Inchinkoto, a herbal medicine, and its ingredients dually exert Mrp2/MRP2-mediated choleresis and Nrf2-mediated antioxidative action in rat livers

2007 ◽  
Vol 292 (5) ◽  
pp. G1450-G1463 ◽  
Author(s):  
Kosuke Okada ◽  
Junichi Shoda ◽  
Masahito Kano ◽  
Sachiko Suzuki ◽  
Nobuhiro Ohtake ◽  
...  
Keyword(s):  
Herbal Medicine ◽  
Biliary Excretion ◽  
Mrna Level ◽  
Heme Oxygenase 1 ◽  
Magic Bullet ◽  
Related Factor ◽  
Mrna Levels ◽  
Chimeric Mice ◽  
Rat Livers ◽  
Antioxidative Action

Inchinkoto (ICKT), a herbal medicine, has been recognized in Japan and China as a “magic bullet” for jaundice. To explore potent therapeutic agents for cholestasis, the effects of ICKT or its ingredients on multidrug resistance-associated protein 2 (Mrp2/ MRP2)-mediated choleretic activity, as well as on antioxidative action, were investigated using rats and chimeric mice with livers that were almost completely repopulated with human hepatocytes. Biliary excretion of Mrp2 substrates and the protein mass, subcellular localization, and mRNA level of Mrp2 were assessed in rats after 1-wk oral administration of ICKT or genipin, a major ingredient of ICKT. Administration of ICKT or genipin to rats for 7 days increased bile flow and biliary excretion of bilirubin conjugates. Mrp2 protein and mRNA levels and Mrp2 membrane densities in the bile canaliculi and renal proximal tubules were significantly increased in ICKT- or genipin-treated rat livers and kidneys. ICKT and genipin, thereby, accelerated the disposal of intravenously infused bilirubin. The treatment also increased hepatic levels of heme oxygenase-1 and GSH by a nuclear factor-E2-related factor (Nrf2)-dependent mechanism. Similar effects of ICKT on MRP2 expression levels were observed in humanized livers of chimeric mice. In conclusion, these findings provide the rationale for therapeutic options of ICKT and its ingredients that should potentiate bilirubin disposal in vivo by enhancing Mrp2/MRP2-mediated secretory capacities in both livers and kidneys as well as Nrf2-mediated antioxidative actions in the treatment of cholestatic liver diseases associated with jaundice.

Regulation of heme oxygenase-1 expression by demethoxy curcuminoids through Nrf2 by a PI3-kinase/Akt-mediated pathway in mouse β-cells

2007 ◽  
Vol 293 (3) ◽  
pp. E645-E655 ◽  
Author(s):  
Subbiah Pugazhenthi ◽  
Leonid Akhov ◽  
Gopalan Selvaraj ◽  
Maorong Wang ◽  
Jawed Alam
Keyword(s):  
Signaling Pathways ◽  
Heme Oxygenase ◽  
Nuclear Translocation ◽  
Regulatory Subunit ◽  
Luciferase Reporter ◽  
Heme Oxygenase 1 ◽  
Related Factor ◽  
Mrna Levels ◽  
Phase 2 ◽  
Β Cells

Curcumin (diferuloylmethane), a component of turmeric, has been shown to have therapeutic properties. Induction of phase 2 detoxifying enzymes is a potential mechanism through which some of the actions of curcumin could proceed. Heme oxygenase-1 (HO-1), an antioxidant phase 2 enzyme, has been reported to have cytoprotective effects in pancreatic β-cells. Curcumin on further purification yields demethoxy curcumin (DMC) and bisdemethoxy curcumin (BDMC). The objective of the present study was to determine the mechanism by which these purified curcuminoids induce HO-1 in MIN6 cells, a mouse β-cell line. Demethoxy curcuminoids induced HO-1 promoter linked to the luciferase reporter gene more effectively than curcumin. The induction was dependent on the presence of antioxidant response element (ARE) sites containing enhancer regions (E1 and E2) in HO-1 promoter and nuclear translocation of nuclear factor-E2-related factor (Nrf2), the transcription factor that binds to ARE. Curcuminoids stimulated multiple signaling pathways that are known to induce HO-1. Inhibition of specific signaling pathways with pharmacological inhibitors and cotransfection experiments suggested the involvement of phosphotidylinositol 3-kinase and Akt. Real-time quantitative RT-PCR analysis showed significant elevation in the mRNA levels of HO-1 and two other phase 2 enzymes, the regulatory subunit of glutamyl cysteine ligase, which is needed for the synthesis of glutathione, and NAD(P)H:quinone oxidoreductase, which detoxifies quinones. DMC and BDMC induced the expression of HO-1 and translocated Nrf2 to nucleus in β-cells of mouse islets. Our observations suggest that demethoxy curcuminoids could be used to induce a cellular defense mechanism in β-cells under conditions of stress as seen in diabetes.

