feeding while protein amount decreased, suggesting influence by mechanisms other than, or in addition to, transcriptional regulation. Thus, response patterns and interactions with length of feeding may differ, depending upon the types of vegetables and enzymes, requiring caution when interpreting the results of short-term feeding studies. [ABSTRACT FROM AUTHOR]

Rationale Chlorine gas (Cl 2 ) is a potent oxidant and trigger of irritant induced asthma. We explored NF-E2–related factor 2 (Nrf2)-dependent mechanisms in the asthmatic response to Cl 2 , using Nrf2 -deficient mice, buthionine sulfoximine (BSO), an inhibitor of glutathione (GSH) synthesis and sulforaphane (SFN), a phytochemical regulator of Nrf2. Methods Airway inflammation and airway hyperresponsiveness (AHR) were assessed 24 and 48 h after a 5-min nose-only exposure to 100 ppm Cl 2 of Nrf2 -deficient and wild type Balb/C mice treated with BSO or SFN. Animals were anesthetized, paralyzed and mechanically ventilated (FlexiVent™) and challenged with aerosolized methacholine. Bronchoalveolar lavage (BAL) was performed and lung tissues were harvested for assessment of gene expression. Results Cl 2 exposure induced a robust AHR and an intense neutrophilic inflammation that, although similar in Nrf2 -deficient mice and wild-type mice at 24 h after Cl 2 exposure, were significantly greater at 48 h post exposure in Nrf2 -deficient mice. Lung GSH and mRNA for Nrf2 -dependent phase II enzymes (NQO-1 and GPX2) were significantly lower in Nrf2 -deficient than wild-type mice after Cl 2 exposure. BSO reduced GSH levels and promoted Cl 2 -induced airway inflammation in wild-type mice, but not in Nrf2 -deficient mice, whereas SFN suppressed Cl 2 -induced airway inflammation in wild-type but not in Nrf2- deficient mice. AHR was not affected by either BSO or SFN at 48 h post Cl 2 exposure. Conclusions Nrf2-dependent phase II enzymes play a role in the resolution of airway inflammation and AHR after Cl 2 exposure. Moderate deficiency of GSH affects the magnitude of acute inflammation but not AHR. [ABSTRACT FROM AUTHOR]

Over the past years, there has been a growing interest in the natural constituents of foods as a potential means of cancer control. To date, epidemiology studies seem to indicate an inverse association between regular consumption of fruit and vegetables and cancer risk. Here, the potential chemopreventive activity of the polyphenolic extract (PPE) of peach ( Prunus persica L. Batsch) and of the freeze-dried fruit in toto (LFT), focusing on the modulation of xenobiotic metabolizing enzymes (XMEs) in vivo , was investigated. Rats were daily supplemented with LFT at 250 and 500 mg/kg b.w. or with the corresponding amount of PPE (2.5 and 5 mL/kg b.w., respectively) for either 7 or 14 days. While PPE treatment resulted in a widespread phase-I inactivation, a complex modulation pattern with drastic decreases (7α-testosterone hydroxylase, pentoxyresorufin O -dealkylase (PROD)), coupled with marked up-regulations of ethoxyresorufin O -deethylase (EROD) and methoxyresorufin O -demethylase (MROD) after LFT administration, was seen. A notable down-regulation (over 50%) following LFT or PPE treatment for the phase-II enzymes was also recorded. The observed remarkable changes in XMEs, if reproduced in humans, might have public health implications. These data suggest caution in promoting peach fruit (mono-diet) consumption or its polyphenolic extract in the field of chemoprevention. [ABSTRACT FROM AUTHOR]

