DNA strand breakage, activation of poly (ADP-ribose) synthetase, and cellular energy depletion are involved in the cytotoxicity of macrophages and smooth muscle cells exposed to peroxynitrite.

Szabó, Csaba; Zingarelli, Basilia; O’Connor, Michael; Salzman, Andrew L.

doi:10.1073/pnas.93.5.1753

Cited by 614 publications

(395 citation statements)

References 39 publications

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“…One of the most important functions is related to the fact that mild genotoxic noxa cause PARP activation that facilitates DNA repair and cell survival. Under pathophysiological conditions, reactive species (such as hydrogen peroxide, hydroxyl radical, and peroxynitrite) trigger severe DNA damage and overactivation of PARP (Szabó et al 1996(Szabó et al , 1998b. Peroxynitrite is considered a key trigger of DNA strand breakage because it can travel significant distances and readily crosses cell membranes.…”

Section: Poly(adp-ribose) Polymerase and Its Activationmentioning

confidence: 99%

The pathogenesis of diabetic complications: the role of DNA injury and poly(ADP-ribose) polymerase activation in peroxynitrite-mediated cytotoxicity

Kiss

Szabó

2005

Mem. Inst. Oswaldo Cruz

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Section: Poly(adp-ribose) Polymerase and Its Activationmentioning

confidence: 99%

The pathogenesis of diabetic complications: the role of DNA injury and poly(ADP-ribose) polymerase activation in peroxynitrite-mediated cytotoxicity

Kiss

Szabó

2005

Mem. Inst. Oswaldo Cruz

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“…An excessive stimulation of PARP-1 can lead to depletion of NAD + /NADH and can therefore interfere with the synthesis of ATP [76], leading to a state of cytopathic hypoxia and cell death. is has been studied in various cells, including macrophages and smooth muscle cells stimulated with oxidizing molecules [77], and enterocytes stimulated with proin ammatory cytokines and oxidizing molecules [78].…”

Section: Activation Of Enzymes In Ol Ed In Dna Damage Repair: Poly (Amentioning

confidence: 99%

Sepsis, mitochondrial failure and multiple organ dysfunction

Dúran-Bedolla

Oca-Sandoval²,

Saldaña-Navor³

et al. 2014

CIM

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Purpose: e purpose of this review is to consider the state of oxidative stress, failure of the antioxidant systems and mitochondrial failure as the main physiopathological mechanisms leading to multiple organ dysfunction during sepsis.Principal ndings: Sepsis is a clinical syndrome caused by a severe infection that triggers an exaggerated in ammatory response. Involved in the pathogenesis of sepsis are the activation of in ammatory, immune, hormonal, metabolic and bioenergetic responses. One of the pivotal factors in these processes is the increase of reactive species accompanied by the failure of the antioxidant systems, leading to a state of irreversible oxidative stress and mitochondrial failure.In a physiological state, reactive species and antioxidant systems are in redox balance. e loss of this balance during both chronic and infectious diseases leads to a state of oxidative stress, which is considered to be the greatest promoter of a systemic in ammatory response.e loss of the redox balance, together with a systemic in ammatory response during sepsis, can lead to progressive and irreversible mitochondrial failure, energy depletion, hypoxia, septic shock, severe sepsis, multiple organ dysfunction and death of the patient. Conclusion:Knowledge of the molecular processes associated with the development of oxidative stress should facilitate the development of e ective therapies and better prognosis for patients with sepsis and organ dysfunction.

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“…In several pathologic situations that involve massive DNA damage, excessive activation of PARP-1 depletes the cellular reserve of both NAD and its precursor ATP, leading to cell death via energy failure (28,29). Recently, it has been shown that ROS-mediated DNA damage triggers activation of the PARP-1 and subsequent cell death (30,31).…”

Section: Introductionmentioning

confidence: 99%

Combination treatment with arsenic trioxide and phytosphingosine enhances apoptotic cell death in arsenic trioxide–resistant cancer cells

Park¹,

Kang²,

Park

et al. 2007

Molecular Cancer Therapeutics

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Resistance to anticancer drugs can sometimes be overcome by combination treatment with other therapeutic drugs. Here, we showed that phytosphingosine treatment in combination with arsenic trioxide (As 2 O 3 ) enhanced cell death of naturally As 2 O 3 -resistant human myeloid leukemia cells. The combination treatment induced an increase in intracellular reactive oxygen species level, mitochondrial relocalization of Bax, poly(ADP-ribose) polymerase-1 (PARP-1) activation, and cytochrome c release from the mitochondria. N-acetyl-L-cysteine, a thiol-containing antioxidant, completely blocked Bax relocalization, PARP-1 activation, and cytochrome c release. Pretreatment of 3,4-dihydro-5-[4-(1-piperidinyl)butoxy]-1(2H)-isoquinolinone, a PARP-1 inhibitor, or PARP-1/small interfering RNA partially attenuated cytochrome c release, whereas the same treatment did not affect Bax relocalization. The combination treatment induced selective activation of p38 mitogen-activated protein kinase (MAPK). Inhibition of p38 MAPK by treatment of SB203580 or expression of dominant-negative forms of p38 MAPK suppressed the combination treatment -induced Bax relocalization but did not affect PARP-1 activation. In addition, antioxidant N-acetyl-L-cysteine completely blocked p38 MAPK activation. These results indicate that phytosphingosine in combination with As 2 O 3 induces synergistic apoptosis in As 2 O 3 -resistant leukemia cells through the p38 MAPKmediated mitochondrial translocation of Bax and the PARP-1 activation, and that p38 MAPK and PARP-1 activations are reactive oxygen species dependent. The molecular mechanism that we elucidated in this study may provide insight into the design of future combination cancer therapies to cells intrinsically less sensitive to As 2 O 3 treatment. [Mol Cancer Ther 2007;6(1):82 -92]

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DNA strand breakage, activation of poly (ADP-ribose) synthetase, and cellular energy depletion are involved in the cytotoxicity of macrophages and smooth muscle cells exposed to peroxynitrite.

Cited by 614 publications

References 39 publications

The pathogenesis of diabetic complications: the role of DNA injury and poly(ADP-ribose) polymerase activation in peroxynitrite-mediated cytotoxicity

The pathogenesis of diabetic complications: the role of DNA injury and poly(ADP-ribose) polymerase activation in peroxynitrite-mediated cytotoxicity

Sepsis, mitochondrial failure and multiple organ dysfunction

Combination treatment with arsenic trioxide and phytosphingosine enhances apoptotic cell death in arsenic trioxide–resistant cancer cells

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