المؤلفون: Kit-Kay Mak, Zhang Shiming, Raghavendra Sakirolla, Madhu Katyayani Balijepalli, Albena T. Dinkova-Kostova, Ola Epemolu, Zulkefeli Mohd, Mallikarjuna Rao Pichika

المصدر: Antioxidants
Volume 12
Issue 2
Pages: 475

مصطلحات موضوعية: microsomal stability, thiophene derivatives, Physiology, Clinical Biochemistry, 6-shogaol, Cell Biology, molecular docking, Zingiber officinale, anti-inflammatory activity, Molecular Biology, Biochemistry, NRF2

الوصف: 6-shogaol is a natural and the most potent bioactive vanilloid in dried Zingiber officinale rhizomes. Many scientific studies have reported the diverse biological activities of 6-shogaol. However, the major drawback of 6-shogaol is its instability at room temperature. We synthesised new shogaol thiophene compounds (STCs) by replacing the pentyl group in the sidechain with thiophene derivatives. The STCs were tested for their nuclear factor erythroid 2-related factor 2 (NRF2) activation ability in murine hepatoma cells (Hepa1c1c-7) by determining their NAD(P)H quinone oxidoreductase 1 (NQO1) inducing ability and expression of NRF2-associated antioxidant genes. The anti-inflammatory activity of STCs was determined in Escherichia coli lipopolysaccharide (LPSEc)-stimulated NR2-proficient and -silenced mouse microglial cells (BV-2) by measuring the inflammatory markers, cytokines, and mediators. The modes of action (interacting with the Kelch domain of KEAP1, covalent bonding with cysteines of KEAP1, and inhibition of GSK-3b enzyme activity) of NRF2 activation by STCs were determined using commercially available kits. The in vitro metabolic stability of the STCs in liver microsomes (humans, rats, and mice) was also investigated. The molecular docking and molecular dynamics studies were conducted to identify the binding poses, stability, and molecular interactions of the STCs in the binding pockets of Kelch and BTB domains of KEAP1 and GSK-3b enzyme. The new STCs were synthesised in good yields of > 85%, with a purity of about 95%, using a novel synthesis method by employing a reusable proline–proline dipeptide catalyst. The STCs are more potent than 6-shogaol in activating NRF2 and reducing inflammation. The nature of substituents on thiophene has a profound influence on the bioactivity of the STCs. Phenylthiophene STC (STC5) is the most potent, while thiophenes containing electron-withdrawing groups showed weaker bioactivity. The bioactivity of 6-shogaol is in the micromolar range, whereas STC5 showed bioactivity in the sub micromolar range. The STCs showed anti-inflammatory effects via NRF2-dependent and NRF2-independent mechanisms. The STCs improved NRF2 activity through multiple (KEAP1-independent and -dependent) mechanisms. The STCs showed decreased reactivity with thiols than 6-shogaol and thus may possess fewer side-effects than 6-shogaol. The STCs were more metabolically stable than 6-shogaol.

وصف الملف: application/pdf

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::a845b98aabbada65bcf0f1f67d9cc980Test

المؤلفون: Noemí Esteras, Thomas S. Blacker, Evgeny A. Zherebtsov, Olga A. Stelmashuk, Ying Zhang, W. Christian Wigley, Michael R. Duchen, Albena T. Dinkova-Kostova, Andrey Y. Abramov

المصدر: Redox Biology. 62:102672

مصطلحات موضوعية: Organic Chemistry, Clinical Biochemistry, Biochemistry

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_________::4827d1fdf2f8ef3dc58db730e456e3b8Test
https://doi.org/10.1016/j.redox.2023.102672Test

المؤلفون: Laura Casares, Rita Moreno, Kevin X. Ali, Maureen Higgins, Sharadha Dayalan Naidu, Graham Neill, Lena Cassin, Anders E. Kiib, Esben B. Svenningsen, Alberto Minassi, Tadashi Honda, Thomas B. Poulsen, Clotilde Wiel, Volkan I. Sayin, Albena T. Dinkova-Kostova, David Olagnier, Laureano de la Vega

