scholarly journals Antimalarial Action of Artesunate Involves DNA Damage Mediated by Reactive Oxygen Species

2014 ◽  
Vol 59 (1) ◽  
pp. 317-325 ◽  
Author(s):  
Anusha M. Gopalakrishnan ◽  
Nirbhay Kumar
Keyword(s):  
Reactive Oxygen Species ◽  
Dna Damage ◽  
Free Radicals ◽  
Cytotoxic Effect ◽  
Molecular Mechanisms ◽  
Antimalarial Activity ◽  
Reactive Oxygen ◽  
Oxygen Species ◽  
Content Type ◽  
Artemisinin Derivatives

ABSTRACTArtemisinin-based combination therapy (ACT) is the recommended first-line treatment forPlasmodium falciparummalaria. It has been suggested that the cytotoxic effect of artemisinin is mediated by free radicals followed by the alkylation ofP. falciparumproteins. The endoperoxide bridge, the active moiety of artemisinin derivatives, is cleaved in the presence of ferrous iron, generating reactive oxygen species (ROS) and other free radicals. However, the emergence of resistance to artemisinin inP. falciparumunderscores the need for new insights into the molecular mechanisms of antimalarial activity of artemisinin. Here we show that artesunate (ART) induces DNA double-strand breaks inP. falciparumin a physiologically relevant dose- and time-dependent manner. DNA damage induced by ART was accompanied by an increase in the intracellular ROS level in the parasites. Mannitol, a ROS scavenger, reversed the cytotoxic effect of ART and reduced DNA damage, and modulation of glutathione (GSH) levels was found to impact ROS and DNA damage induced by ART. Accumulation of ROS, increased DNA damage, and the resulting antiparasite effect suggest a causal relationship between ROS, DNA damage, and parasite death. Finally, we also show that ART-induced ROS production involves a potential role for NADPH oxidase, an enzyme involved in the production of superoxide anions. Our results withP. falciparumprovide novel insights into previously unknown molecular mechanisms underlying the antimalarial activity of artemisinin derivatives and may help in the design of next-generation antimalarial drugs against the most virulentPlasmodiumspecies.

scholarly journals Ascorbate-Dependent Peroxidase (APX) from Leishmania amazonensis Is a Reactive Oxygen Species-Induced Essential Enzyme That Regulates Virulence

2019 ◽  
Vol 87 (12) ◽  
Author(s):  
Lucia Xiang ◽  
Maria Fernanda Laranjeira-Silva ◽  
Fernando Y. Maeda ◽  
Jason Hauzel ◽  
Norma W. Andrews ◽  
...  
Keyword(s):  
Reactive Oxygen Species ◽  
Molecular Mechanisms ◽  
Reactive Oxygen ◽  
Oxygen Species ◽  
Macrophage Infection ◽  
Cutaneous Lesions ◽  
Signaling Mechanism ◽  
Content Type ◽  
Temporal Regulation ◽  
Metacyclic Promastigotes

ABSTRACT The molecular mechanisms underlying biological differences between two Leishmania species that cause cutaneous disease, L. major and L. amazonensis, are poorly understood. In L. amazonensis, reactive oxygen species (ROS) signaling drives differentiation of nonvirulent promastigotes into forms capable of infecting host macrophages. Tight spatial and temporal regulation of H2O2 is key to this signaling mechanism, suggesting a role for ascorbate-dependent peroxidase (APX), which degrades mitochondrial H2O2. Earlier studies showed that APX-null L. major parasites are viable, accumulate higher levels of H2O2, generate a greater yield of infective metacyclic promastigotes, and have increased virulence. In contrast, we found that in L. amazonensis, the ROS-inducible APX is essential for survival of all life cycle stages. APX-null promastigotes could not be generated, and parasites carrying a single APX allele were impaired in their ability to infect macrophages and induce cutaneous lesions in mice. Similar to what was reported for L. major, APX depletion in L. amazonensis enhanced differentiation of metacyclic promastigotes and amastigotes, but the parasites failed to replicate after infecting macrophages. APX expression restored APX single-knockout infectivity, while expression of catalytically inactive APX drastically reduced virulence. APX overexpression in wild-type promastigotes reduced metacyclogenesis, but enhanced intracellular survival following macrophage infection or inoculation into mice. Collectively, our data support a role for APX-regulated mitochondrial H2O2 in promoting differentiation of virulent forms in both L. major and L. amazonensis. Our results also uncover a unique requirement for APX-mediated control of ROS levels for survival and successful intracellular replication of L. amazonensis.

