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Anticancer Research 2004Dietary compounds or nonsteroidal anti-inflammatory drugs (NSAIDs) may reduce cancer rates. Elevation of phase II detoxification enzymes might be one of the mechanisms...
BACKGROUND
Dietary compounds or nonsteroidal anti-inflammatory drugs (NSAIDs) may reduce cancer rates. Elevation of phase II detoxification enzymes might be one of the mechanisms leading to cancer prevention. We investigated the effects of dietary anticarcinogens and NSAIDs on rat gastrointestinal UDP-glucuronosyltransferases (UGT).
MATERIALS AND METHODS
Diets of Wistar rats were supplemented with oltipraz, alpha-tocopherol, beta-carotene, phenethylisothiocyanate (PEITC), sulforaphane analogue compound-30, indole-3-carbinol, D-limonene, relafen, indomethacin, ibuprofen, piroxicam, acetyl salicylic acid or sulindac. Hepatic and intestinal UGT enzyme activities were quantified by using 4-nitrophenol and 4-methylumbelliferone as substrates.
RESULTS
Compound-30, D-limonene, indomethacin, ibuprofen or sulindac enhanced proximal small intestinal UGT activities. Only compound-30 was able to induce mid- and distal small intestinal UGT activities. Large intestinal UGT activities were increased by ibuprofen and sulindac, whereas oltipraz, PEITC and D-limonene gave enhanced hepatic UGT activities.
CONCLUSION
Mainly rat proximal small intestinal and hepatic UGT enzyme activities were induced by dietary anticarcinogens or NSAIDs. Enhanced UGT activities might lead to a more efficient detoxification of carcinogenic compounds and thus could contribute to the prevention of gastrointestinal cancer.
Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Anticarcinogenic Agents; Dietary Supplements; Enzyme Induction; Glucuronosyltransferase; Hymecromone; Intestine, Small; Liver; Nitrophenols; Rats
PubMed: 15161036
DOI: No ID Found -
Drug Metabolism and Disposition: the... Jun 2012The induction of drug-metabolizing enzymes by chemicals is one of the major reasons for drug-drug interactions. In the present study, the regulation of mRNA expression...
The induction of drug-metabolizing enzymes by chemicals is one of the major reasons for drug-drug interactions. In the present study, the regulation of mRNA expression of one arylacetamide deacetylase (Aadac) and 11 carboxylesterases (Cess) by 15 microsomal enzyme inducers (MEIs) was examined in livers of male C57BL/6 mice. The data demonstrated that Aadac mRNA expression was suppressed by three aryl hydrocarbon receptor (AhR) ligands, two constitutive androstane receptor (CAR) activators, two pregnane X receptor (PXR) ligands, and one nuclear factor erythroid 2-related factor 2 (Nrf2) activator. Ces1 subfamily mRNA expression was not altered by most of the MEIs, whereas Ces2 subfamily mRNA was readily induced by the activators of CAR, PXR, and Nrf2 but not by peroxisome proliferator-activated receptor α activators. Studies using null mice demonstrated that 1) AhR was required for the 2,3,7,8-tetrachlorodibenzo-p-dioxin-mediated suppression of Aadac and Ces3a; 2) CAR was involved in the 1,4-bis[2-(3,5-dichloropyridyloxy)]benzene-mediated induction of Aadac, Ces2c, Ces2a, and Ces3a; 3) PXR was required for the pregnenolone-16α-carbonitrile-mediated induction of Aadac, Ces2c, and Ces2a; 4) Nrf2 was required for the oltipraz-mediated induction of Ces1g and Ces2c; and 5) PXR was not required for the DEX-mediated suppression of Cess in livers of mice. In conclusion, the present study systematically investigated the regulation of Cess by MEIs in livers of mice and demonstrated that MEIs modulated mRNA expression of mouse hepatic Cess through the activation of AhR, CAR, PXR, and/or Nrf2 transcriptional pathways.
Topics: Animals; Carboxylic Ester Hydrolases; Liver; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; RNA, Messenger; Transcription Factors
PubMed: 22429928
DOI: 10.1124/dmd.111.043877 -
European Review For Medical and... Dec 2018To evaluate the effect of oltipraz (OPZ) on isoproterenol-induced heart failure (HF) and heart function. We also explore the underlying molecular mechanism of OPZ.