المصدر: Casares, L, Moreno, R, Ali, K X, Higgins, M, Dayalan Naidu, S, Neill, G, Cassin, L, Kiib, A E, Svenningsen, E B, Minassi, A, Honda, T, Poulsen, T B, Wiel, C, Sayin, V I, Dinkova-Kostova, A T, Olagnier, D & de la Vega, L 2022, ' The synthetic triterpenoids CDDO-TFEA and CDDO-Me, but not CDDO, promote nuclear exclusion of BACH1 impairing its activity ', Redox Biology, vol. 51, 102291 . https://doi.org/10.1016/j.redox.2022.102291Test
Casares, L, Moreno, R, Ali, K X, Higgins, M, Dayalan Naidu, S, Neill, G, Cassin, L, Kiib, A E, Svenningsen, E B, Minassi, A, Honda, T, Poulsen, T B, Wiel, C, Sayin, V I, Dinkova-Kostova, A T, Olagnier, D & de la Vega, L 2022, ' The synthetic triterpenoids CDDO-TFEA and CDDO-Me, but not CDDO, promote nuclear exclusion of BACH1 impairing its activity ', Redox Biology, vol. 51, pp. 102291 . https://doi.org/10.1016/j.redox.2022.102291Test

مصطلحات موضوعية: Oxidative Stress, Kelch-Like ECH-Associated Protein 1, HMOX1, NF-E2-Related Factor 2, CDDO, Organic Chemistry, Clinical Biochemistry, BACH1, Oleanolic Acid, Biochemistry, Triterpenes, NRF2

الوصف: The transcription factor BACH1 is a potential therapeutic target for a variety of chronic conditions linked to oxidative stress and inflammation, as well as cancer metastasis. However, only a few BACH1 degraders/inhibitors have been described. BACH1 is a transcriptional repressor of heme oxygenase 1 (HMOX1), which is positively regulated by transcription factor NRF2 and is highly inducible by derivatives of the synthetic oleanane triterpenoid 2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oic acid (CDDO). Most of the therapeutic activities of these compounds are due to their anti-inflammatory and antioxidant properties, which are widely attributed to their ability to activate NRF2. However, with such a broad range of action, these compounds have other molecular targets that have not been fully identified and could also be of importance for their therapeutic profile. Herein we identified BACH1 as a target of two CDDO-derivatives (CDDO-Me and CDDO-TFEA), but not of CDDO. While both CDDO and CDDO-derivatives activate NRF2 similarly, only CDDO-Me and CDDO-TFEA inhibit BACH1, which explains the much higher potency of these CDDO-derivatives as HMOX1 inducers compared with unmodified CDDO. Notably, we demonstrate that CDDO-Me and CDDO-TFEA inhibit BACH1 via a novel mechanism that reduces BACH1 nuclear levels while accumulating its cytoplasmic form. In an in vitro model, both CDDO-derivatives impaired lung cancer cell invasion in a BACH1-dependent and NRF2-independent manner, while CDDO was inactive. Altogether, our study identifies CDDO-Me and CDDO-TFEA as dual KEAP1/BACH1 inhibitors, providing a rationale for further therapeutic uses of these drugs.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::155dea4f5960ffcc085d9f8477eae799Test
https://pure.au.dk/portal/da/publications/the-synthetic-triterpenoids-cddotfea-and-cddome-but-not-cddo-promote-nuclear-exclusion-of-bach1-impairing-its-activityTest(66402709-7e58-4b88-af6c-815f1189769a).html

المؤلفون: Kit-Kay Mak, Shiming Zhang, Jestin Chellian, Zulkefeli Mohd, Ola Epemolu, Albena T. Dinkova-Kostova, Madhu Katyayani Balijepalli, Mallikarjuna Rao Pichika

المصدر: Antioxidants
Volume 12
Issue 3
Pages: 595

مصطلحات موضوعية: swietenine, swietenia macrophylla, diabetes, Physiology, NAFLD, Clinical Biochemistry, oxidative stress, Cell Biology, Molecular Biology, Biochemistry, lipogenesis, NRF2