scholarly journals The Helicobacter pylori CZB Cytoplasmic Chemoreceptor TlpD Forms an Autonomous Polar Chemotaxis Signaling Complex That Mediates a Tactic Response to Oxidative Stress

2016 ◽  
Vol 198 (11) ◽  
pp. 1563-1575 ◽  
Author(s):  
Kieran D. Collins ◽  
Tessa M. Andermann ◽  
Jenny Draper ◽  
Lisa Sanders ◽  
Susan M. Williams ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Reactive Oxygen Species ◽  
Helicobacter Pylori ◽  
Molecular Mechanisms ◽  
Reactive Oxygen ◽  
Host Cells ◽  
Oxygen Species ◽  
Content Type ◽  
Signaling Complex ◽  
H Pylori

ABSTRACTCytoplasmic chemoreceptors are widespread among prokaryotes but are far less understood than transmembrane chemoreceptors, despite being implicated in many processes. One such cytoplasmic chemoreceptor isHelicobacter pyloriTlpD, which is required for stomach colonization and drives a chemotaxis response to cellular energy levels. Neither the signals sensed by TlpD nor its molecular mechanisms of action are known. We report here that TlpD functions independently of the other chemoreceptors. When TlpD is the sole chemoreceptor, it is able to localize to the pole and recruits CheW, CheA, and at least two CheV proteins to this location. It loses the normal membrane association that appears to be driven by interactions with other chemoreceptors and with CheW, CheV1, and CheA. These results suggest that TlpD can form an autonomous signaling unit. We further determined that TlpD mediates a repellent chemotaxis response to conditions that promote oxidative stress, including being in the presence of iron, hydrogen peroxide, paraquat, and metronidazole. Last, we found that all testedH. pyloristrains express TlpD, whereas other chemoreceptors were present to various degrees. Our data suggest a model in which TlpD coordinates a signaling complex that responds to oxidative stress and may allowH. pylorito avoid areas of the stomach with high concentrations of reactive oxygen species.IMPORTANCEHelicobacter pylorisenses its environment with proteins called chemoreceptors. Chemoreceptors integrate this sensory information to affect flagellum-based motility in a process called chemotaxis. Chemotaxis is employed during infection and presumably aidsH. pyloriin encountering and colonizing preferred niches. A cytoplasmic chemoreceptor named TlpD is particularly important in this process, and we report here that this chemoreceptor is able to operate independently of other chemoreceptors to organize a chemotaxis signaling complex and mediate a repellent response to oxidative stress conditions.H. pyloriencounters and must cope with oxidative stress during infection due to oxygen and reactive oxygen species produced by host cells. TlpD's repellent response may allow the bacteria to escape niches experiencing inflammation and elevated reactive oxygen species (ROS) production.

scholarly journals Porphyromonas gingivalis-Induced Reactive Oxygen Species Activate JAK2 and Regulate Production of Inflammatory Cytokines through c-Jun

2014 ◽  
Vol 82 (10) ◽  
pp. 4118-4126 ◽  
Author(s):  
Huizhi Wang ◽  
Huaxin Zhou ◽  
Xiaoxian Duan ◽  
Ravi Jotwani ◽  
Himabindu Vuddaraju ◽  
...  
Keyword(s):  
Reactive Oxygen Species ◽  
Porphyromonas Gingivalis ◽  
Proinflammatory Cytokines ◽  
Molecular Mechanisms ◽  
Reactive Oxygen ◽  
Oxygen Species ◽  
Content Type ◽  
Amino Terminal ◽  
Signaling Axis ◽  
Interfering Rna