Asbestos exposure triggers inflammatory processes associated with oxidative stress and tissue damage linked to malignancy. LGM2605 is the synthetic lignan secoisolariciresinol diglucoside (SDG) with free radical scavenging, antioxidant, and anti-inflammatory properties in diverse inflammatory cell and mouse models, including exposure to asbestos fibers. Nuclear factor-E2 related factor 2 (Nrf2) activation and boosting of endogenous tissue defenses were associated with the protective action of LGM2605 from asbestos-induced cellular damage. To elucidate the role of Nrf2 induction by LGM2605 in protection from asbestos-induced cellular damage, we evaluated LGM2605 in asbestos-exposed macrophages from wild-type (WT) and Nrf2 disrupted (Nrf2−/−) mice. Cells were pretreated with LGM2605 (50 µM and 100 µM) and exposed to asbestos fibers (20 µg/cm2) and evaluated 8 h and 24 h later for inflammasome activation, secreted cytokine levels (interleukin-1β (IL-1β), interleukin-18 (IL-18), interleukin-6 (IL-6), and tumor necrosis factor alpha (TNFα)), cytotoxicity and cell death, nitrosative stress, and Nrf2-regulated enzyme levels. Asbestos exposure induced robust oxidative and nitrosative stress, cell death and cytotoxicity, which were equally mitigated by LGM2605. Inflammasome activation was significantly attenuated in Nrf2−/− macrophages compared to WT, and the protective action of LGM2605 was seen only in WT cells. In conclusion, in a cell model of asbestos-induced toxicity, LGM2605 acts via protective mechanisms that may not involve Nrf2 activation.

The objective of this study was to investigate the tissue-specific mRNA expression of different cytochrome P450 (CYP) isoforms, UDP glucuronsyl transferase 1A1 (UGT1A1) and glutathione-S-transferase (GSTA1) in the different tissues (liver, mammary gland, lungs, spleen, kidney cortex, heart, masseter muscle and tongue) of cattle, using quantitative real-time polymerase chain reaction (qPCR). CYP1A1-like mRNA was expressed in all of the tissues examined, including the liver, with the highest expression level in the kidney. CYP1A2-, 2E1- and 3A4-like mRNAs were only expressed hepatically. Interestingly, significant expression of CYP2B6-like mRNA was recorded in the lung tissue, while CYP2C9-like mRNA was expressed in the liver and kidney tissues of the cattle examined. UGT1A1- and GSTA1-like mRNAs were expressed in all of the examined tissues, except the mammary glands, and the highest expression levels were recorded in the kidney. The high expression of UGT1A1 in the lung tissue and GSTA1 in the liver tissue was unique to cattle; this has not been reported for rats or mice. The findings of this study strongly suggest that the liver, kidneys and lungs of cattle are the major organs contributing to xenobiotics metabolism.

Radiation therapy for the treatment of thoracic malignancies has improved significantly by directing of the proton beam in higher doses on the targeted tumor while normal tissues around the tumor receive much lower doses. Nevertheless, exposure of normal tissues to protons is known to pose a substantial risk in long-term survivors, as confirmed by our work in space-relevant exposures of murine lungs to proton radiation. Thus, radioprotective strategies are being sought. We established that LGM2605 is a potent protector from radiation-induced lung toxicity and aimed in the current study to extend the initial findings of space-relevant, proton radiation-associated late lung damage in mice by looking at acute changes in human lung. We used an ex vivo model of organ culture where tissue slices of donor living human lung were kept in culture and exposed to proton radiation. We exposed donor human lung precision-cut lung sections (huPCLS), pretreated with LGM2605, to 4 Gy proton radiation and evaluated them 30 min and 24 h later for gene expression changes relevant to inflammation, oxidative stress, and cell cycle arrest, and determined radiation-induced senescence, inflammation, and oxidative tissue damage. We identified an LGM2605-mediated reduction of proton radiation-induced cellular senescence and associated cell cycle changes, an associated proinflammatory phenotype, and associated oxidative tissue damage. This is a first report on the effects of proton radiation and of the radioprotective properties of LGM2605 on human lung.