OBJECTIVE
To evaluate the effect of oltipraz (OPZ) on isoproterenol-induced heart failure (HF) and heart function. We also explore the underlying molecular mechanism of OPZ.
MATERIALS AND METHODS
The rats were randomly divided into four groups, including normal control group, isoproterenol (ISO) group, ISO +100 mg/kg OPZ group, and OPZ group. Hemodynamic parameters, such as left-ventricular systolic pressure, were statistically analyzed. Besides, plasma levels of brain natriuretic peptide (BNP), pro-inflammatory cytokines and antioxidant markers were assessed by using enzyme-linked immunosorbent assay (ELISA). Moreover, histopathological examination was applied to assess the degree of cardiac interstitial fibrosis.
RESULTS
OPZ could statistically improve the hemodynamic parameters of the heart function, and could also obviously attenuate cardiac interstitial fibrosis in ISO-induced HF rats when compared with the ISO group. Besides, plasma level of BNP in ISO +100 mg/kg OPZ group dramatically decreased in comparison with that of ISO group. Moreover, compared with ISO group, OPZ treatment significantly reduced the levels of pro-inflammatory cytokines such as tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β). Moreover, OPZ treatment remarkably increased the levels of antioxidant markers such as superoxide dismutase (SOD) and glutathione peroxidase (GPx) in ISO-induced HF rats.
CONCLUSIONS
OPZ administration may provide experimental evidence for the possible effect of OPZ on isoproterenol-induced heart failure in rats. Moreover, OPZ administration may have potential utility for the treatment of heart failure.
Topics: Animals; Anti-Inflammatory Agents; Antioxidants; Biomarkers; Cytokines; Disease Models, Animal; Fibrosis; Heart Failure; Inflammation Mediators; Isoproterenol; Myocytes, Cardiac; Oxidative Stress; Pyrazines; Rats, Sprague-Dawley; Recovery of Function; Thiones; Thiophenes; Ventricular Function, Left; Ventricular Remodeling
PubMed: 30575935
DOI: 10.26355/eurrev_201812_16661 -
OncoTargets and Therapy 2020Prostate cancer (PCa) is a widespread urinary neoplasm and one of the most prevalent and second most frequent malignancies diagnosed in males worldwide. This study aimed...
PURPOSE
Prostate cancer (PCa) is a widespread urinary neoplasm and one of the most prevalent and second most frequent malignancies diagnosed in males worldwide. This study aimed to identify a candidate marker and explore its molecular mechanism in PCa.
METHODS
Gene expression datasets, GSE55945 (n=21) and GSE46602 (n=50), were downloaded from the Gene Expression Omnibus database. Bioinformatic approaches were applied to identify potential markers. Effects of the candidate marker on proliferation, migration, invasion, and ferroptosis (ferrous iron and malondialdehyde (MDA)) in PCa cells and its mechanism were assessed after performing cell transfection.
RESULTS
A total of 1435 common differentially expressed genes were identified in GSE55945 and GSE46602. Five key gene modules were listed based on a protein-protein interaction network, containing five hub genes. Pannexin 2 (), a candidate marker was identified, and findings revealed substantial upregulation of its expression levels in PCa cell lines. Blocking expression of resulted in suppression of proliferation, migration, and invasion in PCa cells, while increasing ferrous iron and MDA levels. However, these effects were rescued by activator, oltipraz. The signaling pathway was consequently applied to determine underlying mechanism of in PCa cells. We established that silencing remarkably reduced protein expression levels in members of signaling pathway ( and ).
CONCLUSION
Our study demonstrated that is implicated in the pathogenesis of PCa, which regulates malignant phenotypes and ferroptosis through signaling pathway, and maybe a potential therapeutic target for PCa.
PubMed: 32547072
DOI: 10.2147/OTT.S249752 -
Oncology Letters Dec 2021The combretastatin A-4/oltipraz hybrid (COH), 5-(3-amino-4-methoxyphenyl)-4-(3,4,5-trimethoxyphenyl)-3-1,2-dithiole-3-one (COH-203) is one of the COH compounds...
