Browsing by Subject "Keap1"
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Item Author Correction: Moderate Nrf2 Activation by Genetic Disruption of Keap1 Has Sex-Specific Effects on Bone Mass in Mice(Springer Nature, 2021-05-10) Yin, Yukun; Corry, Kylie A.; Loughran, John P.; Li, Jiliang; Biology, School of ScienceCorrection to: Scientific Reports https://doi.org/10.1038/s41598-019-57185-1, published online 15 January 2020Item Keap1 modulates the redox cycle and hepatocyte cell cycle in regenerating liver(Taylor & Francis, 2014-08-01) Hu, Min; Zou, Yuhong; Nambiar, Shashank Manohar; Lee, Joonyong; Yang, Yan; Dai, Guoli; Department of Biology, School of ScienceKeap1 negatively controls the activity of transcription factor Nrf2. This Keap1/Nrf2 pathway plays a critical role in combating oxidative stress. We aimed at determining whether and how Keap1 modulates the cell cycle of replicating hepatocytes during liver regeneration. Two-thirds partial hepatectomy (PH) was performed on wild-type mice and Keap1+/- (Keap1 knockdown) mice. We found that, following PH, Keap1 knockdown resulted in a delay in S-phase entry, disruption of S-phase progression, and loss of mitotic rhythm of replicating hepatocytes. These events are associated with dysregulation of c-Met, EGFR, Akt1, p70S6K, Cyclin A2, and Cyclin B1 in regenerating livers. Astonishingly, normal regenerating livers exhibited the redox fluctuation coupled with hepatocyte cell cycle progression, while keeping Nrf2 quiescent. Keap1 knockdown caused severe disruption in both the redox cycle and the cell cycle of replicating hepatocytes. Thus, we demonstrate that Keap1 is a potent regulator of hepatic redox cycle and hepatocyte cell cycle during liver regeneration.Item Mechanotransduction in Living Bone: Effects of the Keap1-Nrf2 Pathway(2019-08) Priddy, Carlie; Li, Jiliang; Dai, Guoli; Wallace, Joseph M.The Keap1-Nrf2 pathway regulates a wide range of cytoprotective genes, and has been found to serve a protective and beneficial role in many body systems. There is limited information available, however, about its role in bone homeostasis. While Nrf2 activation has been suggested as an effective method of increasing bone mass and quality, there have been conflicting reports which associate Keap1 deficiency with detrimental phenotypes. As Keap1 deletion is a common method of Nrf2 activation, further study should address the impacts of various methods of regulating Nrf2 expression. Also, little research has been conducted on the specific pathways by which Nrf2 activation improves bone quality. In this study, the effects of alterations to Nrf2 activation levels were explored in two specific and varied scenarios. In the first experiment, moderate Nrf2 activation was achieved via partial deletion of its sequestering protein, Keap1, in an aging mouse model. The hypothesis tested here is that moderate Nrf2 activation improves bone quality by affecting bone metabolism and response to mechanical loading. The results of this first experiment suggest a subtle, sex-specific effect of moderate Nrf2 activation in aging mice which improves specific indices of bone quality to varying degrees, but does not affect loading-induced bone formation. It is likely that the overwhelming phenotypic impacts associated with aging or the systemic effects of global Keap1 deficiency may increase the difficulty in parsing out significant effects that can be attributed solely to Nrf2 activation. In the second experiment, a cell-specific knockout of Nrf2 in the osteocytes was achieved using a Cre/Lox breeding system. The hypothesis tested here is that osteocyte-specific deletion of Nrf2 impairs bone quality by affecting bone metabolism and response to mechanical loading. The results of this experiment suggest an important role of Nrf2 in osteocyte function which improves certain indices of bone quality, which impacts male and female bones in different 7 ways, but did not significantly impact loading-induced bone formation. Further studies should modify the method of Nrf2 activation in an effort to refine the animal model, allowing the effects of Nrf2 to be isolated from the potential systemic effects of Keap1 deletion. Future studies should also utilize other conditional knockout models to elucidate the effects of Nrf2 in other specific cell types.Item Moderate Nrf2 Activation by Genetic Disruption of Keap1 Has Sex-Specific Effects on Bone Mass in Mice(Nature Research, 2020-01-15) Yin, Yukun; Corry, Kylie A.; Loughran, John P.; Li, Jiliang; Biology, School of ScienceKeap1 is a negative controller of the transcription factor Nrf2 for its activity. The Keap1/Nrf2 signaling pathway has been considered as a master regulator of cytoprotective genes, and exists in many cell types including osteoblasts and osteoclasts. Our previous study shows Nrf2 deletion decreases bone formation. Recent studies show hyperactivation of Nrf2 causes osteopenia in Keap1−/− mice, and Keap1−/− osteoblasts have significantly less proliferative potential than Keap1+/− osteoblasts. We aimed to examine if moderate Nrf2 activation by disruption of Keap1 impacts bone metabolism. We examined bone phenotype of Keap1 heterozygotic mice (Ht) in comparison with Keap1 wild type (WT) mice. Deletion or knockdown of Keap1 enhanced the gene expression of Nrf2, ALP and wnt5a in cultured primary osteoblasts compared to WT control. In male mice, compared with their age-matched littermate WT controls, Keap1 Ht mice showed significant increase in bone formation rate (+30.7%, P = 0.0029), but did not change the ultimate force (P < 0.01). The osteoclast cell numbers (−32.45%, P = 0.01) and surface (−32.58%, P = 0.03) were significantly reduced by Keap1 deficiency in male mice. Compared to male WT mice, serum bone resorption marker in male Keap1 Ht mice was significantly decreased. Our data suggest that moderate Nrf2 activation by disruption of Keap1 improved bone mass by regulating bone remodeling in male mice.Item The role of the Nrf2/Keap1 signaling cascade in mechanobiology and bone health(Elsevier, 2021-11-22) Priddy, Carlie; Li, Jiliang; Biology, School of ScienceIn conjunction with advancements in modern medicine, bone health is becoming an increasingly prevalent concern among a global population with an ever-growing life expectancy. Countless factors contribute to declining bone strength, and age exacerbates nearly all of them. The detrimental effects of bone loss have a profound impact on quality of life. As such, there is a great need for full exploration of potential therapeutic targets that may provide antiaging benefits and increase the life and strength of bone tissues. The Keap1-Nrf2 pathway is a promising avenue of this research. The cytoprotective and antioxidant functions of this pathway have been shown to mitigate the deleterious effects of oxidative stress on bone tissues, but the exact cellular and molecular mechanisms by which this occurs are not yet fully understood. Presently, refined animal and loading models are allowing exploration into the effect of the Keap1-Nrf2 pathway in a tissue-specific or even cell-specific manner. In addition, Nrf2 activators currently undergoing clinical trials can be utilized to investigate the particular cellular mechanisms at work in this cytoprotective cascade. Although the timing and dosing of treatment with Nrf2 activators need to be further investigated, these activators have great potential to be used clinically to prevent and treat osteoporosis.