MicroRNAs (miRNAs) are a class of short noncoding RNAs that modulate gene expression at both transcriptional and post-transcriptional levels. Many studies have extensively revealed the significance of miRNAs in mediating liver development and diseases. However, their role in hepatic detoxification processes has been explored only recently. In this review, we summarized the up-to-date knowledge about miRNA dependent regulation of enzymes involved in all three phases of the drugs and xenobiotics detoxification process. We also discussed the role of miRNA in regulating some upstream nuclear receptors involving gene expression of enzymes for detoxification process in liver. The toxicological significance of miRNAs in liver diseases and future research perspectives are finally presented. [ABSTRACT FROM AUTHOR]

Health benefits associated with consumption of cruciferous vegetables have received considerable attention with a hitherto focus on the role and bioactivity of glucosinolate degradation products. We investigated the in vivo metabolism of intact glucosinolates by following their fate in digesta and in the endogenous metabolism in pigs. This is the first study to show an intact glucosinolate, sinalbin, being absorbed and transformed to a sinalbin metabolite in the liver by glucuronidation expectedly performed by liver phase II enzymes with subsequent excretion to the urine. From LC–MS/MS data we propose a structure of the sinalbin metabolite as containing two 4-oxybenzyl groups. Sinalbin and the metabolite were detected in plasma from the hepatic vein with a ratio of metabolite to sinalbin of approximately 12:1 after 2–4 hours. Induction of liver phase II enzymes by intact glucosinolates indicates that these also themselves are bioactive compounds with potential health risks or beneficial effects. [ABSTRACT FROM AUTHOR]

Cancer chemoprevention involves prevention/delay/reverse of the carcinogenic process through administration of cancer chemopreventive agents (CCA). Compounds which are able to induce detoxification-enzymes, especially monofunctional phase II enzymes, have become in excellent approaches for new CCA. Herein, we report the synthesis of new furoxanyl chalcone-like hybrid compounds as CCA. In vitro studies showed that phenylfuroxanyl derivatives 6 and 9 displayed the best activities being 9 the greatest monofunctional-inducer. Additionally, compounds were non-mutagenic against TA98 Salmonella typhimurium strain (Ames test) and could be used in the prevention of the progression of pre-malignant lesions for their cytotoxic activity against tumoral cells. In vivo proof of concept showed increment on phase II-enzymes activities in liver, colon and mammary gland having derivative 9 the best induction profiles. We probed Nrf2 nuclear translocation is operative for both compounds allowing to exert protective effects via expression of downstream phase-II enzymes. [ABSTRACT FROM AUTHOR]

Brassica vegetables are common components of the diet and have beneficial as well as potentially adverse health effects. Following enzymatic breakdown, some glucosinolates in brassica vegetables produce sulforaphane, phenethyl, and indolylic isothiocyanates that possess anticarcinogenic activity. In contrast, progoitrin and indolylic glucosinolates degrade to goitrin and thiocyanate, respectively, and may decrease thyroid hormone production. Radioiodine uptake to the thyroid is inhibited by 194 µmol of goitrin, but not by 77 µmol of goitrin. Collards, Brussels sprouts, and some Russian kale (Brassica napus) contain sufficient goitrin to potentially decrease iodine uptake by the thyroid. However, turnip tops, commercial broccoli, broccoli rabe, and kale belonging to Brassica oleracae contain less than 10 lmol of goitrin per 100-g serving and can be considered of minimal risk. Using sulforaphane plasma levels following glucoraphanin ingestion as a surrogate for thiocyanate plasma concentrations after indole glucosinolate ingestion, the maximum thiocyanate contribution from indole glucosinolate degradation is estimated to be 10 µM, which is significantly lower than background plasma thiocyanate concentrations (40-69 µM). Thiocyanate generated from consumption of indole glucosinolate can be assumed to have minimal adverse risks for thyroid health. [ABSTRACT FROM AUTHOR]

