The Keap1-Nrf2-ARE gene expression system is the central stress defense/adaptive response signaling pathway in cells. While the pathway is ubiquitous, there are cell-specific effects in each tissue, mediated in part through interactions with other signaling networks. We have begun to identify the cross-talk signals based on “health maintenance” in liver and digestive organs. Notch-Nrf2 cross-talk has been identified from phenotype observations in postnatal hepatic development among various genetically engineered mice. Notch1, which is the major Notch product expressed in hepatocytes, drives expression of the Nrf2-ARE directly. Nrf2-disrupted mice show slower recovery in the early regenerative phase following partial hepatectomy. Furthermore, it has been understood that hepato-cholangiogenesis in postnatal liver growth is mediated by coordinated gene expression through Notch-Nrf2 cross-talk. In cholangiocytes, the Notch intracellular domain might contribute to expression of Nrf2. We are evaluating which genes are major contributors to the cell-specific phenotypes affected by this cross-talk pathway and are elucidating the regulatory details underlying this signaling mechanism.
Diabetes mellitus is a major public health problem worldwide and likely contributes to the etiology of some cancers. The Keap1-Nrf2 pathway plays a protective role by regulating cellular redox homeostasis, as well as regulation of metabolism and energy-balance. We are investigating how Keap1-Nrf2 signaling protects our body against diabetes mellitus and how perturbations of this pathway provoke metabolic disorders. To understand the downstream targets and the molecular mechanisms underlying the protective effect against diabetes, we have established a battery of genetically modified mouse models and perform pathophysiological studies in animal models applying biochemistry, cell biology and immunohistochemistry. An area of emphasis is translational research using small molecules that target activation of the Keap1-Nrf2 pathway, so as to develop new interventional strategies for patients with prediabetes, type 2 diabetes, or potentially type 1 diabetes.
The Keap1-Nrf2 pathway can be induced by thiol-reactive small molecules including dithiolethiones (e.g., oltipraz), isothiocyanates (e.g., sulforaphane) and triterpenoids (e.g., CDDO-Im) that demonstrate protective efficacy in preclinical cancer chemoprevention models. We have conducted a series of clinical trials in Qidong, China, a region where exposures to food- and air-borne carcinogens has been considerable, to evaluate the suitability of broccoli sprout beverages, rich in either sulforaphane or glucoraphanin (its biogenic precursor) or both for their bioavailability, tolerability and pharmacodynamic action in population-based interventions. Well characterized preparations of broccoli sprouts rapidly and persistently enhance the detoxication of air-borne toxins, which may in turn attenuate their associated health risks, including cancer, in exposed individuals. We continue to optimize dose, formulation and biomarkers of pharmacodynamic action.