المؤلفون: Matthew Dodson, Montserrat Rojo de la Vega, Deyu Fang, Donna D. Zhang, Eli Chapman, Boyun Shi, Pengfei Liu, Leyuan Liu, Fei Yue

المصدر: Hepatology

مصطلحات موضوعية: Liver Cirrhosis, 0301 basic medicine, NF-E2-Related Factor 2, Spermidine, Drug Evaluation, Preclinical, digestive system, environment and public health, Article, Proto-Oncogene Proteins c-myc, Mice, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, mental disorders, Autophagy, Hepatic Stellate Cells, Animals, Humans, Caloric restriction mimetic, Transcription factor, Kelch-Like ECH-Associated Protein 1, Hepatology, HEK 293 cells, respiratory system, KEAP1, Cell biology, HEK293 Cells, 030104 developmental biology, Liver, chemistry, Knockout mouse, 030211 gastroenterology & hepatology, Polyamine, Microtubule-Associated Proteins

الوصف: Spermidine (SPD), a naturally occurring polyamine, has been recognized as a caloric restriction mimetic that confers health benefits, presumably by inducing autophagy. Recent studies have reported that oral administration of SPD protects against liver fibrosis and hepatocarcinogenesis through activation of microtubule associated protein 1S (MAP1S)-mediated autophagy. Nuclear factor (erythroid-derived 2)-like 2 (NRF2) is a transcription factor that mediates cellular protection by maintaining the cell's redox, metabolic, and proteostatic balance. In this study, we demonstrate that SPD is a noncanonical NRF2 inducer, and that MAP1S is a component of this noncanonical pathway of NRF2 activation. Mechanistically, MAP1S induces NRF2 signaling through two parallel mechanisms, both resulting in NRF2 stabilization: (1) MAP1S competes with Kelch-like ECH-associated protein 1 (KEAP1) for NRF2 binding through an ETGE motif, and (2) MAP1S accelerates p62-dependent degradation of KEAP1 by the autophagy pathway. We further demonstrate that SPD confers liver protection by enhancing NRF2 signaling. The importance of both NRF2 and p62-dependent autophagy in SPD-mediated liver protection was confirmed using a carbon tetrachloride-induced liver fibrosis model in wild-type, Nrf2-/- , p62-/- and Nrf2-/- ;p62-/- mice, as the protective effect of SPD was significantly reduced in NRF2 or p62 single knockout mice, and completely abolished in the double knockout mice. Conclusion: Our results demonstrate the pivotal role of NRF2 in mediating the health benefit of SPD, particularly in the context of liver pathologies.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::51136a4199fdba7dc0fe9e99d88cd663Test
https://doi.org/10.1002/hep.30616Test

المؤلفون: Jessica Perer, Cody J. Schmidlin, Donna D. Zhang, Georg T. Wondrak, Montserrat Rojo de la Vega

المصدر: Redox Biology
Redox Biology, Vol 37, Iss, Pp 101714-(2020)

مصطلحات موضوعية: 0301 basic medicine, Keratinocytes, DNA damage, NF-E2-Related Factor 2, Clinical Biochemistry, Human skin, medicine.disease_cause, Biochemistry, environment and public health, NRF2, 03 medical and health sciences, chemistry.chemical_compound, Mice, 0302 clinical medicine, ROS, reactive oxygen species, medicine, GSH, glutathione, Animals, Humans, Viability assay, Radiosensitivity, lcsh:QH301-705.5, Skin, Cancer, Gene knockdown, lcsh:R5-920, Radiotherapy, Chemistry, Organic Chemistry, Radiation-Induced Dermatitis, Bixin, RT, radiation therapy, respiratory system, Radiation-induced dermatitis, NRF2, nuclear factor (erythroid-derived 2)-like 2, Oxidative Stress, 030104 developmental biology, lcsh:Biology (General), Cancer research, Quality of Life, IR, ionizing radiation, Radiodermatitis, lcsh:Medicine (General), 030217 neurology & neurosurgery, Oxidative stress, Research Paper

