Redox signaling, wherein reactive and diffusible small molecules are channeled into specific mess... more Redox signaling, wherein reactive and diffusible small molecules are channeled into specific messenger functions, is a critical component of signal transduction. A central principle of redox signaling is that the redox modulators are produced in a highly controlled fashion to specifically modify biotargets. Thiols serve as primary mediators of redox signaling as a function of the rich variety of adducts, which allows initiation of distinct cellular effects. Coupling the inherent reactivity of thiols with highly sensitive and selective chemical analysis protocols can facilitate identification of redox signaling agents, both in solution and in cultured cells. Here, we describe use of capillary zone electrophoresis to both identify and quantitate sulfinamides, which are specific markers of the reaction of thiols with nitroxyl (HNO).
Publisher Summary The multiple effects of nitric oxide (NO) in biological systems have resulted i... more Publisher Summary The multiple effects of nitric oxide (NO) in biological systems have resulted in intense investigation into the mechanisms of NO-mediated events. The chemistry of NO is the primary determinant of its biological properties. However, not all the reactions of NO that can be performed in test tube are pertinent in vivo. This chapter provides a guide through the diverse reactions of NO in biological systems. The scheme of the chemical biology of NO divides the reactions into the two categories of direct and indirect effects. Direct effects are defined as those reactions that are fast enough to occur between NO and specific biological targets. Indirect effects do not involve NO, but rather, are mediated by reactive NO species formed from the reaction of NO with either oxygen or superoxide. These species can mediate either nitrosative or oxidative stress. Aspects of the chemical biology of NO relating to biological molecules such as guanylate cyclase, cytochrome P-450, nitric oxide synthase, catalase, and DNA are reviewed and the possible roles NO performs in different biological situations are explored.
Oxidative stress in applied basic research and clinical practice, 2016
Over the past two decades, nitric oxide (NO) has been at the center of multiple contradictory fin... more Over the past two decades, nitric oxide (NO) has been at the center of multiple contradictory findings regarding its role in cancer biology. With greater understanding, it is now well established that the biphasic effects of NO are concentration dependent. Low flux of NO less than 10 nM is essential for normal physiological functions such as vascular maintenance. Intermediate levels of NO higher than 100 nM affect critical pathways that lead to tumor progression, whereas higher flux NO (>800 nM) induces tumor regression. Nitric oxide synthase (NOS) enzymes, particularly inducible NOS (iNOS), have often been shown to exert both pro- and antitumor effects. The elucidation of the involvement of intermediate NO flux generated by iNOS during cancer progression has led to the rapid development of several classes of NOS inhibitors with potent therapeutic effects. In contrast, the generation of higher NO flux in the tumor microenvironment tips the balance to favor cytostasis and cell killing. Toward this end, several classes of NO donors (e.g., nitrate esters, S-nitrosothiols, and diazeniumdiolates) have been examined both in vitro and in vivo and have demonstrated vast potential as chemotherapeutic agents as well. Recently, nitroxyl (HNO) has emerged as a key player with promising therapeutic potential as it exhibits properties that are often orthogonal to NO. Significant potential of HNO in the treatment of cardiovascular disease, clinical usage as an alcohol deterrent agent, and chemotherapeutic activity are only a few of its properties that have recently been explored. In this chapter, we briefly review some of the key pathways/chemical modifications by which NO and HNO exert their physiological outcome in cancer biology. NOS inhibition and utilization of NO donors as effective therapeutic options for NO-based therapy, HNO donors and their utilization as chemo drugs, and lastly NO/HNO-based hybrid drugs are discussed to show the therapeutic depth and potential for NO and HNO in cancer treatment.
Diazeniumdiolates offer a versatile platform for development of both nitric oxide (NO) and nitrox... more Diazeniumdiolates offer a versatile platform for development of both nitric oxide (NO) and nitroxyl (HNO) donors and have been vital to the study of chemical biology of nitrogen oxides. Derivatization of ionic diazeniumdiolates has been shown to improve the purification process, to dramatically slow the rate of spontaneous decomposition and to provide new therapeutic benefits as a function of addition of bioactive moieties. Decomposition of certain derivatized diazeniumdiolates can also yield acyl nitroso compounds as HNO donors. The breadth of HNO generation profiles from this donor class will allow continued analysis of the pharmacological effects of HNO and may facilitate the search for endogenous HNO. This chapter details the synthesis, structure, and mechanism of decomposition of the widely used HNO donor Angeli’s salt as well as related compounds in the diazeniumdiolate class.
