Aberrant Free Radical Biology Is a Unifying Theme in the Etiology and Pathogenesis of Major Human Diseases

Domann, Frederick E.

doi:10.3390/ijms14048491

Cited by 12 publications

(10 citation statements)

References 24 publications

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“…RNS and ROS stresses are generally treated as a whole (17). It is widely assumed that the sites of peroxynitrite generation are spatially associated with the sources of superoxide production (such as mitochondria) in the context of hypoxia and inflammation (51).…”

Section: Discussionmentioning

confidence: 99%

Nitroso-Redox Balance and Mitochondrial Homeostasis Are Regulated bySTOX1, a Pre-Eclampsia-Associated Gene

Doridot

Châtre²,

Ducat³

et al. 2014

Antioxidants & Redox Signaling

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Aims: Storkhead box 1 (STOX1) is a winged-helix transcription factor that is implicated in the genetic forms of a high-prevalence human gestational disease, pre-eclampsia. STOX1 overexpression confers pre-eclampsia-like transcriptomic features to trophoblastic cell lines and pre-eclampsia symptoms to pregnant mice. The aim of this work was to evaluate the impact of STOX1 on free radical equilibrium and mitochondrial function, both in vitro and in vivo. Results: Transcriptome analysis of STOX1-transgenic versus nontransgenic placentas at 16.5 days of gestation revealed alterations of mitochondria-related pathways. Placentas overexpressing STOX1 displayed altered mitochondrial mass and were severely biased toward protein nitration, indicating nitrosoredox imbalance in vivo. Trophoblast cells overexpressing STOX1 displayed an increased mitochondrial activity at 20% O 2 and in hypoxia, despite reduction of the mitochondrial mass in the former. STOX1 overexpression is, therefore, associated with hyperactive mitochondria, resulting in increased free radical production. Moreover, nitric oxide (NO) production pathways were activated, resulting in peroxynitrite formation. At low oxygen pressure, STOX1 overexpression switched the free radical balance from reactive oxygen species (ROS) to reactive nitrogen species (RNS) in the placenta as well as in a trophoblast cell line. Innovation: In pre-eclamptic placentas, NO interacts with ROS and generates peroxynitrite and nitrated proteins as end products. This process will deprive the maternal organism of NO, a crucial vasodilator molecule. Conclusion: Our data posit STOX1 as a genetic switch in the ROS/RNS balance and suggest an explanation for elevated blood pressure in pre-eclampsia. Antioxid. Redox Signal. 21, 819-834.

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Section: Discussionmentioning

confidence: 99%

Nitroso-Redox Balance and Mitochondrial Homeostasis Are Regulated bySTOX1, a Pre-Eclampsia-Associated Gene

Doridot

Châtre²,

Ducat³

et al. 2014

Antioxidants & Redox Signaling

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“…This suggests that any agent that can inhibit Ddn or deazaflavin biosynthesis could synergize with existing anti-TB drugs. Thus, novel mechanisms to generate ROS/ NOS at sufficiently high concentrations should be investigated as potential novel therapy for TB, as long as they do not cause oxidative damage to the host cells (Domann 2013).…”

Section: Ros and Nos Generationmentioning

confidence: 99%

The Tuberculosis Drug Discovery and Development Pipeline and Emerging Drug Targets

Mdluli

Kaneko

Upton

2015

Cold Spring Harbor Perspectives in Medicine

132

115

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The recent accelerated approval for use in extensively drug-resistant and multidrug-resistanttuberculosis (MDR-TB) of two first-in-class TB drugs, bedaquiline and delamanid, has reinvigorated the TB drug discovery and development field. However, although several promising clinical development programs are ongoing to evaluate new TB drugs and regimens, the number of novel series represented is few. The global early-development pipeline is also woefully thin. To have a chance of achieving the goal of better, shorter, safer TB drug regimens with utility against drug-sensitive and drug-resistant disease, a robust and diverse global TB drug discovery pipeline is key, including innovative approaches that make use of recently acquired knowledge on the biology of TB. Fortunately, drug discovery for TB has resurged in recent years, generating compounds with varying potential for progression into developable leads. In parallel, advances have been made in understanding TB pathogenesis. It is now possible to apply the lessons learned from recent TB hit generation efforts and newly validated TB drug targets to generate the next wave of TB drug leads. Use of currently underexploited sources of chemical matter and lead-optimization strategies may also improve the efficiency of future TB drug discovery. Novel TB drug regimens with shorter treatment durations must target all subpopulations of Mycobacterium tuberculosis existing in an infection, including those responsible for the protracted TB treatment duration. This review summarizes the current TB drug development pipeline and proposes strategies for generating improved hits and leads in the discovery phase that could help achieve this goal. INTRODUCTION AND CURRENT DRUG DEVELOPMENT PIPELINE

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“…This suggests that any agent that can inhibit Ddn or deazaflavin biosynthesis could synergize with existing anti‐TB drugs. Thus, novel mechanisms to generate ROS/NOS at sufficiently high concentrations should be investigated as potential novel therapy for TB, as long as they do not cause oxidative damage to the host cells …”

Section: Emerging Targetsmentioning

confidence: 99%

Tuberculosis drug discovery and emerging targets

Mdluli

Kaneko

Upton

2014

Annals of the New York Academy of Sciences

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Current tuberculosis (TB) therapies take too long and the regimens are complex and subject to adverse effects and drug-drug interactions with concomitant medications. The emergence of drug-resistant TB strains exacerbates the situation. Drug discovery for TB has resurged in recent years, generating compounds (hits) with varying potential for progression into developable leads. In parallel, advances have been made in understanding TB pathogenesis. It is now possible to apply the lessons learned from recent TB hit generation efforts and newly validated TB drug targets to generate the next wave of TB drug leads. Use of currently underexploited sources of chemical matter and lead-optimization strategies may also improve the efficiency of future TB drug discovery. Novel TB drug regimens with shorter treatment durations must target all subpopulations of Mycobacterium tuberculosis existing in an infection, including those responsible for the protracted TB treatment duration. This review proposes strategies for generating improved hits and leads that could help achieve this goal.

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Aberrant Free Radical Biology Is a Unifying Theme in the Etiology and Pathogenesis of Major Human Diseases

Cited by 12 publications

References 24 publications

Nitroso-Redox Balance and Mitochondrial Homeostasis Are Regulated bySTOX1, a Pre-Eclampsia-Associated Gene

Nitroso-Redox Balance and Mitochondrial Homeostasis Are Regulated bySTOX1, a Pre-Eclampsia-Associated Gene

The Tuberculosis Drug Discovery and Development Pipeline and Emerging Drug Targets

Tuberculosis drug discovery and emerging targets

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