الوصف: Radiation therapy is a frontline treatment option for cancer patients; however, the effects of radiotherapy on non-tumor tissue (e.g. radiation-induced dermatitis) often worsen patient quality of life. Previous studies have implicated the importance of redox balance in preventing dermatitis, specifically in reference to modulation of the nuclear factor (erythroid-derived 2)-like 2 (NRF2) signaling pathway. Due to the cytoprotective functions of transcriptional target genes of NRF2, we investigated how modulation of NRF2 expression could affect DNA damage, oxidative stress, and cell viability in response to radiotherapy. Specifically, it was noted that NRF2 knockdown sensitized human skin keratinocytes to ionizing radiation; likewise, genetic ablation of NRF2 in vivo increased radiosensitivity of murine epidermis. Oppositely, pharmacological induction of NRF2 via the apocarotenoid bixin lowered markers of DNA damage and oxidative stress, while preserving viability in irradiated keratinocytes. Mechanistic studies indicated that topical pretreatment using bixin as an NRF2 activator antagonized initial DNA damage by raising cellular glutathione levels. Additionally, topical application of bixin prevented radiation-induced dermatitis, epidermal thickening, and oxidative stress in the skin of SKH1 mice. Overall, these data indicate that NRF2 is critical for mitigating the harmful skin toxicities associated with ionizing radiation, and that topical upregulation of NRF2 via bixin could prevent radiation-induced dermatitis.
Graphical abstract Topical application of bixin induces epidermal NRF2 signaling, preventing IR-induced DNA damage, oxidative stress, and cell death, all of which contribute to cutaneous radiation damage. Thus, induction of NRF2 via topical bixin application could represent a novel strategy for the prevention of radiation-induced dermatitis.Image 1
Highlights • The apocarotenoid bixin prevents IR-induced damage via the NRF2 signaling pathway. • Topical application of bixin prevents radiation-induced dermatitis in vivo. • NRF2 is a critical mediator of bixin protection against IR-induced cutaneous damage. • Glutathione upregulation contributes to bixin protection against IR-induced ROS and genotoxic stress.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::87a7c3b93554c8038b93ea9d4fef5480Test
http://europepmc.org/articles/PMC7494798Test

المؤلفون: Silvia D. Rodrigues, Donna D. Zhang, Eli Chapman, Pak Kin Wong, Bryan Harder, Matthew Dodson, Montserrat Rojo de la Vega, Raul Castro-Portuguez

المصدر: Toxicology and Applied Pharmacology. 341:106-113

مصطلحات موضوعية: 0301 basic medicine, Cell Survival, chemistry.chemical_element, Pharmacology, Biology, Toxicology, medicine.disease_cause, Article, Arsenic, Mice, 03 medical and health sciences, chemistry.chemical_compound, Autophagy, medicine, Animals, Humans, ARSENIC EXPOSURE, Arsenite, chemistry.chemical_classification, Reactive oxygen species, Oxidative Stress, HEK293 Cells, 030104 developmental biology, Proteostasis, chemistry, NIH 3T3 Cells, Unfolded protein response, Reactive Oxygen Species, Oxidative stress, HeLa Cells

الوصف: Prolonged exposure to arsenic has been shown to increase the risk of developing a number of diseases, including cancer and type II diabetes. Arsenic is present throughout the environment in its inorganic forms, and the level of exposure varies greatly by geographical location. The current recommended maximum level of arsenic exposure by the EPA is 10 µg/L, but levels >50 – 1000 µg/L have been detected in some parts of Asia, the Middle East, and the Southwestern United States. One of the most important steps in developing treatment options for arsenic-linked pathologies is to understand the cellular pathways affected by low levels of arsenic. Here, we show that acute exposure to non-lethal, low-level arsenite, an environmentally relevant arsenical, inhibits the autophagy pathway. Furthermore, arsenite-induced autophagy inhibition initiates a transient, but moderate ER stress response. Significantly, low-level arsenite exposure does not exhibit an increase in oxidative stress. These findings indicate that compromised autophagy, and not enhanced oxidative stress occurs early during arsenite exposure, and that restoring the autophagy pathway and proper proteostasis could be a viable option for treating arsenic-linked diseases. As such, our study challenges the existing paradigm that oxidative stress is the main underlying cause of pathologies associated with environmental arsenic exposure.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::f3d66c0d6a966e95250ce81ed40cd7c8Test
https://doi.org/10.1016/j.taap.2018.01.014Test

المؤلفون: Eli Chapman, Aikseng Ooi, Shasha Tao, Montserrat Rojo de la Vega, Donna D. Zhang

المصدر: Molecular Carcinogenesis. 57:182-192

مصطلحات موضوعية: Male, 0301 basic medicine, Cancer Research, Lung Neoplasms, Carcinogenesis, NF-E2-Related Factor 2, Apoptosis, Biology, medicine.disease_cause, Urethane, digestive system, environment and public health, Article, Proto-Oncogene Proteins p21(ras), Mice, 03 medical and health sciences, Isothiocyanates, medicine, Animals, Anticarcinogenic Agents, Lung cancer, Molecular Biology, Carcinogen, Cell Proliferation, Mutation, Cancer prevention, Quassins, Oncogene, Cancer, respiratory system, medicine.disease, Tumor Burden, Mice, Inbred C57BL, Oxidative Stress, 030104 developmental biology, Sulfoxides, Immunology, Disease Progression, Cancer research, KRAS, DNA Damage, Signal Transduction