ABSTRACTPathogen-induced reactive oxygen species (ROS) play a crucial role in host innate immune responses through regulating the quality and quantity of inflammatory mediators. However, the underlying molecular mechanisms of this effect have yet to be clarified. In this study, we examined the mechanism of action of ROS stimulated byPorphyromonas gingivalisin gingival epithelial cells.P. gingivalisinduced the rapid production of ROS, which lead to the phosphorylation of JAK2 and increased levels of secreted proinflammatory cytokines interleukin-6 (IL-6) and IL-1β. Neutralization of ROS byN-acetyl-l-cysteine (NAC) abrogated the phosphorylation of JAK2 and suppressed the production of IL-6 and IL-1β. ROS-mediated phosphorylation of JAK2 induced the phosphoactivation of c-Jun amino-terminal protein kinase (JNK) and the downstream transcriptional regulator c-Jun. Inhibition of JAK2, either pharmacologically or by small interfering RNA (siRNA), reduced both the phosphorylation of these molecules and the production of proinflammatory cytokines in response toP. gingivalis. Furthermore, pharmacological inhibition or siRNA-mediated gene silencing of JNK or c-Jun mimicked the effect of JAK2 inhibition to suppressP. gingivalis-induced IL-6 and IL-1β levels. The results show that ROS-mediated activation of JAK2 is required forP. gingivalis-induced inflammatory cytokine production and that the JNK/c-Jun signaling axis is involved in the ROS-dependent regulation of IL-1β and IL-6 production.

scholarly journals Mitochondrial DNA-depleted A549 cells are resistant to bleomycin

2012 ◽  
Vol 303 (5) ◽  
pp. L413-L424 ◽  
Author(s):  
Sukhdev S. Brar ◽  
Joel N. Meyer ◽  
Carl D. Bortner ◽  
Bennett Van Houten ◽  
William J. Martin
Keyword(s):  
Reactive Oxygen Species ◽  
Dna Damage ◽  
Mitochondrial Dna ◽  
Molecular Mechanisms ◽  
Caspase 3 ◽  
A549 Cells ◽  
Reactive Oxygen ◽  
Alveolar Epithelial Cells ◽  
Oxygen Species ◽  
Alveolar Epithelial

Alveolar epithelial cells are considered to be the primary target of bleomycin-induced lung injury, leading to interstitial fibrosis. The molecular mechanisms by which bleomycin causes this damage are poorly understood but are suspected to involve generation of reactive oxygen species and DNA damage. We studied the effect of bleomycin on mitochondrial DNA (mtDNA) and nuclear DNA (nDNA) in human alveolar epithelial A549 cells. Bleomycin caused an increase in reactive oxygen species production, DNA damage, and apoptosis in A549 cells; however, bleomycin induced more mtDNA than nDNA damage. DNA damage was associated with activation of caspase-3, cleavage of poly(ADP-ribose) polymerase, and cleavage and activation of protein kinase D1 (PKD1), a newly identified mitochondrial oxidative stress sensor. These effects appear to be mtDNA-dependent, because no caspase-3 or PKD1 activation was observed in mtDNA-depleted (ρ0) A549 cells. Survival rate after bleomycin treatment was higher for A549 ρ0 than A549 cells. These results suggest that A549 ρ0 cells are more resistant to bleomycin toxicity than are parent A549 cells, likely in part due to the depletion of mtDNA and impairment of mitochondria-dependent apoptotic pathways.

Cytotoxic effect of formaldehyde with free radicals via increment of cellular reactive oxygen species

Toxicology ◽  
2005 ◽  
Vol 210 (2-3) ◽  
pp. 235-245 ◽  
Author(s):  
Yoshiro Saito ◽  
Keiko Nishio ◽  
Yasukazu Yoshida ◽  
Etsuo Niki
Keyword(s):  
Reactive Oxygen Species ◽  
Free Radicals ◽  
Cytotoxic Effect ◽  
Reactive Oxygen ◽  
Oxygen Species ◽  
Cellular Reactive Oxygen Species

scholarly journals Role of Bacillus subtilis DNA Glycosylase MutM in Counteracting Oxidatively Induced DNA Damage and in Stationary-Phase-Associated Mutagenesis

2015 ◽  
Vol 197 (11) ◽  
pp. 1963-1971 ◽  
Author(s):  
Martha Gómez-Marroquín ◽  
Luz E. Vidales ◽  
Bernardo N. Debora ◽  
Fernando Santos-Escobar ◽  
Armando Obregón-Herrera ◽  
...  
Keyword(s):  
Reactive Oxygen Species ◽  
Hydrogen Peroxide ◽  
Dna Damage ◽  
Bacillus Subtilis ◽  
Stationary Phase ◽  
Reactive Oxygen ◽  
Dna Glycosylase ◽  
Oxygen Species ◽  
Content Type