The interaction of asbestos fibers with macrophages generates harmful reactive oxygen species (ROS) and subsequent oxidative cell damage that are key processes linked to malignancy. Secoisolariciresinol diglucoside (SDG) is a non-toxic, flaxseed-derived pluripotent compound that has antioxidant properties and may thus function as a chemopreventive agent for asbestos-induced mesothelioma. We thus evaluated synthetic SDG (LGM2605) in asbestos-exposed, elicited murine peritoneal macrophages as an in vitro model of tissue phagocytic response to the presence of asbestos in the pleural space. Murine peritoneal macrophages (MFs) were exposed to crocidolite asbestos fibers (20 µg/cm²) and evaluated at various times post exposure for cytotoxicity, ROS generation, malondialdehyde (MDA), and levels of 8-iso Prostaglandin F2α (8-isoP). We then evaluated the ability of LGM2605 to mitigate asbestos-induced oxidative stress by administering LGM2605 (50 ^M) 4-h prior to asbestos exposure. We observed a significant (p < 0.0001), time-dependent increase in asbestos-induced cytotoxicity, ROS generation, and the release of MDA and 8-iso Prostaglandin F2α, markers of lipid peroxidation, which increased linearly over time. LGM2605 treatment significantly (p < 0.0001) reduced asbestos-induced cytotoxicity and ROS generation, while decreasing levels of MDA and 8-isoP by 71%-88% and 41%-73%, respectively. Importantly, exposure to asbestos fibers induced cell protective defenses, such as cellular Nrf2 activation and the expression of phase II antioxidant enzymes, HO-1 and Nqo1 that were further enhanced by LGM2605 treatment. LGM2605 boosted antioxidant defenses, as well as reduced asbestos-induced ROS generation and markers of oxidative stress in murine peritoneal macrophages, supporting its possible use as a chemoprevention agent in the development of asbestos-induced malignant mesothelioma. [ABSTRACT FROM AUTHOR]

Pulmonary fibrosis (PF) is characterized by excessive accumulation of extracellular matrix components in the alveolar region which distorts the normal lung architecture and impairs the respiratory function. The aim of this study is to evaluate the anti-fibrotic effect of celastrol, a quinine-methide tri-terpenoid mainly found in Thunder God Vine root extracts against bleomycin (BLM)-induced PF through the enhancement of antioxidant defense system. A single intratracheal instillation of BLM (3 U/kg.bw) was administered in rats to induce PF. Celastrol (5 mg/kg) was given intraperitoneally, twice a week for a period of 28 days. BLM-induced rats exhibits declined activities of enzymatic and non-enzymatic antioxidants which were restored upon treatment with celastrol. BLM-induced rats show increased total and differential cell counts as compared to control and celastrol treated rats. Histopathological analysis shows increased inflammation and alveolar damage; while assay of hydroxyproline and Masson's trichrome staining shows an increased collagen deposition in BLM-challenged rats that were decreased upon celastrol treatment. Celastrol also reduces inflammation in BLM-induced rats as evidenced by decrease in the expressions of mast cells, Tumor necrosis factor-alpha (TNF- α) and matrix metalloproteinases (MMPs) 2 and 9. Further, Western blot analysis shows that celastrol is a potent inducer of NF-E2-related factor 2 (Nrf2) and it restores the activities of Phase II enzymes such as hemoxygenase-1 (HO-1), glutathione-S-transferase (GSTs) and NADP(H): quinine oxidoreductase (NQO1) which were declined upon BLM administration. The results of this study show evidence on the protective effect of celastrol against BLM-induced PF through its antioxidant and anti-fibrotic effects. [ABSTRACT FROM AUTHOR]

Methanolic extracts of bran from black glutinous rice cultivars were screened for potential health benefits using cellular bioassays for quinone reductase ( QR) induction in murine hepatoma cells and inhibition of NO production in lipopolysaccharide ( LPS)-activated RAW 264.7 macrophages. Fractionation of the crude extract by semi-preparative HPLC afforded respective fractions enriched in phenolic acids, anthocyanins and proanthocyanidins. The relative potency of QR induction was phenolic acids > proanthocyanidins > anthocyanins, and the activity of the crude extract was conserved among the aggregate of these fractions. In contrast, all three fractions were more potent than the crude extract in terms of anti-inflammatory effect. This suggests synergism effects among anti-inflammatory agents through partial purification. Inhibition of macrophage NO production by binary mixtures of gallic acid or caffeic acid with the anthocyanin-rich fraction indicated potential synergism. These results warrant further efforts to identify the active agents and substantiate synergistic interactions through isobologram analysis. [ABSTRACT FROM AUTHOR]