الوصف: Our previous studies have reported the effect of swietenine (a major bioactive component of Swietenia macrophylla seeds) in reversing and potentiating the effect of metformin in hyperglycemia and hyperlipidaemia in diabetic rats. Moreover, we reported that the anti-inflammatory effect of swietenine is mediated via the activation of nuclear factor erythroid 2-related factor 2 (Nrf2). This study evaluated the effect of swietenine and its mechanisms in nonalcoholic fatty liver disease (NAFLD) in high-fat diet/streptozotocin-induced diabetic mice. The effect was assessed by determining blood biochemical parameters (glucose, cholesterol, triglycerides, alanine transaminase (ALT), asparate transaminase (AST), alkaline phosphatase (ALP), glutathione (GSH), total antioxidant capacity (TAC), and malondialdehyde (MDA)) and liver biochemical parameters (liver index, cholesterol, and triglycerides). Hepatic lipid accumulation (initial causative factor in NAFLD) was determined by oil-O-red staining. Gene expression (qPCR) and immunohistochemical studies were performed to elucidate the mechanism of swietenine’s effect in NAFLD. The critical regulators (genes and proteins) involved in lipogenesis (ACLY, ACC1, FASN, SREBP1c, and ChREBPβ) and oxidative stress (Nrf2, NQO-1 and HO-1) pathways were determined. In mice fed with a high-fat diet followed by streptozotocin injection, the liver cholesterol, triglycerides, and lipids were elevated. These increases were reversed by the oral administration of swietenine, 80 mg/kg body weight, on alternate days for eight weeks. Gene expression and immunohistochemical studies showed that swietenine reversed the elevated levels of crucial enzymes of lipogenesis (ACLY, ACC1 and FASN) and their master transcription factors (SREBP1c and ChREBPβ). Furthermore, swietenine activated the Nrf2 antioxidant defense mechanism, as evidenced by the upregulated levels of Nrf2, NQO-1, and HO-1. It is concluded that swietenine shows beneficial effects in diabetes-induced NAFLD via inhibiting lipogenesis and activating the Nrf2 pathway.

وصف الملف: application/pdf

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::0f61260d3697a1f66b61bbfcca0973cfTest
https://doi.org/10.3390/antiox12030595Test

المؤلفون: Ying Zhang, Elena V. Knatko, Maureen Higgins, Sharadha Dayalan Naidu, Gillian Smith, Tadashi Honda, Laureano de la Vega, Albena T. Dinkova-Kostova

المصدر: Antioxidants; Volume 11; Issue 2; Pages: 262

مصطلحات موضوعية: Physiology, Clinical Biochemistry, Cell Biology, respiratory system, AKR1B10, AKR1C1, colorectal cancer, DLD1, Nrf2, NQO1, pirin, Molecular Biology, Biochemistry

الوصف: The evolutionary conserved non-heme Fe-containing protein pirin has been implicated as an important factor in cell proliferation, migration, invasion, and tumour progression of melanoma, breast, lung, cervical, prostate, and oral cancers. Here we found that pirin is overexpressed in human colorectal cancer in comparison with matched normal tissue. The overexpression of pirin correlates with activation of transcription factor nuclear factor erythroid 2 p45-related factor 2 (Nrf2) and increased expression of the classical Nrf2 target NAD(P)H:quinone oxidoreductase 1 (NQO1), but interestingly and unexpectedly, not with expression of the aldo-keto reductase (AKR) family members AKR1B10 and AKR1C1, which are considered to be the most overexpressed genes in response to Nrf2 activation in humans. Using pharmacologic and genetic approaches to either downregulate or upregulate Nrf2, we show that pirin is regulated by Nrf2 in human and mouse cells and in the mouse colon in vivo. The small molecule pirin inhibitor TPhA decreased the viability of human colorectal cancer (DLD1) cells, but this decrease was independent of the levels of pirin. Our study demonstrates the Nrf2-dependent regulation of pirin and encourages the pursuit for specific pirin inhibitors.

