Chlamydia muridarum Infection of Macrophages Elicits Bactericidal Nitric Oxide Production via Reactive Oxygen Species and Cathepsin B

The ability of certain species ofChlamydiato inhibit the biogenesis of phagolysosomes permits their survival and replication within macrophages. The survival of macrophage-adapted chlamydiae correlates with the multiplicity of infection (MOI), and optimal chlamydial growth occurs in macrophages infected at an MOI of ≤1. In this study, we examined the replicative capacity ofChlamydia muridarumin the RAW 264.7 murine macrophage cell line at different MOIs.C. muridarumproductively infected these macrophages at low MOIs but yielded few viable elementary bodies (EBs) when macrophages were infected at a moderate (10) or high (100) MOI. While high MOIs caused cytotoxicity and irreversible host cell death, macrophages infected at a moderate MOI did not show signs of cytotoxicity until late in the infectious cycle. Inhibition of host protein synthesis rescuedC. muridarumin macrophages infected at a moderate MOI, implying that chlamydial growth was blocked by activated defense mechanisms. Conditioned medium from these macrophages was antichlamydial and contained elevated levels of interleukin 1β (IL-1β), IL-6, IL-10, and beta interferon (IFN-β). Macrophage activation depended on Toll-like receptor 2 (TLR2) signaling, and cytokine production required live, transcriptionally active chlamydiae. A hydroxyl radical scavenger and inhibitors of inducible nitric oxide synthase (iNOS) and cathepsin B also reversed chlamydial killing. High levels of reactive oxygen species (ROS) led to an increase in cathepsin B activity, and pharmacological inhibition of ROS and cathepsin B reduced iNOS expression. Our data demonstrate that MOI-dependent TLR2 activation of macrophages results in iNOS induction via a novel ROS- and cathepsin-dependent mechanism to facilitateC. muridarumclearance.

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The Dynll1-Cox4i1 Complex Regulates Intracellular Pathogen Clearance via Release of Mitochondrial Reactive Oxygen Species

Infection and Immunity ◽

10.1128/iai.00738-19 ◽

2020 ◽

Vol 88 (4) ◽

Cited By ~ 2

Author(s):

Jiangbei Yuan ◽

Zihan Zheng ◽

Liting Wang ◽

Haiying Ran ◽

Xiangyu Tang ◽

...

Keyword(s):

Reactive Oxygen Species ◽

Listeria Monocytogenes ◽

Membrane Proteins ◽

Defense Mechanisms ◽

Reactive Oxygen ◽

Cellular Membrane ◽

Oxygen Species ◽

Dynein Light Chain ◽

Mitochondrial Reactive Oxygen Species ◽

Content Type

ABSTRACT Cellular membrane proteins are a critical part of the host defense mechanisms against infection and intracellular survival of Listeria monocytogenes. The complex spatiotemporal regulation of bacterial infection by various membrane proteins has been challenging to study. Here, using mass spectrometry analyses, we depicted the dynamic expression landscape of membrane proteins upon L. monocytogenes infection in dendritic cells. We showed that Dynein light chain 1 (Dynll1) formed a persistent complex with the mitochondrial cytochrome oxidase Cox4i1, which is disturbed by pathogen insult. We discovered that the dissociation of the Dynll1-Cox4i1 complex is required for the release of mitochondrial reactive oxygen species and serves as a regulator of intracellular proliferation of Listeria monocytogenes. Our study shows that Dynll1 is an inhibitor of mitochondrial reactive oxygen species and can serve as a potential molecular drug target for antibacterial treatment.

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Endotoxin Potentiates Cocaine-Mediated Hepatotoxicity by Nitric Oxide and Reactive Oxygen Species

International Journal of Toxicology ◽

10.1080/10915810305117 ◽

2003 ◽

Vol 22 (4) ◽

pp. 305-316 ◽

Cited By ~ 16

Author(s):

Ramez Labib ◽

Rita Turkall ◽

Mohamed S. Abdel-Rahman

Keyword(s):