Aims A large meta-analysis of randomized clinical trials has seriously questioned chemoprevention based on vitamins including vitamin E (VE), and an increased risk for cancer among long-term users was actually seen. However, the mechanism underlying these findings still remain unknown. To clarify the mechanism, in an in vivo model we studied the putative disruption of redox homeostasis and the perturbation of carcinogen metabolizing enzymes determined by VE. Main methods Male Sprague–Dawley rats were treated ip with either 100 or 200 mg/kg b.w. daily for 7 or 14 consecutive days. Controls received vehicle only. Cytochrome P450 (CYP) content, CYP-reductase, CYP-linked monooxygenases, as well as phase-II and the antioxidant enzymes catalase and NAD(P)H:quinone reductase were investigated in both liver and kidney. Free radical species in tissue subcellular preparations were measured by electronic paramagnetic resonance (EPR) spectroscopy coupled to a radical probe technique. Key findings No substantial changes of hepatic xenobiotic metabolism enzymes were determined by VE. Conversely, a powerful booster effect of various renal phase-I carcinogen bioactivating enzymes at both dosages and observational times was recorded. While no relevant changes of post-oxidative phase-II reactions were found in the liver, a significant inactivating effect was caused by VE in renal tissues. Antioxidant enzymes were found mainly downregulated by the treatment. In the kidney, a marked free radical over-generation linked to CYP induction was observed. Significance This study proved that VE acts as a co-carcinogen and pro-oxidant agent. Such epigenetic mechanisms may contribute to explain the harmful outcomes observed in humans. [ABSTRACT FROM AUTHOR]

Olive oil, the primary source of dietary fat in the Mediterranean diet, is reported to have benefits on bone health, mechanisms of which remain obscure. Here we investigated the protective effects of hydroxytyrosol (HT), a major polyphenol in olive on preosteoblast toxicity induced by acrolein, the major component of cigarette smoke. Acrolein at 75 µM, induced significant oxidative stress which was attributed to the inhibition of Nrf2 nuclear translocation and suppression of phase II enzymes. And HT could efficiently promote Phase II enzymes activation and prevent the decrease of antioxidative enzymes, protect the autophagy pathway and maintain the normal level of mitochondrial complexes. These results indicated that cigarettes smoking could damage preosteoblast cells by inducing oxidative stress and mitochondrial dysfunction. While through activation of Keap1/Nrf2 pathway, olive component HT could contribute to cellular protection and potential bone health. [ABSTRACT FROM AUTHOR]

The C-8 phenol group is essential to exert the bioactivities of daphnetin, but it is readily conjugated with glucuronic acid prior to excretion. In this study, daphnetin-7-methylether (7 M- DNP) was used to investigate the effect of 7-methyl substitution on daphnetin glucuronidation in human/rat liver ( HLM/ RLM) and intestine ( HIM/ RIM) microsomes, and recombinant UDP-glucuronosyltransferases ( UGTs). Compared with daphnetin, the Vmax/ Km values of 7 M- DNP via 8- O-glucuronidation were 2.1-fold lower in HLM, 1.7-fold lower in HIM, and 2.4-fold lower in RLM, suggesting an improvement in metabolic stability. Different from daphnetin 8- O-glucuronidation exclusively catalyzed by UGT1 A6 and UGT1 A9, UGT1 A1, -1A3, -1A7, -1A8, and -1A9 showed glucuronidation activity toward 7 M- DNP. Kinetics studies, chemical inhibition, and the relative activity factor approach were used to demonstrate that UGT1 A9 was mainly responsible for the reaction in HLM, whereas UGT1 A1 was a primary contributor in HIM. The Vmax/ Km values of 7 M- DNP glucuronidation in HLM and HIM were 0.61-0.74-fold lower than those of rat, suggesting the differences between the two species. The bioactivity analysis demonstrated that 7 M- DNP had an anti-inflammatory activity comparable to that of daphnetin. These findings indicated that the outcomes of 7-methyl substitution on daphnetin might be positive, but this should be confirmed in future in vivo studies. © 2015 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 104:3557-3564, 2015 [ABSTRACT FROM AUTHOR]