scholarly journals Defatted Rice Bran Supplementation in Diets of Finishing Pigs: Effects on Physiological, Intestinal Barrier, and Oxidative Stress Parameters

Animals ◽  
2020 ◽  
Vol 10 (3) ◽  
pp. 449
Author(s):  
Lijuan Fan ◽  
Ruihua Huang ◽  
Chengwu Wu ◽  
Yang Cao ◽  
Taoran Du ◽  
...  
Keyword(s):  
Rice Bran ◽  
Waste Product ◽  
Intestinal Barrier ◽  
Control Group ◽  
Heme Oxygenase 1 ◽  
Related Factor ◽  
Mrna Levels ◽  
Finishing Pigs ◽  
Quinone Oxidoreductase ◽  
Defatted Rice Bran

Rice bran is a waste product with low cost and high fiber content, giving it an added advantage over corn and soybean meal, which have to be purchased and always at a relatively higher cost. Under the background of increased attention to sustainable agriculture, it is significant to find alternative uses for this byproduct. A total of 35 finishing pigs were allotted to five dietary treatments: a control group with basal diet and four experimental diets where corn was equivalently substituted by 7%, 14%, 21%, and 28% defatted rice bran (DFRB), respectively. With increasing levels of DFRB, the neutrophil to lymphocyte ratio (NLR) linearly decreased (p < 0.05). In the jejunum, the mRNA level of nuclear factor erythroid-2 related factor-2 (Nrf2) exhibited a quadratic response (p < 0.01) with incremental levels of DFRB. In the colon, the mRNA levels of mucin 2 (MUC2), Nrf2, and NAD(P)H: quinone oxidoreductase 1 (NQO1) were upregulated (linear, p < 0.05) and heme oxygenase-1 (HO-1) was upregulated (linear, p < 0.01). Overall, using DFRB to replace corn decreased the inflammatory biomarkers of serum and showed potential function in modulating the intestinal barrier by upregulating the mRNA expression levels of MUC2 and downregulating that of Nrf2, NQO1, and HO-1 in the colon.

scholarly journals Discovery of 4-Anilinoquinolinylchalcone Derivatives as Potential NRF2 Activators

Molecules ◽  
2020 ◽  
Vol 25 (14) ◽  
pp. 3133
Author(s):  
Yu-Tse Kao ◽  
Yi-Siao Chen ◽  
Kai-Wei Tang ◽  
Jin-Ching Lee ◽  
Chih-Hua Tseng ◽  
...  
Keyword(s):  
Target Genes ◽  
Hacat Cell ◽  
Effective Means ◽  
Mrna Level ◽  
Firefly Luciferase ◽  
Luciferase Reporter ◽  
Stable Cell Line ◽  
Heme Oxygenase 1 ◽  
Related Factor ◽  
Nrf2 Activator

Activation of nuclear factor erythroid-2-related factor 2 (NRF2) has been proven to be an effective means to prevent the development of cancer, and natural curcumin stands out as a potent NRF2 activator and cancer chemopreventive agent. In this study, we have synthesized a series of 4-anilinoquinolinylchalcone derivatives, and used a NRF2 promoter-driven firefly luciferase reporter stable cell line, the HaCaT/ARE cells, to screen a panel of these compounds. Among them, (E)-3-{4-[(4-acetylphenyl)amino]quinolin-2-yl}-1-(4-fluorophenyl)prop-2-en-1-one (13b) significantly increased NRF2 activity in the HaCaT cell with a half maximal effective concentration (EC50) value of 1.95 μM. Treatment of compound 13b upregulated HaCaT cell NRF2 expression at the protein level. Moreover, the mRNA level of NRF2 target genes, heme oxygenase-1 (HO-1), glutamate-cysteine ligase catalytic subunit (GCLC), and glucose-6-phosphate dehydrogenase (G6PD) were significantly increased in HaCaT cells upon the compound 13b treatment. The molecular docking results exhibited that the small molecule 13b is well accommodated by the bound region of Kelch-like ECH-associated protein 1 (Keap1)-Kelch and NRF2 through stable hydrogen bonds and hydrophobic interaction, which contributed to the enhancement of affinity and stability between the ligand and receptor. Compound 13b has been identified as the lead compound for further structural optimization.

