Browsing by Author "Moerland, Jessica A."

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    Health position paper and redox perspectives - Bench to bedside transition for pharmacological regulation of NRF2 in noncommunicable diseases
    (Elsevier, 2025) Cuadrado, Antonio; Cazalla, Eduardo; Bach, Anders; Bathish, Boushra; Naidu, Sharadha Dayalan; DeNicola, Gina M.; Dinkova-Kostova, Albena T.; Fernández-Ginés, Raquel; Grochot-Przeczek, Anna; Hayes, John D.; Kensler, Thomas W.; León, Rafael; Liby, Karen T.; López, Manuela G.; Manda, Gina; Shivakumar, Akshatha Kalavathi; Hakomäki, Henriikka; Moerland, Jessica A.; Motohashi, Hozumi; Rojo, Ana I.; Sykiotis, Gerasimos P.; Taguchi, Keiko; Valverde, Ángela M.; Yamamoto, Masayuki; Levonen, Anna-Liisa; Medicine, School of Medicine
    Nuclear factor erythroid 2-related factor 2 (NRF2) is a redox-activated transcription factor regulating cellular defense against oxidative stress, thereby playing a pivotal role in maintaining cellular homeostasis. Its dysregulation is implicated in the progression of a wide array of human diseases, making NRF2 a compelling target for therapeutic interventions. However, challenges persist in drug discovery and safe targeting of NRF2, as unresolved questions remain especially regarding its context-specific role in diseases and off-target effects. This comprehensive review discusses the dualistic role of NRF2 in disease pathophysiology, covering its protective and/or destructive roles in autoimmune, respiratory, cardiovascular, and metabolic diseases, as well as diseases of the digestive system and cancer. Additionally, we also review the development of drugs that either activate or inhibit NRF2, discuss main barriers in translating NRF2-based therapies from bench to bedside, and consider the ways to monitor NRF2 activation in vivo.
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    The Triterpenoid CDDO-Methyl Ester Reduces Tumor Burden, Reprograms the Immune Microenvironment, and Protects from Chemotherapy-Induced Toxicity in a Preclinical Mouse Model of Established Lung Cancer
    (MDPI, 2024-05-21) Moerland, Jessica A.; Liby, Karen T.; Medicine, School of Medicine
    NRF2 activation protects epithelial cells from malignancy, but cancer cells can upregulate the pathway to promote survival. NRF2 activators including CDDO-Methyl ester (CDDO-Me) inhibit cancer in preclinical models, suggesting NRF2 activation in other cell types may promote anti-tumor activity. However, the immunomodulatory effects of NRF2 activation remain poorly understood in the context of cancer. To test CDDO-Me in a murine model of established lung cancer, tumor-bearing wildtype (WT) and Nrf2 knockout (KO) mice were treated with 50-100 mg CDDO-Me/kg diet, alone or combined with carboplatin/paclitaxel (C/P) for 8-12 weeks. CDDO-Me decreased tumor burden in an Nrf2-dependent manner. The combination of CDDO-Me plus C/P was significantly (p < 0.05) more effective than either drug alone, reducing tumor burden by 84% in WT mice. CDDO-Me reduced the histopathological grade of WT tumors, with a significantly (p < 0.05) higher proportion of low-grade tumors and a lower proportion of high-grade tumors. These changes were augmented by combination with C/P. CDDO-Me also protected WT mice from C/P-induced toxicity and improved macrophage and T cell phenotypes in WT mice, reducing the expression of CD206 and PD-L1 on macrophages, decreasing immunosuppressive FoxP3+ CD4+ T cells, and increasing activation of CD8+ T cells in a Nrf2-dependent manner.