A5020432333- Genomics, phytochemicals, and oxidative stress
- Glutathione Transferases and Polymorphisms
- Coenzyme Q10 studies and effects
- Heme Oxygenase-1 and Carbon Monoxide
- Autophagy in Disease and Therapy
- Heat shock proteins research
- Endoplasmic Reticulum Stress and Disease
- Aldose Reductase and Taurine
- RNA Research and Splicing
- Moringa oleifera research and applications
- Cell Adhesion Molecules Research
- Immune Cell Function and Interaction
- Genetic Neurodegenerative Diseases
- Biochemical Acid Research Studies
- Muscle Physiology and Disorders
- Synthesis and Biological Evaluation
- Free Radicals and Antioxidants
- Sirtuins and Resveratrol in Medicine
- Cannabis and Cannabinoid Research
- Social and Behavioral Studies
- Immune cells in cancer
- Lipid metabolism and biosynthesis
- Plant Stress Responses and Tolerance
- Peroxisome Proliferator-Activated Receptors
- FOXO transcription factor regulation
Ninewells Hospital
2021-2025
University of Dundee
2014-2025
Johns Hopkins Medicine
2018-2020
Johns Hopkins University
1990-2020
Significance Chronic neuroinflammation and oxidative stress are likely complicit in driving disease progression Huntington's (HD). Here, we describe the mechanism of action a unique chemical scaffold that is highly selective for activation NRF2, master transcriptional regulator cellular antiinflammatory antioxidant defense genes. The use this revealed NRF2 responses were muted HD patient-derived neural stem cells, suggesting increased susceptibility critical renewable cell population to...
Hippocampal sclerosis is a common acquired disease that major cause of drug-resistant epilepsy. A mechanism has been proposed to lead from brain insult hippocampal the excessive generation reactive oxygen species, and consequent mitochondrial failure. Here we use novel strategy increase endogenous antioxidant defences using RTA 408, which show activates nuclear factor erythroid 2-related 2 (Nrf2, encoded by NFE2L2) through inhibition kelch like ECH associated protein 1 (KEAP1) its primary...
STRUCTURE: Omaveloxolone {N-[(4aS,6aR,6bS,8aR,12aS,14aR,14bS)-11-cyano-2,2,6a,6b, 9,9,12a-heptamethyl-10,14-dioxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,12a,14,14a,14b-octa-decahydropicen-4a-yl]-2,2-difluoropropanamide} is a semisynthetic triterpenoid based on the natural product oleanolic acid. It contains highly reactive cyanoenone functionality, which binds covalently and reversibly by Michael addition to cysteines in proteins, such as cysteine-based sensor protein Kelch-like ECH-associated 1...
Numerous small molecules (termed inducers), many of which are electrophiles, upregulate cytoprotective responses and inhibit pro-inflammatory pathways by activating nuclear factor-erythroid 2 p45-related factor (NRF2). Key to NRF2 activation is the ability chemically modifying critical sensor cysteines in main negative regulator NRF2, Kelch-like ECH-associated protein 1 (KEAP1), C151, C273 C288 best characterized. This study aimed establish requirement for these cysteine sensor(s) biological...
Heat shock factor 1 (HSF1) monitors the structural integrity of proteome. Phosphorylation at S326 is a hallmark for HSF1 activation, but identity kinase(s) phosphorylating this site has remained elusive. We show here that dietary agent phenethyl isothiocyanate (PEITC) inhibits heat protein 90 (Hsp90), main negative regulator HSF1; activates p38 mitogen-activated kinase (MAPK); and increases phosphorylation, trimerization, nuclear translocation HSF1, transcription luciferase reporter, as well...
Abstract Autophagy plays a critical role in the maintenance of cellular homeostasis by degrading proteins, lipids and organelles. is activated response to stress, but its regulation context other stress pathways, such as those mediated heat shock factor 1 (HSF1) nuclear factor-erythroid 2 p45-related (NRF2), not well understood. We found that Michael acceptor bis (2-hydoxybenzylidene)acetone (HBB2), dual activator NRF2 HSF1, protects against development UV irradiation-mediated cutaneous...
Transcription factor nuclear erythroid 2 p45-related (Nrf2) and its main negative regulator, Kelch-like ECH-associated protein 1 (Keap1), are at the interface between redox intermediary metabolism, allowing adaptation survival under conditions of oxidative, inflammatory, metabolic stress. Nrf2 is principal determinant homeostasis, contributes to mitochondrial function integrity cellular bioenergetics. Using proteomics lipidomics, we show that genetic downregulation Keap1 in mice, consequent...
Systemic sclerosis (SSc) is an autoimmune connective tissue disease that leads to skin fibrosis. Altered metabolism has recently been described in diseases and SSc. Itaconate a product of the Krebs cycle intermediate cis-aconitate immunomodulator. This work examines role cell-permeable derivative itaconate, 4-octyl itaconate (4-OI), SSc healthy dermal fibroblasts were exposed 4-OI. The levels collagen Nrf2-target genes pro-inflammatory cytokines interleukin 6 (IL-6) monocyte chemotactic...
The transcription factor BACH1 is a potential therapeutic target for variety of chronic conditions linked to oxidative stress and inflammation, as well cancer metastasis. However, only few degraders/inhibitors have been described. transcriptional repressor heme oxygenase 1 (HMOX1), which positively regulated by NRF2 highly inducible derivatives the synthetic oleanane triterpenoid 2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oic acid (CDDO). Most activities these compounds are due their...
Inhibitors of Kelch-like ECH-associated protein 1 (Keap1) increase the activity transcription factor nuclear erythroid 2-related 2 (Nrf2) by stalling its ubiquitination and degradation. This enhances expression genes encoding proteins involved in drug detoxification, redox homeostasis, mitochondrial function. Nrf2 activation offers a potential therapeutic approach for conditions including Alzheimer's Parkinson's diseases, vascular inflammation, chronic obstructive airway disease....
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, oral cancers. Here we found that is overexpressed human colorectal cancer comparison with matched normal tissue. overexpression correlates activation transcription nuclear erythroid 2 p45-related (Nrf2) increased expression the classical Nrf2 target NAD(P)H:quinone...
Pharmacologic inhibition of the protein-protein interaction (PPI) interface Keap1:Nrf2 complex, which leads to Nrf2 activation and cytoprotective gene expression, offers a promising strategy for disease prevention treatment. To facilitate identification validation small-molecule PPI inhibitors in cellular environment low- medium-throughput manner, we detail two adapted thermal shift assay (CETSA) protocols, Keap1-CETSA, an immunoblotting-based methodology detecting endogenous Keap1,...
LAMA2, coding for the laminin-α2 chain, is a crucial ECM component, particularly abundant in skeletal muscle. Mutations
Transcription factor nuclear erythroid 2 p45-related (Nrf2) is the principal determinant of cellular redox homeostasis, contributing to mitochondrial function, integrity and bioenergetics. The main negative regulator Nrf2 Kelch-like ECH associated protein 1 (Keap1), a substrate adaptor for Cul3/Rbx1 ubiquitin ligase, which continuously targets ubiquitination proteasomal degradation. Loss-of-function mutations in Keap1 occur frequently lung cancer, leading constitutive activation. We used...