scholarly journals Neuroprotective Effect ofBrassica oleraceaSprouts Crude Juice in a Cellular Model of Alzheimer’s Disease

2015 ◽  
Vol 2015 ◽  
pp. 1-17 ◽  
Author(s):  
Alessandra Masci ◽  
Roberto Mattioli ◽  
Paolo Costantino ◽  
Simona Baima ◽  
Giorgio Morelli ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Phenolic Compounds ◽  
Chromatin Condensation ◽  
Amyloid Peptide ◽  
Antioxidant Compounds ◽  
Heme Oxygenase 1 ◽  
Related Factor ◽  
Mrna Levels ◽  
Model Of Alzheimer’S Disease

β-Amyloid peptide (Aβ) aberrant production and aggregation are major factors implicated in the pathogenesis of Alzheimer’s disease (AD), causing neuronal deathviaoxidative stress. Several studies have highlighted the importance of polyphenolic antioxidant compounds in the treatment of AD, but complex food matrices, characterized by a different relative content of these phytochemicals, have been neglected. In the present study, we analyzed the protective effect on SH-SY5Y cells treated with the fragment Aβ25–35by two crude juices of broccoli sprouts containing different amounts of phenolic compounds as a result of different growth conditions. Both juices protected against Aβ-induced cytotoxicity and apoptotic cell death as evidenced by cell viability, nuclear chromatin condensation, and apoptotic body formation measurements. These effects were mediated by the modulation of the mitochondrial function and of theHSP70gene transcription and expression. Furthermore, the juices upregulated the intracellular glutathione content and mRNA levels or activity of antioxidant enzymes such as heme oxygenase-1, thioredoxin, thioredoxin reductase, and NAD(P)H:quinone oxidoreductase 1viaactivation of NF-E2-related factor 2 (Nrf2). Although the effects of the two juices were similar, the juice enriched in phenolic compounds showed a greater efficacy in inducing the activation of the Nrf2 signalling pathway.

scholarly journals The Ratio of Hmox1/Nrf2 mRNA Level in the Tumor Tissue Is a Predictor of Distant Metastasis in Colorectal Cancer

2016 ◽  
Vol 2016 ◽  
pp. 1-6 ◽  
Author(s):  
Liang-Che Chang ◽  
Chung-Wei Fan ◽  
Wen-Ko Tseng ◽  
Hui-Ping Chein ◽  
Tsan-Yu Hsieh ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Distant Metastasis ◽  
Tumor Tissue ◽  
Mrna Level ◽  
Heme Oxygenase 1 ◽  
Mrna Levels ◽  
Nrf2 Pathway ◽  
Normal Tissues ◽  
Serum Carcinoembryonic Antigen ◽  
Polymerase Chain

Heme oxygenase 1 (Hmox1) plays an important role in the growth and spread of tumor, and its expression is regulated positively by Nrf2 [nuclear factor (erythroid-derived 2)-like 2; NFE2L2] and negatively by kelch-like ECH-associated protein 1 (Keap1) and by BTB and CNC homology 1 (Bach1). Both Hmox1 and Nrf2 contribute to distant metastasis of cancer. The mRNA levels of Hmox1, Nrf2, Keap1, and Bach1 in the tumor and normal tissues of 84 subjects with colorectal cancer (CRC) were determined by real-time polymerase chain reaction. The tumor had lower Hmox1 but higher Bach1 mRNA levels than the normal tissue. The correlations of Hmox1 with components of the Nrf2 pathway were not significant in the tumor tissue of CRC subjects with distant metastasis. The ratio of Hmox1/Nrf2 mRNA level (by percentage) in the tumor tissue was lower in the subjects with distant metastasis (97.4% (84.4–111.1%)) than in those without (101.0% (92.7–136.5%)) and was a predictor for distant metastasis in CRC (odds ratio: 0.83; 95% confidence interval: 0.68–0.97) along with serum carcinoembryonic antigen (1.0027, 1.006–1.064). The mRNA level of Hmox1 in the tumor tissue of CRC is not correlated with that of the Nrf2 pathway molecules, and its ratio to the Nrf2 level may be useful for suggesting distant metastasis in CRC.

scholarly journals Epigallocatechin 3-Gallate Has a Neuroprotective Effect in Retinas of Rabbits with Ischemia/Reperfusion through the Activation of Nrf2/HO-1