The combretastatin A-4/oltipraz hybrid (COH), 5-(3-amino-4-methoxyphenyl)-4-(3,4,5-trimethoxyphenyl)-3-1,2-dithiole-3-one (COH-203) is one of the COH compounds synthesized by our previous study, which has been reported to affect a number of cancer cell lines, such as SGC-7901, KB, HT-1080, HepG2, SMMC-7721 and BEL-7402. The sensitivity of human acute leukemia cell lines to COH-203, and the mechanism underlying its anti-proliferative effects remain unknown, which was investigated in the present study. In the present study, it was demonstrated that COH-203 had notable time- and dose-dependent antiproliferative effects on the human acute promyelocytic leukemia HL-60 cell line. Furthermore, COH-203 treatment resulted in cell cycle arrest at G/M phase in a dose-dependent manner, and subsequently induced apoptosis. Western blot analysis revealed that upregulation of cyclin B was associated with G/M arrest. In addition, treatment with COH-203 resulted in downregulated expression of Bcl-2. This result revealed that COH-203-induced apoptosis in HL-60 cells may occur via the mitochondrial pathway in a caspase-dependent manner.
PubMed: 34671429
DOI: 10.3892/ol.2021.13076 -
PloS One 2020Nuclear factor erythroid-2 related factor 2 (NRF2) encoded by the NFE2L2 gene is a transcription factor critical for protecting cells from chemically-induced oxidative...
Nuclear factor erythroid-2 related factor 2 (NRF2) encoded by the NFE2L2 gene is a transcription factor critical for protecting cells from chemically-induced oxidative stress. We developed computational procedures to identify chemical modulators of NRF2 in a large database of human microarray data. A gene expression biomarker was built from statistically-filtered gene lists derived from microarray experiments in primary human hepatocytes and cancer cell lines exposed to NRF2-activating chemicals (oltipraz, sulforaphane, CDDO-Im) or in which the NRF2 suppressor Keap1 was knocked down by siRNA. Directionally consistent biomarker genes were further filtered for those dependent on NRF2 using a microarray dataset from cells after NFE2L2 siRNA knockdown. The resulting 143-gene biomarker was evaluated as a predictive tool using the correlation-based Running Fisher algorithm. Using 59 gene expression comparisons from chemically-treated cells with known NRF2 activating potential, the biomarker gave a balanced accuracy of 93%. The biomarker was comprised of many well-known NRF2 target genes (AKR1B10, AKR1C1, NQO1, TXNRD1, SRXN1, GCLC, GCLM), 69% of which were found to be bound directly by NRF2 using ChIP-Seq. NRF2 activity was assessed across ~9840 microarray comparisons from ~1460 studies examining the effects of ~2260 chemicals in human cell lines. A total of 260 and 43 chemicals were found to activate or suppress NRF2, respectively, most of which have not been previously reported to modulate NRF2 activity. Using a NRF2-responsive reporter gene in HepG2 cells, we confirmed the activity of a set of chemicals predicted using the biomarker. The biomarker will be useful for future gene expression screening studies of environmentally-relevant chemicals.
Topics: Biomarkers; Data Mining; Databases, Genetic; Hep G2 Cells; Humans; NF-E2-Related Factor 2; Transcriptome
PubMed: 32986742
DOI: 10.1371/journal.pone.0239367 -
Toxicology Letters Jul 2009Myeloid cell leukemia-1 (Mcl-1) is an anti-apoptotic protein that is regulated by the constitutive androstane receptor (CAR). Activation of CAR can protect the liver...
Myeloid cell leukemia-1 (Mcl-1) is an anti-apoptotic protein that is regulated by the constitutive androstane receptor (CAR). Activation of CAR can protect the liver against bile acid-induced toxicity and it may have a role in cell death via apoptosis by altering expression of Bcl-2 family proteins such as myeloid cell leukemia-1 (Mcl-1). Our aim was to determine if activation of CAR reduces hepatocellular apoptosis during cholestasis as a mechanism of hepatoprotection. CAR(+/+) (WT) and CAR(-/-) (CAR-null) mice were pre-treated with compounds known to activate CAR prior to induction of intrahepatic cholestasis using the secondary bile acid lithocholic acid (LCA). Pre-treatment with the CAR activators phenobarbital (PB) and TCPOBOP (TC), as well as the non-CAR activator pregnenolone 16alpha-carbontrile (PCN), protected against LCA-induced liver injury in WT mice, whereas liver injury was more extensive without CAR (CAR-null). Unexpectedly, expression of anti-apoptotic Mcl-1 and Bcl-x(L) was not increased in hepatoprotected mice. Compared to unprotected groups, apoptosis was decreased in hepatoprotected mice as evidenced by the absence of cleaved caspase 3 (cCasp3). In contrast to the cytoplasmic localization in the injured livers (LCA and oltipraz), Mcl-1 protein was localized in the nucleus of hepatoprotected livers to potentially promote cell survival. This study demonstrates that although apoptosis is reduced in hepatoprotected mice pre-treated with CAR and non-CAR activators; hepatoprotection is not directly a result of CAR-induced Mcl-1 expression.