Nitric Oxide ◽

Reactive Oxygen Species ◽

Free Radical ◽

Kupffer Cells ◽

Oxidant Stress ◽

Treatment Protocol ◽

Reactive Oxygen ◽

Radical Scavenger ◽

Oxygen Species ◽

Hydroxyl Free Radical

Exposure to small, noninjurious doses of the inflammagen, bacterial endotoxin (lipopolysaccharide, LPS) augments the toxicity of certain hepatotoxicants, including cocaine. The mechanism of this interaction has not been clearly elucidated, but it seems that aspects of the inflammatory response initiated by exposure to LPS may be responsible. In particular, this study examined the role of Kupffer cells and the modulating effects of nitric oxide (NO) and reactive oxygen species (ROS) on the LPS potentiation of cocaine-mediated hepatotoxicity (CMH). Mice were administered oral cocaine hy-drochloride for 5 consecutive days at a dose of 20 mg/kg with and without 12 times 106 EU LPS/kg given intraperitoneally (IP) 4 hours after the last cocaine injection. Pretreatment regimens consisted of administration of 300 mg/kg, IP, of aminoguanidine (AM) or 1,3-dimethylthiourea (DMU) at 1 hour or 15 minutes, respectively, before each cocaine administration. In another group, mice were pretreated with saline using the same cocaine and LPS treatment protocol, but received a single pretreatment of 7 mg gadolinium chloride (Gd Cl3)/kg intravenously (IV), or sterile saline 24 hours prior to the LPS administration. The Gd Cl3 (Kupffer cell inhibitor) pretreatment inhibited the LPS potentiation of CMH, but did not reverse the effects of cocaine alone. On the other hand, AM (NO synthase inhibitor), decreased the synthesis of NO as observed by the decrease in the plasma nitrate/nitrite level and completely reversed the hepatotoxic effects of cocaine and LPS alone and in combination. Moreover, DMU (hydroxyl free radical scavenger) ameliorated the effects of cocaine and significantly reduced the hepatotoxicity observed with the cocaine and LPS administration. These data suggest that cocaine sensitizes the liver and subsequent activation of Kupffer cells by LPS leads to the formation of increased levels of NO, which can promote oxidant stress and thus provide an environment favoring the generation of more reactive species such as the hydroxyl free radical.

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Melanin Protects Paracoccidioides brasiliensis from the Effects of Antimicrobial Photodynamic Inhibition and Antifungal Drugs

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.04917-14 ◽

2015 ◽

Vol 59 (7) ◽

pp. 4003-4011 ◽

Cited By ~ 16

Author(s):

Ludmila Matos Baltazar ◽

Silvia Maria Cordeiro Werneck ◽

Betânia Maria Soares ◽

Marcus Vinicius L. Ferreira ◽

Danielle G. Souza ◽

...

Keyword(s):

Nitric Oxide ◽

Reactive Oxygen Species ◽

Amphotericin B ◽

Reactive Oxygen ◽

Antifungal Drugs ◽

Yeast Cells ◽

Health Concern ◽

Oxygen Species ◽

Protective Function ◽

Content Type

ABSTRACTParacoccidioidomycosis (PCM) is a public health concern in Latin America and South America that when not correctly treated can lead to patient death. In this study, the influence of melanin produced byParacoccidioidesspp. on the effects of treatment with antimicrobial photodynamic inhibition (aPI) and antifungal drugs was evaluated. aPI was performed using toluidine blue (TBO) as a photosensitizer and a 630-nm light-emitting diode (LED) light. The antifungals tested were itraconazole and amphotericin B. We evaluated the effects of each approach, aPI or antifungals, against nonmelanized and melanized yeast cells by performing susceptibility tests and by quantifying oxidative and nitrosative bursts during the experiments. aPI reduced nonmelanized cells by 3.0 log units and melanized cells by 1.3 log units. The results showed that melanization protects the fungal cell, probably by acting as a scavenger of nitric oxide and reactive oxygen species, but not of peroxynitrite. Melanin also increased the MICs of itraconazole and amphotericin B, and the drugs were fungicidal for nonmelanized and fungistatic for melanized yeast cells. Our study shows that melanin production byParacoccidioidesyeast cells serves a protective function during aPI and treatment with itraconazole and amphotericin B. The results suggest that melanin binds to the drugs, changing their antifungal activities, and also acts as a scavenger of reactive oxygen species and nitric oxide, but not of peroxynitrite, indicating that peroxynitrite is the main radical that is responsible for fungal death after aPI.