Cyclic nitroxides are a large group of compounds composed of diverse stable radicals also known as synthetic antioxidants. Although nitroxides are valuable for use in several skin conditions, in in vivo conditions they have several drawbacks, such as nonspecific dispersion in normal tissue, preferential renal clearance and rapid reduction of the nitroxide to the corresponding hydroxylamine. However, these drawbacks can be easily addressed by encapsulating the nitroxides within microemulsions. This approach would allow nitroxide activity and therefore their valuable effects (e.g. activation of the Keap1-Nrf2-EpRE pathway) to continue. In this work, nitroxides were encapsulated in a microemulsion composed of biocompatible ingredients. The nanometric size and shape of the vehicle microemulsion and nitroxide microemulsion displayed high similarity, indicating that the stability of the microemulsions was preserved. Our studies demonstrated that nitroxide microemulsions were more potent inducers of the Keap1-Nrf2-EpRE pathway than the free nitroxides, causing the activation of phase II enzymes. Moreover, microemulsions containing nitroxides significantly reduced UVB-induced cytotoxicity in the skin. Understanding the mechanism of this improved activity may expand the usage of many other Nrf2 modulating molecules in encapsulated form, as a skin protection strategy against oxidative stress-related conditions. [ABSTRACT FROM AUTHOR]

Solids from wastewater of the tortilla industry, known as nejayote, are a potential source of chemopreventive phenolic compounds. Phenolic compounds were identified and quantified in nejayote solids obtained by filtration, as well as its antioxidant activity and chemopreventive effect. Bound phenolics and antioxidant capacity of nejayote were concentrated in the nejayote solution obtained after filtration (FSS) through 280 μm. Additionally, FSS contained 84, 79, 72 and 97% more bound ferulic, coumaric, 8-O-4-diferulic and 5-5′-diferulic acids, respectively, compared to total nejayote solids. Feruloyl putrescines, especially coumaroyl-feruloyl putrescine, isolated from bound FSS exerted 105% and 12.45% higher chemopreventive effect than nejayote and bound FSS, respectively. Feruloyl putrescines are potent phase II inducers due to their double nitrogen linked Michael acceptors structure. Feruloyl putrescines in nejayote are a source of natural chemopreventive agents capable of inducing phase II enzymes. [ABSTRACT FROM AUTHOR]

Benzo(a)pyrene (B(a)P), which is commonly used as an indicator species for polycyclic aromatic hydrocarbon (PAH) contamination, has a large number of hazardous consequences on human health. In the presence of the enzyme cytochrome-P-450 1A1 (CYP1A1), it undergoes metabolic activation to form reactive intermediates that are capable of inducing mutagenic, cytotoxic, teratogenic and carcinogenic effects in various species and tissues. Research within the last few years has shown that flavonoids exhibit chemopreventive effect against these toxins. In the present study, the protective effect of silymarin (a flavonoid) against B(a)P-induced toxicity was monitored in Wistar rats by evaluating the levels of hepatic phase I (CYP1A1), phase II enzymes (glutathione-S-transferase, epoxide hydroxylases, uridinediphosphate glucuronosyltransferases, NAD(P)H: quinone oxidoreductase 1, sulfotransferases), cellular antioxidant enzyme heme oxygenase and total glutathione. The results reveal that silymarin possesses substantial protective effect against B(a)P-induced damages by inhibiting phase I detoxification enzyme CYP1A1 and modulating phase II conjugating enzymes, which were confirmed by histopathological analysis. Overall, the inhibition of CYP1A1 and the modulation of phase II enzymes may provide, in part, the molecular basis for the effect of silymarin against B(a)P. [ABSTRACT FROM AUTHOR]

