Areas of Investigation and Significance:
Inflammation is a complex system of a host systemic and local response to injury and infection. Inflammation contributes to almost all disease processes, including immunological and vascular pathology, sepsis, uveitis, cancer and chemical and metabolic injury. It is well established that increased expression of cytokines elicits the cytotoxic actions of oxidative stress signals in many inflammatory diseases. As over 100,000 deaths in the U.S., each year can be attributed to an excessive inflammatory response to bacterial infections. Moreover, cytokines play a critical role in several cardiovascular and neurological degenerative diseases as well as cancer. Hence elucidation of the mechanisms that mediate and regulate cytokine signals is of profound importance to understanding and managing a very large array of disease processes. The chief objective of our lab investigations is to systematically investigate (1) the involvement of aldose reductase in the inflammatory signals induced various oxidants using in vitro cultured cells and in vivo experimental animal models, and (2) to delineate the role of aldose reductase and various anti-oxidant natural food supplements in the pathways used by activated macrophages and monocytes to control inflammation.
We combine genetic, biochemical and cell biological approaches to analyze oxidative stress –induced inflammatory responses regulated by polyol pathway enzyme aldose reductase. We use transgenic and knockout mouse models for elucidating the molecular pathways that regulate inflammatory complications. In addition to standard models of diabetes complications, our lab also uses in vitro cultured cells as well as in vivo rodent and murine models for inflammatory complications. For cancer studies: we use nude mice xenografts, orthotopic implantation of human tumors, chemical and genetic mouse models. For sepsis complications: we use both bacterial endotoxin and cecum ligation puncture models in mice. For uveitis complications: we use endotoxin –induced uveitis as well as experimental autoimmune-induced uveitis in both rats and mice. My long-term goal is to understand how lipid peroxidation products mediate molecular signaling that leads to inflammation. In particular, by exploring the role of a unique cellular oxidant system mediated by aldose reductase, we expect to learn how oxidative stress signals mediated by ROS are modified and inactivated by cells upon disrupting aldose reductase’s functionality. Understanding the cross-talk between aldose reductase and its reduced lipid aldehyde products with signals associated with various transcription factors is important in developing potential therapeutic approaches for various inflammatory complications.
My long-standing collaboration with Dr. Satish K Srivastava, Department of Biochemistry and Molecular Biology, resulted several important findings in oxidative stress and cell signaling. Our studies that show aldose reductase mediates inflammatory signaling are now at a stage where we can perform translational research. Some of our key findings include:
- Demonstrated that the polyol pathway enzyme aldose reductase reduces lipid aldehydes and their conjugates with glutathione more efficiently than aldo-sugars.
- Identified a specific glutathione binding site in aldose reductase
- Solved crystal structure of glutathione analogue bound aldose reductase
- Identified a novel role of aldose reductase in hyperglycemic, cytokine and bacterial endotoxin-induced cell signaling.
- Found that aldose reductase inhibition prevents NF-kB and AP-1 activation.
- Found that aldose reductase catalyzed product of glutathione-HNE is a novel mediator of oxidative signaling.
- Identified that inhibition of aldose reductase prevents inflammatory cytokine and chemokine synthesis and their autocrine/paracrine effects.
- Found that inhibition of aldose reductase prevents bacterial-endotoxin –induced sepsis and cardiomyopathy in mice.
- Demonstrated that aldose reductase mediates hyperglycemia –induced expression of TNF-a and its autocrine actions in smooth muscle cells.
- Found that inhibition of aldose reductase prevents colon cancer cell growth in mice.
- Found that inhibition of aldose reductase prevents ocular inflammation, uveitis in rats.
- Found that aldose reductase inhibition could prevent airway inflammatory complications such as COPD and asthma.
- Found that a fat soluble vitamin B1 analogue, benfotiamine supplementation could be used to prevent ocular inflammatory disease uveitis.
Ongoing and Future studies:
- Found that a inhibition of AR prevents angiogenesis as well as colon cancer metastasis.
- How aldose reductase catalyzed lipid aldehydes regulate protein kinases and transcription factors.
- How aldose reductase is involved in the pathophysiology of multi-organ failure in sepsis.
- How antioxidants and aldose reductase inhibitors prevent uveitis
- How microRNAs contribute to inflammatory complications
- Why cancer stem cells are resistant to chemotherapy
- Clinical studies using aldose reductase inhibitors in prevention of inflammatory complications