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Overlapping and Complementary Oxidative Stress Defense Mechanisms in Nontypeable Haemophilus influenzae

Journal of Bacteriology ◽

10.1128/jb.01973-14 ◽

2014 ◽

Vol 197 (2) ◽

pp. 277-285 ◽

Cited By ~ 10

Author(s):

Alistair Harrison ◽

Beth D. Baker ◽

Robert S. Munson

Keyword(s):

Oxidative Stress ◽

Reactive Oxygen Species ◽

Haemophilus Influenzae ◽

Fenton Reaction ◽

Defense Mechanisms ◽

Reactive Oxygen ◽

Chronic Obstructive ◽

Oxygen Species ◽

Nontypeable Haemophilus Influenzae ◽

Content Type

The Gram-negative commensal bacterium nontypeableHaemophilus influenzae(NTHI) can cause respiratory tract diseases that include otitis media, sinusitis, exacerbations of chronic obstructive pulmonary disease, and bronchitis. During colonization and infection, NTHI withstands oxidative stress generated by reactive oxygen species produced endogenously, by the host, and by other copathogens and flora. These reactive oxygen species include superoxide, hydrogen peroxide (H2O2), and hydroxyl radicals, whose killing is amplified by iron via the Fenton reaction. We previously identified genes that encode proteins with putative roles in protection of the NTHI isolate strain 86-028NP against oxidative stress. These include catalase (HktE), peroxiredoxin/glutaredoxin (PgdX), and a ferritin-like protein (Dps). Strains were generated with mutations inhktE,pgdX, anddps. ThehktEmutant and apgdX hktEdouble mutant were more sensitive than the parent to killing by H2O2. Conversely, thepgdXmutant was more resistant to H2O2due to increased catalase activity. Supporting the role of killing via the Fenton reaction, binding of iron by Dps significantly mitigated the effect of H2O2-mediated killing. NTHI thus utilizes several effectors to resist oxidative stress, and regulation of free iron is critical to this protection. These mechanisms will be important for successful colonization and infection by this opportunistic human pathogen.

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Faculty Opinions recommendation of Sources of vascular nitric oxide and reactive oxygen species and their regulation

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.734520172.793578224 ◽

2020 ◽

Author(s):

Paschalis-Thomas Doulias

Keyword(s):

Nitric Oxide ◽

Reactive Oxygen Species ◽

Reactive Oxygen ◽

Oxygen Species

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The Role of Reactive Oxygen Species, Kinases, Hydrogen Sulfide, and Nitric Oxide in the Regulation of Autophagy and Their Impact on Ischemia and Reperfusion Injury in the Heart

Current Cardiology Reviews ◽

10.2174/1573403x16666201014142446 ◽

2020 ◽

Vol 16 ◽

Author(s):

Andrey Krylatov ◽

Leonid Maslov ◽

Sergey Y. Tsibulnikov ◽

Nikita Voronkov ◽

Alla Boshchenko ◽

...

Keyword(s):

Nitric Oxide ◽

Reactive Oxygen Species ◽

Hydrogen Sulfide ◽

Ischemia Reperfusion ◽

Reactive Oxygen ◽

Ischemia And Reperfusion ◽

Oxygen Species ◽

Ischemia And Reperfusion Injury ◽

Adaptive Process

: There is considerable evidence in the heart that autophagy in cardiomyocytes is activated by hypoxia/reoxygenation (H/R) or in hearts by ischemia/reperfusion (I/R). Depending upon the experimental model and duration of ischemia, increases in autophagy in this setting maybe beneficial (cardioprotective) or deleterious (exacerbate I/R injury). Aside from the conundrum as to whether or not autophagy is an adaptive process, it is clearly regulated by a number of diverse molecules including reactive oxygen species (ROS), various kinases, hydrogen sulfide (H2S) and nitric oxide (NO). The purpose this review is to address briefly the controversy regarding the role of autophagy in this setting and to examine a variety of disparate molecules that are involved in its regulation.

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Plasmonic Enhancement of Nitric Oxide Generation

Nanoscale ◽

10.1039/d1nr02126e ◽

2021 ◽

Author(s):

Rachael Knoblauch ◽

Chris Geddes

Keyword(s):

Nitric Oxide ◽

Reactive Oxygen Species ◽

Reactive Nitrogen Species ◽

Reactive Oxygen ◽

Reactive Nitrogen ◽

Oxygen Species ◽

Nitrogen Species ◽

Plasmonic Enhancement ◽

Cancer Treatments

While the utility of reactive oxygen species in photodynamic therapies for both cancer treatments and antimicrobial applications has received much attention, the inherent potential of reactive nitrogen species (RNS) including...