Topics: Animals; Apoptosis; Caspase 3; Cholestasis, Intrahepatic; Constitutive Androstane Receptor; Cytoprotection; Disease Models, Animal; Lithocholic Acid; Liver; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Myeloid Cell Leukemia Sequence 1 Protein; Phenobarbital; Pregnenolone Carbonitrile; Proto-Oncogene Proteins c-bcl-2; Pyrazines; Pyridines; RNA, Messenger; Receptors, Cytoplasmic and Nuclear; Thiones; Thiophenes; Transcription Factors; bcl-X Protein
PubMed: 19433268
DOI: 10.1016/j.toxlet.2009.03.005 -
International Journal of Molecular... Dec 2018Central presbycusis is the most common sensory disorder in the elderly population, however, the underlying molecular mechanism remains unclear. NF‑E2‑related factor...
Central presbycusis is the most common sensory disorder in the elderly population, however, the underlying molecular mechanism remains unclear. NF‑E2‑related factor 2 (Nrf2) is a key transcription factor in the cellular response to oxidative stress, however, the role of Nrf2 in central presbycusis remains to be elucidated. The aim of the present study was to investigate the pathogenesis of central presbycusis using a mimetic aging model induced by D‑galactose (D‑gal) in vivo and in vitro. The degeneration of the cell was determined with transmission electron microscopy, terminal deoxynucleotidyl transferase‑mediated deoxyuridine 5'‑triphosphate nick‑end labeling staining, and senescence‑associated β‑galactosidase staining. The expression of protein was detected by western blotting and immunofluorescence. The quantification of the mitochondrial DNA (mtDNA) 4,834‑base pair (bp) deletion and mRNA was detected by TaqMan quantitative polymerase chain reaction (qPCR) and reverse transcription‑qPCR respectively. Cell apoptosis and intracellular ROS in vitro were determined with flow cytometry. The levels of nuclear Nrf2, and the mRNA levels of Nrf2‑regulated antioxidant genes, were downregulated in the auditory cortex of aging rats, which was accompanied by an increase in 8‑hydroxy‑2'‑deoxyguanosine formation, an accumulation of mtDNA 4,834‑bp deletion, and neuron degeneration. In addition, oltipraz, a typical Nrf2 activator, was found to protect cells against D‑gal‑induced mtDNA damage and mitochondrial dysfunction by activating Nrf2 target genes in vitro. It was also observed that activating Nrf2 with oltipraz inhibited cell apoptosis and delayed senescence. Taken together, the data of the present study suggested that the age‑associated decline in Nrf2 signaling activity and the associated mtDNA damage in the auditory cortex may be implicated in the degeneration of the auditory cortex. Therefore, the restoration of Nrf2 signaling activity may represent a potential therapeutic strategy for central presbycusis.
Topics: Aging; Animals; Apoptosis; Auditory Cortex; DNA Damage; DNA, Mitochondrial; In Situ Nick-End Labeling; Male; Malondialdehyde; NF-E2-Related Factor 2; Oxidative Stress; PC12 Cells; Presbycusis; Rats
PubMed: 30272261
DOI: 10.3892/ijmm.2018.3907 -
Oncology Discovery 2013There seems to be little doubt that xenobiotic and plant derived organosulfur compounds have enormous benefits for in vitro cellular functions and for a multitude of...