Redox signaling, wherein reactive and diffusible small molecules are channeled into specific mess... more Redox signaling, wherein reactive and diffusible small molecules are channeled into specific messenger functions, is a critical component of signal transduction. A central principle of redox signaling is that the redox modulators are produced in a highly controlled fashion to specifically modify biotargets. Thiols serve as primary mediators of redox signaling as a function of the rich variety of adducts, which allows initiation of distinct cellular effects. Coupling the inherent reactivity of thiols with highly sensitive and selective chemical analysis protocols can facilitate identification of redox signaling agents, both in solution and in cultured cells. Here, we describe use of capillary zone electrophoresis to both identify and quantitate sulfinamides, which are specific markers of the reaction of thiols with nitroxyl (HNO).
Publisher Summary The multiple effects of nitric oxide (NO) in biological systems have resulted i... more Publisher Summary The multiple effects of nitric oxide (NO) in biological systems have resulted in intense investigation into the mechanisms of NO-mediated events. The chemistry of NO is the primary determinant of its biological properties. However, not all the reactions of NO that can be performed in test tube are pertinent in vivo. This chapter provides a guide through the diverse reactions of NO in biological systems. The scheme of the chemical biology of NO divides the reactions into the two categories of direct and indirect effects. Direct effects are defined as those reactions that are fast enough to occur between NO and specific biological targets. Indirect effects do not involve NO, but rather, are mediated by reactive NO species formed from the reaction of NO with either oxygen or superoxide. These species can mediate either nitrosative or oxidative stress. Aspects of the chemical biology of NO relating to biological molecules such as guanylate cyclase, cytochrome P-450, nitric oxide synthase, catalase, and DNA are reviewed and the possible roles NO performs in different biological situations are explored.
Oxidative stress in applied basic research and clinical practice, 2016
Over the past two decades, nitric oxide (NO) has been at the center of multiple contradictory fin... more Over the past two decades, nitric oxide (NO) has been at the center of multiple contradictory findings regarding its role in cancer biology. With greater understanding, it is now well established that the biphasic effects of NO are concentration dependent. Low flux of NO less than 10 nM is essential for normal physiological functions such as vascular maintenance. Intermediate levels of NO higher than 100 nM affect critical pathways that lead to tumor progression, whereas higher flux NO (>800 nM) induces tumor regression. Nitric oxide synthase (NOS) enzymes, particularly inducible NOS (iNOS), have often been shown to exert both pro- and antitumor effects. The elucidation of the involvement of intermediate NO flux generated by iNOS during cancer progression has led to the rapid development of several classes of NOS inhibitors with potent therapeutic effects. In contrast, the generation of higher NO flux in the tumor microenvironment tips the balance to favor cytostasis and cell killing. Toward this end, several classes of NO donors (e.g., nitrate esters, S-nitrosothiols, and diazeniumdiolates) have been examined both in vitro and in vivo and have demonstrated vast potential as chemotherapeutic agents as well. Recently, nitroxyl (HNO) has emerged as a key player with promising therapeutic potential as it exhibits properties that are often orthogonal to NO. Significant potential of HNO in the treatment of cardiovascular disease, clinical usage as an alcohol deterrent agent, and chemotherapeutic activity are only a few of its properties that have recently been explored. In this chapter, we briefly review some of the key pathways/chemical modifications by which NO and HNO exert their physiological outcome in cancer biology. NOS inhibition and utilization of NO donors as effective therapeutic options for NO-based therapy, HNO donors and their utilization as chemo drugs, and lastly NO/HNO-based hybrid drugs are discussed to show the therapeutic depth and potential for NO and HNO in cancer treatment.
Diazeniumdiolates offer a versatile platform for development of both nitric oxide (NO) and nitrox... more Diazeniumdiolates offer a versatile platform for development of both nitric oxide (NO) and nitroxyl (HNO) donors and have been vital to the study of chemical biology of nitrogen oxides. Derivatization of ionic diazeniumdiolates has been shown to improve the purification process, to dramatically slow the rate of spontaneous decomposition and to provide new therapeutic benefits as a function of addition of bioactive moieties. Decomposition of certain derivatized diazeniumdiolates can also yield acyl nitroso compounds as HNO donors. The breadth of HNO generation profiles from this donor class will allow continued analysis of the pharmacological effects of HNO and may facilitate the search for endogenous HNO. This chapter details the synthesis, structure, and mechanism of decomposition of the widely used HNO donor Angeli’s salt as well as related compounds in the diazeniumdiolate class.
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Papers by Katrina Miranda