The notion that (poly)phenols act as direct free radical scavengers is being challenged by mere chemical and biochemical considerations such as bioavailability and intracellular concentrations. An alternative hypothesis that is gaining considerable traction is that (poly)phenols are processed by the body as xenobiotics via the Keap1/Nrf2/ARE signaling axis, leading to the induction of Phase II enzymes. However, there are no solid human data to confirm this interesting supposition. In this study, we tested the activities of hydroxytyrosol (HT) on Phase II enzymes’ expression in a double-blind, randomized, placebo-controlled study. We tested two HT doses, i.e. 5 and 25 mg/d, vs. placebo following a Latin square design. We report that HT is well tolerated but does not significantly modify Phase II enzyme expression in peripheral blood mononuclear cells. Moreover, we were unable to record significant effects on a variety of surrogate markers of cardiovascular disease such as lipid profile and inflammation and oxidation markers. Available evidence indicates that the “hormesis hypothesis” that (poly)phenols activate Phase II enzymes requires solid human confirmation that might be provided by future trials. This study is registered at ClinicalTrials.gov (identifier: NCT02273622 ). [ABSTRACT FROM AUTHOR]

The transcription factor Nrf2 controls the expression of genes encoding cytoprotective enzymes and proteins. Its activation is related to conformational changes in the inhibitory protein Keap1 and/or Nrf2 phosphorylation by upstream kinases. Activation of Nrf2 can lead to the induction of phase II enzymes responsible for the inactivation of potential carcinogens. This may constitute an important strategy of chemoprevention. Moreover, these enzymatic systems participating in the biotransformation of drugs can reduce their therapeutic effects, contributing to drug resistance. For this reason, a clear understanding of the role of Nrf2 is essential to assess the beneficial and adverse effects of its up-regulation, particularly in relation to the prevention and treatment of cancer. This article summarizes the current state of knowledge on the significance of Nrf2 in tumorigenesis. [ABSTRACT FROM AUTHOR]

The interaction of asbestos fibers with macrophages generates harmful reactive oxygen species (ROS) and subsequent oxidative cell damage that are key processes linked to malignancy. Secoisolariciresinol diglucoside (SDG) is a non-toxic, flaxseed-derived pluripotent compound that has antioxidant properties and may thus function as a chemopreventive agent for asbestos-induced mesothelioma. We thus evaluated synthetic SDG (LGM2605) in asbestos-exposed, elicited murine peritoneal macrophages as an in vitro model of tissue phagocytic response to the presence of asbestos in the pleural space. Murine peritoneal macrophages (MFs) were exposed to crocidolite asbestos fibers (20 µg/cm2) and evaluated at various times post exposure for cytotoxicity, ROS generation, malondialdehyde (MDA), and levels of 8-iso Prostaglandin F2α (8-isoP). We then evaluated the ability of LGM2605 to mitigate asbestos-induced oxidative stress by administering LGM2605 (50 µM) 4-h prior to asbestos exposure. We observed a significant (p < 0.0001), time-dependent increase in asbestos-induced cytotoxicity, ROS generation, and the release of MDA and 8-iso Prostaglandin F2α, markers of lipid peroxidation, which increased linearly over time. LGM2605 treatment significantly (p < 0.0001) reduced asbestos-induced cytotoxicity and ROS generation, while decreasing levels of MDA and 8-isoP by 71%–88% and 41%–73%, respectively. Importantly, exposure to asbestos fibers induced cell protective defenses, such as cellular Nrf2 activation and the expression of phase II antioxidant enzymes, HO-1 and Nqo1 that were further enhanced by LGM2605 treatment. LGM2605 boosted antioxidant defenses, as well as reduced asbestos-induced ROS generation and markers of oxidative stress in murine peritoneal macrophages, supporting its possible use as a chemoprevention agent in the development of asbestos-induced malignant mesothelioma.