There seems to be little doubt that xenobiotic and plant derived organosulfur compounds have enormous benefits for in vitro cellular functions and for a multitude of diseases, including cancer. Since there are numerous reviews on anticancer activities of plant organosulfurs, the focus herein will be on alterations associated with xenobiotic organosulfurs. Benefits of 2-mercaptoethanol (2-Me), N-Acetyl-cysteine, cysteamine, thioproline, piroxicam, disulfiram, amifostine, sulindac, celecoxib, oltipraz and their derivates on transplanted homologous tumors and on autochthonous cancers with a viral-, radiation-, chemical carcinogen-, and undefined-etiology are assessed. Because all organosulfurs were not tested for activity in each of the etiology categories, comparative evaluations are restricted. In general, all 'appeared' to lower the incidence of cancer irrespective of etiology; however, since most of these values were determined at ages much younger than at a natural-end-of-life-age, differences most likely, instead, reflect a delayed initiation and/or a slowed progression of tumorigenesis. The poorest, long-term benefits of early intervention protocols occurred for viral- and chemical carcinogen-induced cancers. In addition, once tumorigenesis was beyond the initiation stage, outcomes of organosulfur therapies were extremely poor, indicating that they will not be of significant value as stand alone treatments. More importantly, except for the lifetime prevention of spontaneous and radiation-induced mammary tumors by daily dietary 2-Me, similar life long prevention of tumorigenesis was not achieved with other xenobiotics or any of nature's plant organosulfurs. These results raise an interesting question: Is the variability in incidence found for different organosulfurs associated with (a) their structure, (b) the length of the untreated latency period, (c) treatment duration/dose, and/or (d) the etiology-inducing agent?
PubMed: 25383193
DOI: 10.7243/2052-6199-1-4 -
Drug Metabolism and Disposition: the... Apr 2009UDP-glucuronosyltransferases (UGTs) catalyze the addition of UDP-glucuronic acid to endo- and xenobiotics, enhancing their water solubility and elimination. Many...
Induction of mouse UDP-glucuronosyltransferase mRNA expression in liver and intestine by activators of aryl-hydrocarbon receptor, constitutive androstane receptor, pregnane X receptor, peroxisome proliferator-activated receptor alpha, and nuclear factor erythroid 2-related factor 2.
UDP-glucuronosyltransferases (UGTs) catalyze the addition of UDP-glucuronic acid to endo- and xenobiotics, enhancing their water solubility and elimination. Many exogenous compounds, such as microsomal enzyme inducers (MEIs), alter gene expression through xenobiotic-responsive transcription factors, namely, the aryl hydrocarbon receptor (AhR), constitutive androstane receptor (CAR), pregnane X receptor (PXR), peroxisome proliferator-activated receptor alpha (PPARalpha), and nuclear factor erythroid 2-related factor 2 (Nrf2). These transcription factors regulate xenobiotic-inducible expression of hepatic and intestinal biotransformation enzymes and transporters. The purpose of this study was to determine hepatic and intestinal inducibility of mouse Ugt mRNA by MEIs. Male C57BL/6 mice were treated for four consecutive days with activators of AhR [2,3,7,8-tetrachlorodibenzodioxin (TCDD), polychlorinated biphenyl 126, and beta-naphthoflavone], CAR [1,4-bis[2-(3,5-dichloropyridyloxy)]benzene (TCPOBOP), phenobarbital, and diallyl sulfide], PXR [pregnenolone-16alpha-carbonitrile (PCN), spironolactone, and dexamethasone], PPARalpha (clofibrate, ciprofibrate, and diethylhexylphthalate), and Nrf2 (oltipraz, ethoxyquin, and butylated hydroxyanisole), respectively. Ugt1a1 mRNA expression in liver was induced by activators of all five transcription factor pathways, Ugt1a5 by Nrf2 activators, Ugt1a6 by all the pathways except CAR, and Ugt1a9 by all the pathways except Nrf2. Ugt2b35 mRNA in liver was induced by AhR activators and Ugt2b36 by CAR and PPARalpha activators. Throughout the small and large intestine, the AhR ligand TCDD increased Ugt1a6 and Ugt1a7 mRNA. In small intestine, the PXR activator PCN increased Ugt1a1, Ugt1a6, Ugt1a7, Ugt2b34, and Ugt2b35 mRNA in the duodenum. In conclusion, chemical activation of AhR, CAR, PXR, PPARalpha, and Nrf2 in mouse results in induction of distinct Ugt gene sets in liver and intestine, predominantly the Ugt1a isoforms.
Topics: Animals; Constitutive Androstane Receptor; Gene Expression Regulation, Enzymologic; Glucuronosyltransferase; Intestines; Liver; Male; Mice; Mice, Inbred C57BL; NF-E2 Transcription Factor; PPAR alpha; Pregnane X Receptor; RNA, Messenger; Receptors, Aryl Hydrocarbon; Receptors, Cytoplasmic and Nuclear; Receptors, Steroid; Transcription Factors
PubMed: 19144771
DOI: 10.1124/dmd.108.024190