Katrina M Miranda
Work Summary
We seek to produce new drugs that harness molecules produced during the natural immune response in order to treat cancer and pain. Such compounds may also provide new treatments for heart failure and alcoholism.
We seek to produce new drugs that harness molecules produced during the natural immune response in order to treat cancer and pain. Such compounds may also provide new treatments for heart failure and alcoholism.
PMID: 15579020;Abstract:
Nitric oxide has emerged as one of the most important and diverse players in physiology. This small diatomic radical stunned researchers because of its existence and unique biological properties in human physiology. Over the last two decades it was found that NO often has fickle behavior in pathophysiological mechanisms. Where benefiting the host in one case yet inducing and augmenting injury in another. This has lead to confusion in is NO good or bad? Much of the answers to this dichotomy lies in the chemistry of NO and its related nitrogen oxide species. To help understand the complex chemistry with perspective to biology, a discussion on the chemical biology of NO is useful. The chemical biology defines the relevant chemical reaction of NO and nitrogen monoxide in the context of the biological conditions. We discuss in this article the chemistry of nitrogen oxide with different types of biological motifs. Reaction of NO with metal complexes and radicals require low concentration, where formation of reactive nitrogen oxide species require considerably higher amounts and generally are isolated to specific microenvironments in vivo. Though many reactive nitrogen oxide species are formed from chemical reactions with NO, there are several which appear to not require NO to be present, HNO and NO2. These two species have unique physiological effects and represent additional complexity to this biological picture. From this discussion, a picture can be formed concerning the possible chemical dynamics, which can be plausible in different biological mechanisms. © 2004 Bentham Science Publishers Ltd.
PMID: 21235346;PMCID: PMC3070000;Abstract:
The importance of nitric oxide in mammalian physiology has been known for nearly 30 years. Similar attention for other nitrogen oxides such as nitroxyl (HNO) has been more recent. While there has been speculation as to the biosynthesis of HNO, its pharmacological benefits have been demonstrated in several pathophysiological settings such as cardiovascular disorders, cancer, and alcoholism. The chemical biology of HNO has been identified as related to, but unique from, that of its redox congener nitric oxide. A summary of these findings as well as a discussion of possible endogenous sources of HNO is presented in this review. © 2011 Mary Ann Liebert, Inc.
Nitric oxide (NO) synthase 2 (NOS2), a major inflammatory protein, modulates disease progression via NO in a number of pathologies, including cancer. The role of NOS2-derived NO is not only flux-dependent, which is higher in mouse vs human cells, but also varies based on spatial and temporal distribution both within tumor cells and in the tumor microenvironment. NO donors have been utilized to mimic NO flux conditions and to investigate the effects of varied NO concentrations. As a wide range of effects mediated by NO and other nitrogen oxides such as nitroxyl (HNO) have been elucidated, multiple NO- and HNO-releasing compounds have been developed as potential therapeutics, including as tumor modulators. One of the challenges is to determine differences in biomarker expression from extracellular vs intracellular generation of NO or HNO. Taking advantage of new NO and HNO releasing agents, we have characterized the gene expression profile of estrogen receptor-negative human breast cancer (MDA-MB-231) cells following exposure to aspirin, the NO donor DEA/NO, the HNO donor IPA/NO andtheir intracellularly-activated prodrug conjugates DEA/NO-aspirin and IPA/NO-aspirin. Comparison of the gene expression profiles demonstrated that several genes were uniquely expressed with respect to NO or HNO, such as miR-21, HSP70, cystathionine γ-lyase and IL24. These findings provide insight into targets and pathways that could be therapeutically exploited by the redox related species NO and HNO.
PMID: 12880485;Abstract:
The role of nitric oxide (NO) in cellular physiology and signaling has been an important aspect in biomedical science over the last decade. As NO is a small uncharged radical, the chemistry of NO within the redox environment of the cell dictates the majority of its biological effects. The mechanisms that have received the most attention from a biological perspective involve reactions with oxygen and superoxide, despite the rich literature of metal-NO chemistry. However, NO and its related species participate in important chemistry with metalloproteins. In addition to the well known direct interactions of NO with heme proteins such as soluble guanylate cyclase and oxyhemoglobin, there is much important, but often underappreciated, chemistry between other nitrogen oxides and heme/metal proteins. Here the basic chemistry of nitrosylation and the interactions of NO and other nitrogen oxides with metal-oxo species such as found in peroxidases and monoxygenases are discussed.