وصف الملف: application/pdf

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::dc19d47633338eeb5e59a8ad51f1bd81Test

المؤلفون: Mai H. Mekkawy, Albena T. Dinkova-Kostova, Mostafa M. Ghorab, Heba M. Karam, Aiten M. Soliman, Maureen Higgins

المصدر: Bioorganicmedicinal chemistry letters. 42

مصطلحات موضوعية: Antioxidant, Halogenation, NF-E2-Related Factor 2, medicine.medical_treatment, Clinical Biochemistry, Pharmaceutical Science, medicine.disease_cause, 01 natural sciences, Biochemistry, Median lethal dose, Antioxidants, chemistry.chemical_compound, Structure-Activity Relationship, In vivo, Drug Discovery, medicine, Humans, Molecular Biology, Quinazolinones, chemistry.chemical_classification, Reactive oxygen species, Sulfonamides, Dose-Response Relationship, Drug, Molecular Structure, 010405 organic chemistry, Chemistry, Organic Chemistry, Malondialdehyde, KEAP1, Molecular biology, 0104 chemical sciences, 010404 medicinal & biomolecular chemistry, Oxidative Stress, Molecular Medicine, Oxidative stress, Acetamide

الوصف: Reactive oxygen species (ROS) play an integral role in the pathogenesis of most diseases. This work presents the design and synthesis of fourteen new diiodoquinazolinone derivatives bearing benzenesulfonamide moiety with variable acetamide tail and evaluation of their ability to activate nuclear factor erythroid 2-related factor 2 (Nrf2) using its classical target NAD(P)H: quinone oxidoreductase 1 (NQO1) in Hepa1c1c7 murine hepatoma cells. The N-(2-chloropyridin-3-yl)-2-((6,8-diiodo-4-oxo-3-(4-sulfamoylphenyl)-3,4-dihydroquinazolin-2-yl)thio) acetamide 17 was the most potent NQO1 inducer (CD = 25 µM) with free radical scavenging activity (IC50 = 28 µM) and in vivo median lethal dose (LD50) of 500 mg/Kg. The possible radioprotective activity of compound 17 was evaluated in (7 Gy) irradiated mice. Compound 17 showed a reduction in radiation induced oxidative stress as evidenced by the lower levels of ROS, malondialdehyde (MDA) and NQO1 in liver tissues. Moreover, compound 17 showed improvement in the complete blood count (CBC) of irradiated mice and decreased mortality over 30 days following irradiation. Additionally, docking studies inside the Nrf2-binding site of Kelch-like ECH associated protein 1 (Keap1), the main negative regulator of Nrf2, confirmed that 17 revealed the same interactions with the key amino acids as those of the co-crystallized ligand. This study identifies 17 as a novel antioxidant that protects against the harmful effect of radiation.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::7a02466f1c4857fb78d12859b05326d5Test
https://pubmed.ncbi.nlm.nih.gov/33811990Test

المؤلفون: Eduardo Muñoz, Albena T. Dinkova-Kostova, María E. Prados, Giovanni Apendino, Laura Casares, Juan D. Unciti-Broceta, Maureen Higgins, Laureano de la Vega, Diego Caprioglio, Daiana Mattoteia

المصدر: Redox Biology
Redox Biology, Vol 37, Iss, Pp 101689-(2020)

مصطلحات موضوعية: Antioxidant, NF-E2-Related Factor 2, medicine.medical_treatment, Short Communication, Clinical Biochemistry, Inflammation, Pharmacology, medicine.disease_cause, Biochemistry, Neuroprotection, environment and public health, digestive system, Antioxidants, Cannabidiol derivative/ NRF2/ BACH1/ HMOX1/ neurodegenerative diseases, Cell Line, Mice, In vivo, medicine, Animals, lcsh:QH301-705.5, lcsh:R5-920, Chemistry, Multiple sclerosis, Organic Chemistry, Nrf2 activators, Neurodegenerative Diseases, respiratory system, medicine.disease, Disease Models, Animal, Oxidative Stress, Basic-Leucine Zipper Transcription Factors, lcsh:Biology (General), medicine.symptom, lcsh:Medicine (General), Cannabidiol, Oxidative stress, medicine.drug

