RFG3

ROS and Disease Prevention

ROS/Oxidative Stress

Relevance to Swehsc : 

The progressive nature of colorectal cancer (CRC) and poor prognosis associated with the metastatic phase of the disease create an urgent need for the development of more efficacious strategies targeting colorectal carcinogenesis.

Cluster of Efforts: 

The progressive nature of colorectal cancer (CRC) and poor prognosis associated with the metastatic phase of the disease create an urgent need for the development of more efficacious strategies targeting colorectal carcinogenesis. Cumulative evidence suggests that the redox-sensitive transcription factor Nrf2 (nuclear factor-E2-related factor 2), a master regulator of the cellular antioxidant defence, represents a promising molecular target for CRC chemoprevention. Recently, we have identified cinnamon, the ground bark of Cinnamomum aromaticum (cassia cinnamon) and Cinnamomum verum (Ceylon cinnamon), as a rich dietary source of the Nrf2 inducer cinnamaldehyde (CA) eliciting the Nrf2-regulated antioxidant response in human epithelial colon cells, conferring cytoprotection against electrophilic and genotoxic insult. Here, we have explored the molecular mechanism underlying CA-induced Nrf2 activation in colorectal epithelial cells and have examined the chemopreventive potential of CA in a murine CRC model comparing Nrf2+/+ and Nrf2-/- mice. In HCT116 cells, CA caused a Keap1-C151-dependent increase in Nrf2 protein half-life via blockage of ubiquitination with upregulation of cytoprotective Nrf2 target genes and elevation of cellular glutathione. After optimizing colorectal Nrf2 activation and target gene expression by dietary CA-supplementation regimens, we demonstrated that CA suppresses AOM/DSS-induced inflammatory colon carcinogenesis with modulation of molecular markers of colorectal carcinogenesis. Dietary suppression of CRC using CA supplementation was achieved in Nrf2+/+ but not in Nrf2-/- mice confirming the Nrf2-dependence of CA-induced chemopreventive effects. Taken together, our data suggest feasibility of CRC suppression by dietary CA, an FDA-approved food additive derived from the third most consumed spice in the world.

Milestones: 

Nrf2-dependent suppression of azoxymethane/dextran sulfate sodium-induced colon carcinogenesis by the cinnamon-derived dietary factor cinnamaldehyde. Long M, Tao S, Rojo de la Vega M, Jiang T, Wen Q, Park SL, Zhang DD*, Wondrak GT*. 2015. Cancer Prevention Res PMID: 25712056

NRF2-Mediated Cell Stress

Relevance to Swehsc : 

Hrd1 suppresses Nrf2-mediated cellular protection durling liver cirrhosis.

Cluster of Efforts: 

Increased endoplasmic reticulum (ER) stress and reactive oxygen species (ROS) are the salient features of end-stage liver diseases. Using liver tissues from liver cirrhosis patients, we observed up-regulation of the XBP1-Hrd1 arm of the ER stress response pathway and down-regulation of the Nrf2-mediated antioxidant response pathway. We further confirmed this negative regulation of Nrf2 by Hrd1 using Hrd1 conditional knockout mice. Down-regulation of Nrf2 was a surprising result, since the high levels of ROS should have inactivated Keap1, the primary ubiquitin ligase regulating Nrf2 levels. Here, we identified Hrd1 as a novel E3 ubiquitin ligase responsible for compromised Nrf2 response during liver cirrhosis. In cirrhotic livers, activation of the XBP1-Hrd1 arm of ER stress transcriptionally up-regulated Hrd1, resulting in enhanced Nrf2 ubiquitylation and degradation and attenuation of the Nrf2 signaling pathway. Our study reveals not only the convergence of ER and oxidative stress response pathways but also the pathological importance of this cross-talk in liver cirrhosis. Finally, we showed the therapeutic importance of targeting Hrd1, rather than Keap1, to prevent Nrf2 loss and suppress liver cirrhosis.

Development of Biosensor Technology

Relevance to Swehsc : 

Pak Kin Wong, Ph.D., has developed several microfluidic and sincle cell biosensor technologies. 

Cluster of Efforts: 

Investigator:

  • Pak Kin Wong, Ph.D.
Milestones: 

Ability to monitor the dynamic response of cells under environmental insults and developing novel countermeasures for the high-risk populations. 

Expertise and Technology

  • Wong:  Developed several microfluidic and single cell biosensor technologies for monitoring the dynamic response of cells under environmental insults and developing novel countermeasures for the high-risk populations.  

Outreach

Pre-college Interns get Head start for Science Careers

Glycooxidative Stress and Diabetes

Diabetes is an excellent example of how environmental factors interact with susceptibility genes leading to poor clinical outcomes. The Hispanic population is particularly affected by the diabetes epidemic, but this predisposition is poorly understood. Glucose levels or glycated hemoglobin (HbA1C) do not successfully predict all individuals at risk of diabetes or diabetes complications.

Oxidative Stress

Mechanisms of cell death are usually classified into two pathways, apoptosis and oncosis/necrosis. Necrosis/oncosis typically occurs in response to toxic injury, including that induced by chemical exposure and reactive oxygen species (ROS). In contrast to apoptosis, oncosis is characterized by cell and organelle swelling that eventually leads to the loss of plasma membrane integrity. The generation of ROS has been implicated in the pathogenesis of renal ischemia/reperfusion injury, and many other pathological conditions.

Glyco-oxidative stress modulates diabetes severity

Relevance to Swehsc : 

Diabetes is at epidemic proportions in Native American communities, and to a lesser extent in the general population. Understanding the role of environmental stressors on disease outcome holds the promise of improving patient management and potentially identifying new treatment targets.

Cluster of Efforts: 

Lau (RFG3), Stump (RFG3), Billheimer (IHSFC-Biostats), Tsaprailis (Proteomics): Technology and Research Initiative Funds (TRIF), NIEHS/ES006694 Pilot Project, NIDDK/DK083948, NCRR/S10RR022384

Milestones: 
  • Drs. Lau and Stump have collected blood and urine samples from >100 subjects, predominantly of Hispanic ethnicity. Quantification of free MG and MG-adducts in urine is in progress.
  • MS-based proteomics approaches to differentially profile and quantitate serum protein modification by MG in normal subjects and T2D patients, revealed several novel potential biomarkers. One of these, MG-modified fibrinogen is now being validated. This biomarker appears to offer superior discrimination of diabetic complications than conventional biomarkers that capture glucose binding only as glycated hemoglobin (HbA1C)
  • Urinary arsenic metabolites (As)/24 hrs were also measured (Gandolfi, RFG1) in 14 subjects without diabetes and 19 subjects with diabetes. Total urinary As was significantly elevated in diabetes (p<0.05).

 

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