2020 ◽  
Vol 21 (10) ◽  
pp. 3716 ◽  
Author(s):  
Josué Rivera-Pérez ◽  
Martín Martínez-Rosas ◽  
César A. Conde-Castañón ◽  
Julia D. Toscano-Garibay ◽  
Nancy J. Ruiz-Pérez ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Lipid Peroxidation ◽  
Protective Effect ◽  
Nuclear Translocation ◽  
Ischemia Reperfusion ◽  
Neuronal Cells ◽  
Heme Oxygenase 1 ◽  
Related Factor ◽  
Mrna Levels ◽  
Neuroprotective Efficacy

Retinal ischemia-reperfusion (rI/R) generates an oxidative condition causing the death of neuronal cells. Epigallocatechin 3-gallate (EGCG) has antioxidant and anti-inflammatory properties. Nonetheless, its correlation with the pathway of nuclear factor erythroid 2-related factor 2/heme oxygenase-1 (Nrf2/HO-1) for the protection of the retina is unknown. We aimed to evaluate the neuroprotective efficacy of single-doses of EGCG in rI/R and its association with Nrf2/Ho-1 expression. In albino rabbits, rI/R was induced and single-doses of EGCG in saline (0–30 mg/kg) were intravenously administered to select an optimal EGCG concentration that protects from retina damage. To reach this goal, retinal structural changes, gliosis by glial fibrillary acidic protein (GFAP) immunostaining, and lipid peroxidation level by TBARS (thiobarbituric acid reactive substance) assay were determined. EGCG in a dose of 15 mg/kg (E15) presented the lowest levels of histological damage, gliosis, and oxidative stress in the studied groups. To determine the neuroprotective efficacy of E15 in a timeline (6, 24, and 48 h after rI/R), and its association with the Nrf2/HO-1 pathway, the following assays were done by immunofluorescence: apoptosis (TUNEL assay), necrosis (high-mobility group box-1; HMGB1), Nrf2, and HO-1. In addition, the Ho-1 mRNA (qPCR) and lipid peroxidation levels were evaluated. E15 showed a protective effect during the first 6 h, compared to 24 and 48 h after rI/R, as revealed by a decrease in the levels of all damage markers. Nuclear translocation Nrf2 and HO-1 staining were increased, including Ho-1 mRNA levels. In conclusion, a single dose of E15 decreases the death of neuronal cells induced by oxidative stress during the first 6 h after rI/R. This protective effect is associated with the nuclear translocation of Nrf2 and with an elevation of Ho-1 expression.

scholarly journals The Mitochondria-Targeted Antioxidant SkQ1 Downregulates Aryl Hydrocarbon Receptor-Dependent Genes in the Retina of OXYS Rats with AMD-Like Retinopathy

2014 ◽  
Vol 2014 ◽  
pp. 1-9 ◽  
Author(s):  
M. L. Perepechaeva ◽  
A. Yu. Grishanova ◽  
E. A. Rudnitskaya ◽  
N. G. Kolosova
Keyword(s):  
Aryl Hydrocarbon Receptor ◽  
Wistar Rats ◽  
Mrna Level ◽  
Clinical Signs ◽  
Age Related Macular Degeneration ◽  
Oxys Rats ◽  
Related Factor ◽  
Mrna Levels ◽  
Aryl Hydrocarbon ◽  
Age Related

The mitochondria-targeted antioxidant SkQ1 is a novel drug thought to retard development of age-related diseases. It has been shown that SkQ1 reduces clinical signs of retinopathy in senescence-accelerated OXYS rats, which are a known animal model of human age-related macular degeneration (AMD). The aim of this work was to test whether SkQ1 affects transcriptional activity ofAhR(aryl hydrocarbon receptor) andNrf2(nuclear factor erythroid 2-related factor 2), which are considered as AMD-associated genes in the retina of OXYS and Wistar rats. Our results showed that onlyAhRandAhR-dependent genes were sensitive to SkQ1. Dietary supplementation with SkQ1 decreased theAhRmRNA level in both OXYS and Wistar rats. At baseline, the retinalCyp1a1mRNA level was lower in OXYS rats. SkQ1 supplementation decreased theCyp1a1mRNA level in Wistar rats, but this level remained unchanged in OXYS rats. BaselineCyp1a2andCyp1b1mRNA expression was stronger in OXYS than in Wistar rats. In the OXYS strain,Cyp1a2andCyp1b1mRNA levels decreased as a result of SkQ1 supplementation. These data suggest that the Cyp1a2 and Cyp1b1 enzymes are involved in the pathogenesis of AMD-like retinopathy of OXYS rats and are possible therapeutic targets of SkQ1.