الوصف: Oxidative stress and inflammation in the brain are two key hallmarks of neurodegenerative diseases (NDs) such as Alzheimer's, Parkinson's, Huntington's and multiple sclerosis. The axis NRF2-BACH1 has anti-inflammatory and anti-oxidant properties that could be exploited pharmacologically to obtain neuroprotective effects. Activation of NRF2 or inhibition of BACH1 are, individually, promising therapeutic approaches for NDs. Compounds with dual activity as NRF2 activators and BACH1 inhibitors, could therefore potentially provide a more robust antioxidant and anti-inflammatory effects, with an overall better neuroprotective outcome. The phytocannabinoid cannabidiol (CBD) inhibits BACH1 but lacks significant NRF2 activating properties. Based on this scaffold, we have developed a novel CBD derivative that is highly effective at both inhibiting BACH1 and activating NRF2. This new CBD derivative provides neuroprotection in cell models of relevance to Huntington's disease, setting the basis for further developments in vivo.

وصف الملف: application/pdf

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::8de4a453fd64e589b62478d05efde73bTest
https://pubmed.ncbi.nlm.nih.gov/32863231Test

المؤلفون: Suqing Zheng, René V. Bensasson, Albena T. Dinkova-Kostova, Wei Li, Akira Saito, Vincent Zoete, Tadashi Honda

المصدر: Bioorganic & Medicinal Chemistry Letters. 26:4345-4349

مصطلحات موضوعية: 0301 basic medicine, Stereochemistry, Clinical Biochemistry, Pharmaceutical Science, Electrons, Alkenes, 01 natural sciences, Biochemistry, Mice, 03 medical and health sciences, Cell Line, Tumor, Nitriles, Drug Discovery, NAD(P)H Dehydrogenase (Quinone), Animals, Potency, Reactivity (chemistry), Sulfhydryl Compounds, Enzyme inducer, Molecular Biology, HOMO/LUMO, chemistry.chemical_classification, Kelch-Like ECH-Associated Protein 1, Molecular Structure, biology, Bicyclic molecule, 010405 organic chemistry, Chemistry, Organic Chemistry, Ketones, 0104 chemical sciences, 030104 developmental biology, Enzyme, Electron affinity (data page), Cyclization, Cytoprotection, Enzyme Induction, biology.protein, Quantum Theory, Molecular Medicine, Signal Transduction

الوصف: Tricyclic, bicyclic, and monocyclic compounds containing cyanoenones induce various anti-inflammatory and cytoprotective enzymes through activation of the Keap1/Nrf2/ARE (antioxidant response element) pathway. The potency of these compounds as Nrf2 activators was determined using a prototypic cytoprotective enzyme NAD(P)H:quinone oxidoreductase 1 (NQO1) in Hepa1c1c7 murine hepatoma cells. The electron affinity (EA) of the compounds, expressed as the energy of their lowest unoccupied molecular orbital [E (LUMO)], was evaluated using two types of quantum mechanical calculations: the semiempirical (AM1) and the density functional theory (DFT) methods. We observed striking linear correlations [r = 0.897 (AM1) and 0.936 (DFT)] between NQO1 inducer potency of these compounds and their E (LUMO) regardless of the molecule size. Importantly and interestingly, this finding demonstrates that the EA is the essentially important factor that determines the reactivity of the cyanoenones with Keap1.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::3b72f814fedbc5f4e00f65a00584375eTest
https://doi.org/10.1016/j.bmcl.2016.07.028Test

المؤلفون: Albena T. Dinkova-Kostova, Noemí Esteras, Andrey Y. Abramov

المصدر: Biological Chemistry. 397:383-400

مصطلحات موضوعية: 0301 basic medicine, NF-E2-Related Factor 2, Clinical Biochemistry, Biology, Mitochondrion, medicine.disease_cause, Biochemistry, Glycogen Synthase Kinase 3, 03 medical and health sciences, GSK-3, medicine, Animals, Humans, Amyotrophic lateral sclerosis, Molecular Biology, Transcription factor, Neurodegeneration, Brain, Membrane Transport Proteins, Neurodegenerative Diseases, Lipid Metabolism, medicine.disease, KEAP1, Mitochondria, Cell biology, 030104 developmental biology, DNAJA3, Energy Metabolism, Oxidative stress