ABSTRACTReactive oxygen species (ROS) promote the synthesis of the DNA lesion 8-oxo-G, whose mutagenic effects are counteracted in distinct organisms by the DNA glycosylase MutM. We report here that inBacillus subtilis,mutMis expressed during the exponential and stationary phases of growth. In agreement with this expression pattern, results of a Western blot analysis confirmed the presence of MutM in both stages of growth. In comparison with cells of a wild-type strain, cells ofB. subtilislacking MutM increased their spontaneous mutation frequency to Rifrand were more sensitive to the ROS promoter agents hydrogen peroxide and 1,1′-dimethyl-4,4′-bipyridinium dichloride (Paraquat). However, despite MutM's proven participation in preventing ROS-induced-DNA damage, the expression ofmutMwas not induced by hydrogen peroxide, mitomycin C, or NaCl, suggesting that transcription of this gene is not under the control of the RecA, PerR, or σBregulons. Finally, the role of MutM in stationary-phase-associated mutagenesis (SPM) was investigated in the strainB. subtilisYB955 (hisC952 metB5 leuC427). Results revealed that under limiting growth conditions, amutMknockout strain significantly increased the amount of stationary-phase-associatedhis,met, andleurevertants produced. In summary, our results support the notion that the absence of MutM promotes mutagenesis that allows nutritionally stressedB. subtiliscells to escape from growth-limiting conditions.IMPORTANCEThe present study describes the role played by a DNA repair protein (MutM) in protecting the soil bacteriumBacillus subtilisfrom the genotoxic effects induced by reactive oxygen species (ROS) promoter agents. Moreover, it reveals that the genetic inactivation ofmutMallows nutritionally stressed bacteria to escape from growth-limiting conditions, putatively by a mechanism that involves the accumulation and error-prone processing of oxidized DNA bases.

scholarly journals 4-Hydroxychalcone Induces Cell Death via Oxidative Stress in MYCN-Amplified Human Neuroblastoma Cells

2019 ◽  
Vol 2019 ◽  
pp. 1-16 ◽  
Author(s):  
Amnah M. Alshangiti ◽  
Eszter Tuboly ◽  
Shane V. Hegarty ◽  
Cathal M. McCarthy ◽  
Aideen M. Sullivan ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Reactive Oxygen Species ◽  
Cell Death ◽  
Cytotoxic Effect ◽  
Neuroblastoma Cells ◽  
Reactive Oxygen ◽  
Prognostic Indicator ◽  
Oxygen Species ◽  
Human Neuroblastoma Cells ◽  
Human Neuroblastoma

Neuroblastoma is an embryonal malignancy that arises from cells of sympathoadrenal lineage during the development of the nervous system. It is the most common pediatric extracranial solid tumor and is responsible for 15% of childhood deaths from cancer. Fifty percent of cases are diagnosed as high-risk metastatic disease with a low overall 5-year survival rate. More than half of patients experience disease recurrence that can be refractory to treatment. Amplification of the MYCN gene is an important prognostic indicator that is associated with rapid disease progression and a poor prognosis, highlighting the need for new therapeutic approaches. In recent years, there has been an increasing focus on identifying anticancer properties of naturally occurring chalcones, which are secondary metabolites with variable phenolic structures. Here, we report that 4-hydroxychalcone is a potent cytotoxin for MYCN-amplified IMR-32 and SK-N-BE (2) neuroblastoma cells, when compared to non-MYCN-amplified SH-SY5Y neuroblastoma cells and to the non-neuroblastoma human embryonic kidney cell line, HEK293t. Moreover, 4-hydroxychalcone treatment significantly decreased cellular levels of the antioxidant glutathione and increased cellular reactive oxygen species. In addition, 4-hydroxychalcone treatment led to impairments in mitochondrial respiratory function, compared to controls. In support of this, the cytotoxic effect of 4-hydroxychalcone was prevented by co-treatment with either the antioxidant N-acetyl-L-cysteine, a pharmacological inhibitor of oxidative stress-induced cell death (IM-54) or the mitochondrial reactive oxygen species scavenger, Mito-TEMPO. When combined with the anticancer drugs cisplatin or doxorubicin, 4-hydroxychalcone led to greater reductions in cell viability than was induced by either anti-cancer agent alone. In summary, this study identifies a cytotoxic effect of 4-hydroxychalcone in MYCN-amplified human neuroblastoma cells, which rationalizes its further study in the development of new therapies for pediatric neuroblastoma.

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