الوصف: Targeting the transcription factor NRF2 has been recognized as a feasible strategy for cancer prevention and treatment, but many of the mechanistic details underlying its role in cancer development and progression are lacking. Therefore, careful mechanistic studies of the NRF2 pathway in cancer initiation and progression are needed to identify which therapeutic avenue—activation or inhibition—is appropriate in a given context. Moreover, while numerous reports confirm the protective effect of NRF2 activation against chemical carcinogenesis little is known of its role in cancer arising from spontaneous mutations. Here, we tested the effects of NRF2 modulation (activation by sulforaphane or inhibition by brusatol) in lung carcinogenesis using a chemical (vinyl carbamate) model in A/J mice and a genetic (conditional KrasG12D oncogene expression, to simulate spontaneous oncogene mutation) model in C57BL/6J mice. Mice were treated with NRF2 modulators before carcinogen exposure or KrasG12D expression to test the role of NRF2 in cancer initiation, or treated after tumor development to test the role of NRF2 in cancer progression. Lung tissues were analyzed to determine tumor burden, as well as status of NRF2 and KRAS pathways. Additionally, proliferation, apoptosis, and oxidative DNA damage were assessed. Overall, NRF2 activation prevents initiation of chemically induced cancer, but promotes progression of pre-existing tumors regardless of chemical or genetic etiology. Once tumors are initiated, NRF2 inhibition is effective against the progression of chemically and spontaneously induced tumors. These results have important implications for NRF2-targeted cancer prevention and intervention strategies.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::996b8b8d91426b14f449e2447aa31069Test
https://doi.org/10.1002/mc.22745Test

المؤلفون: Matthew Dodson, Eli Chapman, Montserrat Rojo de la Vega, Donna D. Zhang

المصدر: Current Opinion in Toxicology. 1:62-70

مصطلحات موضوعية: 0301 basic medicine, Activator (genetics), Autophagy, Regulator, Antioxidant response element, respiratory system, Pharmacology, Biology, Toxicology, medicine.disease_cause, Bioinformatics, digestive system, environment and public health, Article, 03 medical and health sciences, 030104 developmental biology, 0302 clinical medicine, 030220 oncology & carcinogenesis, Tissue damage, medicine, Disease prevention, Carcinogenesis, Transcription factor

الوصف: Pharmacological activation of the transcription factor nuclear factor-erythroid derived 2-like 2 (NRF2), the key regulator of the cellular antioxidant response, has been recognized as a feasible strategy to reduce oxidative/electrophilic stress and prevent carcinogenesis or other chronic illnesses, such as diabetes and chronic kidney disease. In contrast, due to the discovery of the “dark side” of NRF2, where prolonged activation of NRF2 causes tissue damage, cancer progression, or chemoresistance, efforts have been devoted to identify inhibitors. Currently, only one NRF2 activator has been approved for use in the clinic, while no specific NRF2 inhibitors have been discovered. Future development of NRF2-targeted therapeutics should be based on our current understanding of the regulatory mechanisms of this protein. In addition to the KEAP1-dependent mechanisms, the recent discovery of other pathways involved in the degradation of NRF2 have opened up new possibilities for the development of safe and specific therapeutics. Here, we review available and putative NRF2-targeted therapeutics and discuss their modes of action as well as their potential for disease prevention and treatment.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::15d07eb695f126e909d6c53a1dd82fa8Test
https://doi.org/10.1016/j.cotox.2016.10.005Test

المؤلفون: Aikseng Ooi, Joe G.N. Garcia, Joseph B Mascarenhas, Xiaoguang Sun, Pengfei Liu, Ting Wang, Michael J. Kerins, Saad Sammani, Matthew Dodson, Donna D. Zhang, Montserrat Rojo de la Vega

مصطلحات موضوعية: 0301 basic medicine, Transcriptional Activation, Transcription, Genetic, NF-E2-Related Factor 2, Lung injury, Response Elements, digestive system, environment and public health, Cell Line, 03 medical and health sciences, Mice, Transcription (biology), Cell Line, Tumor, Replication Protein A, Transcriptional regulation, Animals, Humans, Antioxidant Response Elements, Promoter Regions, Genetic, Gene, Psychological repression, Multidisciplinary, Genome, Chemistry, MYLK, respiratory system, Cell biology, DNA-Binding Proteins, Repressor Proteins, 030104 developmental biology, Proteostasis, PNAS Plus, A549 Cells