الوصف: The nuclear factor erythroid-derived 2 (NF-E2)-related factor 2 (Nrf2) is a transcription factor well-known for its function in controlling the basal and inducible expression of a variety of antioxidant and detoxifying enzymes. As part of its cytoprotective activity, increasing evidence supports its role in metabolism and mitochondrial bioenergetics and function. Neurodegenerative diseases are excellent candidates for Nrf2-targeted treatments. Most neurodegenerative conditions such as Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis, frontotemporal dementia and Friedreich’s ataxia are characterized by oxidative stress, misfolded protein aggregates, and chronic inflammation, the common targets of Nrf2 therapeutic strategies. Together with them, mitochondrial dysfunction is implicated in the pathogenesis of most neurodegenerative disorders. The recently recognized ability of Nrf2 to regulate intermediary metabolism and mitochondrial function makes Nrf2 activation an attractive and comprehensive strategy for the treatment of neurodegenerative disorders. This review aims to focus on the potential therapeutic role of Nrf2 activation in neurodegeneration, with special emphasis on mitochondrial bioenergetics and function, metabolism and the role of transporters, all of which collectively contribute to the cytoprotective activity of this transcription factor.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::82b203cc5d84e06233220baa32b16a02Test
https://doi.org/10.1515/hsz-2015-0295Test

المؤلفون: Albena T. Dinkova-Kostova, Sudhir Chowdhry, Michael McMahon, John D. Hayes

المصدر: Antioxidants & Redox Signaling. 13:1713-1748

مصطلحات موضوعية: NF-E2-Related Factor 2, Physiology, Clinical Biochemistry, Vesicular Transport Proteins, Biology, Response Elements, medicine.disease_cause, environment and public health, Biochemistry, Antioxidants, Ubiquitin, Neoplasms, Maf Transcription Factors, medicine, Anticarcinogenic Agents, Humans, Molecular Biology, Gene, Transcription factor, Adaptor Proteins, Signal Transducing, Cell Proliferation, General Environmental Science, Kelch-Like ECH-Associated Protein 1, Intracellular Signaling Peptides and Proteins, Signal transducing adaptor protein, Cell Biology, Cullin Proteins, KEAP1, Regulatory sequence, Trans-Activators, biology.protein, General Earth and Planetary Sciences, Carrier Proteins, Carcinogenesis, Signal Transduction, Transcription Factors

الوصف: The cap'n'collar (CNC) bZIP transcription factor Nrf2 controls expression of genes for antioxidant enzymes, metal-binding proteins, drug-metabolising enzymes, drug transporters, and molecular chaperones. Many chemicals that protect against carcinogenesis induce Nrf2-target genes. These compounds are all thiol-reactive and stimulate an adaptive response to redox stress in cells. Such agents induce the expression of genes that posses an antioxidant response element (ARE) in their regulatory regions. Under normal homeostatic conditions, Nrf2 activity is restricted through a Keap1-dependent ubiquitylation by Cul3-Rbx1, which targets the CNC-bZIP transcription factor for proteasomal degradation. However, as the substrate adaptor function of Keap1 is redox-sensitive, Nrf2 protein evades ubiquitylation by Cul3-Rbx1 when cells are treated with chemopreventive agents. As a consequence, Nrf2 accumulates in the nucleus where it heterodimerizes with small Maf proteins and transactivates genes regulated through an ARE. In this review, we describe synthetic compounds and phytochemicals from edible plants that induce Nrf2-target genes. We also discuss evidence for the existence of different classes of ARE (a 16-bp 5'-TMAnnRTGABnnnGCR-3' versus an 11-bp 5'-RTGABnnnGCR-3', with or without the embedded activator protein 1-binding site 5'-TGASTCA-3'), species differences in the ARE-gene battery, and the identity of critical Cys residues in Keap1 required for de-repression of Nrf2 by chemopreventive agents.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::3105d8745b9c25143471f4cfab538b09Test
https://doi.org/10.1089/ars.2010.3221Test