Apples abundant in phenolic compounds show a variety of biological activities that may contribute to health beneficial effects against cardiovascular diseases, diabetes, obesity and cancer. We investigated the effect of cloudy apple juice (CAJ) on the hepatic and mammary gland carcinogen metabolizing enzymes, DNA damage and liver injury, altered by 7,12-dimethylbenz[a]anthracene (DMBA). Sprague-Dawley female rats were gavaged with CAJ (10 ml/kg b.w.) for 28 consecutive days. DMBA was administered i.p. on the 27th and the 28th days. In the liver, feeding with CAJ decreased the activities of CYP1A1 and 1A2 and increased phase II enzymes. The activities of all enzymes tested were enhanced in the animals treated with DMBA alone and in combination with CAJ. The most significant changes in the level of the hepatic enzymes tested were observed for GST alpha and NQO1. In mammary gland CAJ induced an increase in the level of GST mu and GST pi, while DMBA and CAJ combined administration elevated GST pi only. This may be beneficial as GST pi is involved in the DMBA detoxification. Additionally, pretreatment with CAJ reduced the level of most of the blood biochemical liver and kidney markers elevated as a result of DMBA treatment. These findings indicate that CAJ may interfere with enzyme system involved in carcinogen metabolism. However, this effect seems to be dependent on tissue and carcinogen and is moderately effective in the case of DMBA . Moreover, CAJ can also provide some protection against the liver and kidney damage. [ABSTRACT FROM AUTHOR]

The correlation among selenium uptake, the content of bioactive compounds in sprouts, and biological activities triggered in cultured human cells by sprout extracts was investigated. Seeds of Brassica crops and rye were treated with SeO2 water solution. The selenium levels in sprouts increased from 1.0-4.1 to 53.3-382 μg/g dw with no influence on plant physiology according to the indices used. Neither the composition of glucosinolates (GL) in Brassica sprouts nor the myrosinase activity nor the composition of GL breakdown lipophilic products were significantly affected. In all Brassica sprouts, conversion to health-promoting isothiocyanates (ITC) and indoles corresponded to only 1% of total GLs. Low ITC concentration may explain observed lack of induction of glutathione S-transferases (GST) and quinone oxidoreductase (NQO) detoxifying enzymes in HT29 cells exposed to sprout extracts. The insignificant impact on cell growth and genome function suggests that Brassica sprouts may be safe vehicle of selenium to combat its dietary deficiency. [ABSTRACT FROM AUTHOR]

Dominant mutations in superoxide dismutase 1 (SOD1) are a frequent cause of the lethal neurodegenerative disease amyotrophic lateral sclerosis (ALS). The nuclear factor erythroid 2-related factor 2 (Nrf2)/antioxidant response element (ARE) signaling pathway is the major cellular defense mechanism against oxidative stress, however, its role in ALS remains to be fully elucidated. Therefore, the present study aimed to investigate whether the human SOD1-G93A gene affected the Nrf2/ARE signaling pathway in an ALS cell model. The soma became round and the number of neurites decreased in the NSC-34 cells transfected with the hSOD1-G93A gene, and the neurites were shorter and oxidative stress was increased compared with the normal NSC-34 cells. Furthermore, the mRNA and protein expression of Nrf2, heme oxygenase-1 and NAD(P)H: quinone oxidoreductase 1 was significantly decreased in the NSC-34 cells transfected with the human SOD1-G93A gene. The present study indicated that human SOD1-G93A damaged the Nrf2/ARE signaling pathway in the ALS cell model and reduced the ability of cells to protect against oxidative injury. [ABSTRACT FROM AUTHOR]

Highlights: [•] Ugts are important phase II enzymes, of which little is known in fish. [•] Design of primers for RT-qPCR is challenging due to high sequence homologies. [•] We specify eight different Ugts in zebrafish. [•] We report tissue-, sex- and developmental specific transcription profiles. [•] Regulation of ugts by arylhydrocarbon receptor 2 is demonstrated. [Copyright &y& Elsevier]