الوصف: NRF2 regulates cellular redox homeostasis, metabolic balance, and proteostasis by forming a dimer with small musculoaponeurotic fibrosarcoma proteins (sMAFs) and binding to antioxidant response elements (AREs) to activate target gene transcription. In contrast, NRF2-ARE-dependent transcriptional repression is unreported. Here, we describe NRF2-mediated gene repression via a specific seven-nucleotide sequence flanking the ARE, which we term the NRF2-replication protein A1 (RPA1) element (NRE). Mechanistically, RPA1 competes with sMAF for NRF2 binding, followed by interaction of NRF2-RPA1 with the ARE-NRE and eduction of promoter activity. Genome-wide in silico and RNA-seq analyses revealed this NRF2-RPA1-ARE-NRE complex mediates negative regulation of many genes with diverse functions, indicating that this mechanism is a fundamental cellular process. Notably, repression of MYLK, which encodes the nonmuscle myosin light chain kinase, by the NRF2-RPA1-ARE-NRE complex disrupts vascular integrity in preclinical inflammatory lung injury models, illustrating the translational significance of NRF2-mediated transcriptional repression. Our findings reveal a gene-suppressive function of NRF2 and a subset of negatively regulated NRF2 target genes, underscoring the broad impact of NRF2 in physiological and pathological settings.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::26a3bf237231693e180c2c5a0ab6e21fTest
https://europepmc.org/articles/PMC6217430Test/

المؤلفون: Christine Gross, R. Clark Lantz, Heidi M. Mansour, Stephen M. Black, Ting Wang, Donna D. Zhang, Eli Chapman, Matthew Dodson, Joe G.N. Garcia, Montserrat Rojo de la Vega

المصدر: Current Pharmacology Reports. 2:91-101

مصطلحات موضوعية: 0301 basic medicine, ARDS, Inflammation, Lung injury, medicine.disease_cause, Biochemistry, Article, 03 medical and health sciences, Drug Discovery, Genetics, medicine, Pharmacology, Lung, business.industry, Autophagy, respiratory system, medicine.disease, Molecular medicine, respiratory tract diseases, 3. Good health, 030104 developmental biology, medicine.anatomical_structure, Respiratory failure, Immunology, medicine.symptom, business, Oxidative stress

الوصف: Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are the clinical manifestations of severe lung damage and respiratory failure. Characterized by severe inflammation and compromised lung function, ALI/ARDS result in very high mortality of affected individuals. Currently, there are no effective treatments for ALI/ARDS, and ironically, therapies intended to aid patients (specifically mechanical ventilation, MV) may aggravate the symptoms. Key events contributing to the development of ALI/ARDS are: increased oxidative and proteotoxic stresses, unresolved inflammation, and compromised alveolar-capillary barrier function. Since the airways and lung tissues are constantly exposed to gaseous oxygen and airborne toxicants, the bronchial and alveolar epithelial cells are under higher oxidative stress than other tissues. Cellular protection against oxidative stress and xenobiotics is mainly conferred by Nrf2, a transcription factor that promotes the expression of genes that regulate oxidative stress, xenobiotic metabolism and excretion, inflammation, apoptosis, autophagy, and cellular bioenergetics. Numerous studies have demonstrated the importance of Nrf2 activation in the protection against ALI/ARDS, as pharmacological activation of Nrf2 prevents the occurrence or mitigates the severity of ALI/ARDS. Another promising new therapeutic strategy in the prevention and treatment of ALI/ARDS is the activation of autophagy, a bulk protein and organelle degradation pathway. In this review, we will discuss the strategy of concerted activation of Nrf2 and autophagy as a preventive and therapeutic intervention to ameliorate ALI/ARDS.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::421f95b4f737e329e584be09751bca3aTest
https://doi.org/10.1007/s40495-016-0053-2Test

المؤلفون: Pak Kin Wong, Montserrat Rojo de la Vega, Andrew J. Ambrose, Gang Luo, Matthew Dodson, Eli Chapman, Tao Jiang, Pengfei Liu, Donna D. Zhang, Aram B. Cholanians

مصطلحات موضوعية: 0301 basic medicine, inorganic chemicals, Vesicle fusion, chemistry.chemical_element, Biology, Membrane Fusion, Arsenic, 03 medical and health sciences, Mice, Phagosomes, Autophagy, Animals, Humans, Qc-SNARE Proteins, Molecular Biology, Phagosome, integumentary system, Cell Biology, Transfection, Environmental exposure, Qb-SNARE Proteins, Cell biology, 030104 developmental biology, Proteostasis, chemistry, NIH 3T3 Cells, SNARE complex, Lysosomes, Research Article, HeLa Cells, Protein Binding