Trilobatin Protects Cardiomyocytes from Hypoxia/ Reperfusion Injury by Regulating the Nuclear Factor Erythroid 2-Related Factor 2/Heme Oxygenase-1 Pathway

2020 ◽  
Vol 19 (2) ◽  
pp. 133-138
Author(s):  
Wenyu Chen ◽  
Hui He
Keyword(s):  
Heme Oxygenase ◽  
Molecular Mechanisms ◽  
Heme Oxygenase 1 ◽  
Related Factor ◽  
Cellular Injury ◽  
Nuclear Factor ◽  
Oxygen Species ◽  
H9c2 Cells ◽  
Natural Plant ◽  
Induced Changes

Trilobatin is a natural plant-derived glycosylated flavonoid that has been shown to exhibit multiple beneficial pharmacologic activities including protection of heart against H/R-induced cardiomyocyte injury. However, the molecular mechanisms underlying protection from H/R-induced cardiomyocyte injury remain unknown. Using H9C2 cells as a model, we examined the effect of trilobatin on H/R-induced cellular injury, apoptosis, and generation of reactive oxygen species. The results showed that trilobatin protected H9C2 cells not only from cell death and apoptosis, but also counteracted H/R-induced changes in malondialdehyde, superoxide dismutase, glutathione, and glutathione peroxidase. The evaluation of the mechanism underlying the effect of trilobatin on protection from H/R-induced cellular injury suggested changes in the regulation of nuclear factor erythroid 2-related factor 2/heme oxygenase-1 pathway.

HIF1A is Overexpressed in Medulloblastoma and its Inhibition Reduces Proliferation and Increases EPAS1 and ATG16L1 Methylation

2018 ◽  
Vol 18 (3) ◽  
pp. 287-294 ◽  
Author(s):  
Gustavo Alencastro Veiga Cruzeiro ◽  
Maristella Bergamo dos Reis ◽  
Vanessa Silva Silveira ◽  
Regia Caroline Peixoto Lira ◽  
Carlos Gilberto Carlotti Jr ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Cell Line ◽  
Cellular Proliferation ◽  
Mrna Level ◽  
Relevant Information ◽  
Protein Stabilization ◽  
Mrna Levels ◽  
Medulloblastoma Cell Line ◽  
Pediatric Medulloblastoma ◽  
Fresh Frozen

Background: Genetic and epigenetic modifications are closely related to tumor initiation and progression and can provide guidance for understanding tumor functioning, potentially leading to the discovery of new therapies. Studies have associated hypoxia-related genes to tumor progression and chemo/radioresistance in brain tumors. Information on the expression profile of hypoxiarelated genes in pediatric medulloblastoma, although scarce, may reveal relevant information that could support treatment decisions. Objective: Our study focused on evaluation the of CA9, CA12, HIF1A, EPAS1, SCL2A1 and VEGF genes in 41 pediatric fresh-frozen medulloblastoma sample. Additionally, we analyzed the effect of hypoxia and normoxia in the pediatric medulloblastoma cell-line UW402. Furthermore, we assessed the effects of HIF1A knockdown in cell-proliferation and methylation levels of genes related to hypoxia, apoptosis and autophagy. Method: qPCR was performed to evaluate mRNA levels, and Western blot to confirm HIF1A silencing in both patient samples and cell line. Pyrosequencing was performed to asses the methylation levels after HIF1A knockdown in the UW402 cell line. Results: A higher HIF1A mRNA level was observed in MB patients when compared to the cerebellum (non-tumor match). In UW402 MB cell-line, chemically induced hypoxic resulted in an increase of mRNA levels of HIF1A, VEGF, SCL2A1 and CA9 genes. Additionally, HIF1A knockdown induced a decrease in the expression of hypoxia related genes and a decrease of 30% in cell proliferation was also observed. Also, a significant increase in the methylation of ATG16L1 promoter and decrease in the methylation of EPAS1 promoter were observed after HIF1A knockdown. Conclusion: HIF1A knockdown in medulloblastoma cells lead to decreased cellular proliferation, suggesting that HIF1A can be a potential therapeutic target to be explored in the medulloblastoma. However, the mechanisms behind HIF1A protein stabilization and function are very complex and more data need to be generated to potentially use HIF1A as a therapeutical target.

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