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Reactive Oxygen Species-Dependent Nitric Oxide Production in Reciprocal Interactions of Glioma and Microglial Cells

Journal of Cellular Physiology ◽

10.1002/jcp.24659 ◽

2014 ◽

Vol 229 (12) ◽

pp. 2015-2026 ◽

Cited By ~ 21

Author(s):

Shing-Chuan Shen ◽

Ming-Shun Wu ◽

Hui-Yi Lin ◽

Liang-Yo Yang ◽

Yi-Hsuan Chen ◽

...

Keyword(s):

Nitric Oxide ◽

Reactive Oxygen Species ◽

Reactive Oxygen ◽

Microglial Cells ◽

Nitric Oxide Production ◽

Oxygen Species ◽

Reciprocal Interactions ◽

Oxide Production

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The role of oxidative/nitrosative stress in pathogenesis of paracetamol-induced toxic hepatitis

Medicinski pregled ◽

10.2298/mpns1012827r ◽

2010 ◽

Vol 63 (11-12) ◽

pp. 827-832 ◽

Cited By ~ 7

Author(s):

Tatjana Radosavljevic ◽

Dusan Mladenovic ◽

Danijela Vucevic ◽

Rada Jesic-Vukicevic

Keyword(s):

Oxidative Stress ◽

Nitric Oxide ◽

Reactive Oxygen Species ◽

Liver Injury ◽

Kupffer Cells ◽

Reactive Oxygen ◽

Oxygen Species ◽

Severe Liver ◽

Hepatocellular Necrosis

Introduction. Paracetamol is an effective analgesic/antipyretic drug when used at therapeutic doses. However, the overdose of paracetamol can cause severe liver injury and liver necrosis. The mechanism of paracetamol-induced liver injury is still not completely understood. Reactive metabolite formation, depletion of glutathione and alkylation of proteins are the triggers of inhibition of mitochondrial respiration, adenosine triphosphate depletion and mitochondrial oxidant stress leading to hepatocellular necrosis. Role of oxidative stress in paracetamol-induced liver injury. The importance of oxidative stress in paracetamol hepatotoxicity is controversial. Paracetamol induced liver injury cause the formation of reactive oxygen species. The potent sources of reactive oxygen are mitochondria, neutrophils, Kupffer cells and the enzyme xatnine oxidase. Free radicals lead to lipid peroxidation, enzymatic inactivation and protein oxidation. Role of mitochondria in paracetamol-induced oxidative stress. The production of mitochondrial reactive oxygen species is increased, and the glutathione content is decreased in paracetamol overdose. Oxidative stress in mitochondria leads to mito?chondrial dysfunction with adenosine triphosphate depletion, increase mitochondrial permeability transition, deoxyribonu?cleic acid fragmentation which contribute to the development of hepatocellular necrosis in the liver after paracetamol overdose. Role of Kupffer cells in paracetamol-induced liver injury. Paracetamol activates Kupffer cells, which then release numerous cytokines and signalling molecules, including nitric oxide and superoxide. Kupffer cells are important in peroxynitrite formation. On the other hand, the activated Kupffer cells release anti-inflammatory cytokines. Role of neutrophils in paracetamol-induced liver injury. Paracetamol-induced liver injury leads to the accumulation of neutrophils, which release lysosomal enzymes and generate superoxide anion radicals through the enzyme nicotinamide adenine dinucleotide phosphate oxidase. Hydrogen peroxide, which is influenced by the neutrophil-derived enzyme myeloperoxidase, generates hypochlorus acid as a potent oxidant. Role of peroxynitrite in paracetamol-induced oxidative stress. Superoxide can react with nitric oxide to form peroxynitrite, as a potent oxidant. Nitrotyrosine is formed by the reaction of tyrosine with peroxynitrite in paracetamol hepatotoxicity. Conclusion. Overdose of paracetamol may produce severe liver injury with hepatocellular necrosis. The most important mechanisms of cell injury are metabolic activation of paracetamol, glutathione depletion, alkylation of proteins, especially mitochondrial proteins, and formation of reactive oxygen/nitrogen species.

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