الوصف: Environmental exposure to arsenic is linked to adverse health effects, including cancer and diabetes. Pleiotropic cellular effects are observed with arsenic exposure. Previously, we demonstrated that arsenic dysregulated the autophagy pathway at low, environmentally relevant concentrations. Here we show that arsenic blocks autophagy by preventing autophagosome-lysosome fusion. Specifically, arsenic disrupts formation of the STX17-SNAP29-VAMP8 SNARE complex, where SNAP29 mediates vesicle fusion through bridging STX17-containing autophagosomes to VAMP8-bearing lysosomes. Mechanistically, arsenic inhibits SNARE complex formation, at least in part, by enhancing O-GlcNAcylation of SNAP29. Transfection of O-GlcNAcylation-defective, but not wild-type, SNAP29 into clustered regularly interspaced short palindromic repeat (CRISPR)-mediated SNAP29 knockout cells abolishes arsenic-mediated autophagy inhibition. These findings reveal a mechanism by which low levels of arsenic perturb proteostasis through inhibition of SNARE complex formation, providing a possible therapeutic target for disease intervention in the more than 200 million people exposed to unsafe levels of arsenic.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::6214e163f91d21df80c3b1db4f46d99fTest
https://europepmc.org/articles/PMC5954189Test/

المؤلفون: Donna D. Zhang, Montserrat Rojo de la Vega

المصدر: Cellular and Molecular Gastroenterology and Hepatology
Cellular and Molecular Gastroenterology and Hepatology, Vol 5, Iss 3, Pp 422-423 (2018)

مصطلحات موضوعية: 0301 basic medicine, Hepatology, business.industry, Computer science, Gastroenterology, Data science, 03 medical and health sciences, 030104 developmental biology, 0302 clinical medicine, Text mining, Editorial, 030220 oncology & carcinogenesis, lcsh:Diseases of the digestive system. Gastroenterology, lcsh:RC799-869, business

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::afd097607066865f1959a88732d00ec0Test
https://pubmed.ncbi.nlm.nih.gov/29675456Test

المؤلفون: Montserrat Rojo de la Vega, Donna D. Zhang, Georg T. Wondrak

المصدر: Frontiers in Pharmacology
Frontiers in Pharmacology, Vol 9 (2018)

مصطلحات موضوعية: 0301 basic medicine, Premature aging, bixin, Human skin, Pharmacology, digestive system, environment and public health, PUVA, NRF2, sunburn, 03 medical and health sciences, chemistry.chemical_compound, skin oxidative stress, medicine, Pharmacology (medical), Sunburn, Psoralen, Original Research, integumentary system, lcsh:RM1-950, Bixin, photodamage, Environmental exposure, respiratory system, medicine.disease, UV, 3. Good health, lcsh:Therapeutics. Pharmacology, 030104 developmental biology, chemistry, Photoprotection, hair graying, Skin cancer

الوصف: Environmental exposure to solar ultraviolet (UV) radiation causes acute photodamage, premature aging, and skin cancer, attributable to UV-induced genotoxic, oxidative, and inflammatory stress. The transcription factor NRF2 [nuclear factor erythroid 2 (E2)-related factor 2] is the master regulator of the cellular antioxidant response protecting skin against various environmental stressors including UV radiation and electrophilic pollutants. NRF2 in epidermal keratinocytes can be activated using natural chemopreventive compounds such as the apocarotenoid bixin, an FDA-approved food additive and cosmetic ingredient from the seeds of the achiote tree (Bixa orellana). Here, we tested the feasibility of topical use of bixin for NRF2-dependent skin photoprotection in two genetically modified mouse models [SKH1 and C57BL/6J (Nrf2+/+ versus Nrf2-/- )]. First, we observed that a bixin formulation optimized for topical NRF2 activation suppresses acute UV-induced photodamage in Nrf2+/+ but not Nrf2-/- SKH1 mice, a photoprotective effect indicated by reduced epidermal hyperproliferation and oxidative DNA damage. Secondly, it was demonstrated that topical bixin suppresses PUVA (psoralen + UVA)-induced hair graying in Nrf2+/+ but not Nrf2-/- C57BL/6J mice. Collectively, this research provides the first in vivo evidence that topical application of bixin can protect against UV-induced photodamage and PUVA-induced loss of hair pigmentation through NRF2 activation. Topical NRF2 activation using bixin may represent a novel strategy for human skin photoprotection, potentially complementing conventional sunscreen-based approaches.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::2fd4fbcd633d17b158f654be28a59acfTest
https://doi.org/10.3389/fphar.2018.00287Test