Molecular visualizing and quantifying immune-associated peroxynitrite fluxes in phagocytes and mouse inflammation model

Li, Zan; Yan, Shihai; Chen, Chen; Geng, Zhirong; Chang, Jiayin; Chen, Chunxia; Huang, Binghuan; Wang, Zhi-Lin.

doi:10.1016/j.bios.2016.11.036

Cited by 62 publications

(20 citation statements)

References 39 publications

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“…By applying a recently developed protocol that uses a fluorescent sensor targeted to membranes of the endoplasmic reticulum and allowing for the assessment of phagocytosis by measuring the related peroxynitrite formation, we were able to show that carnosine enhances the phagocytic activity of RAW 264.7 macrophages (Figure 8). Our results are in accordance with two previous studies carried out by Li et al [96] and Rios et al [97], demonstrating an enhanced peroxynitrite production during the process of phagocytosis. The above-mentioned studies along with the one published by Alvarez et al [98], showing the intraphagosomal formation of peroxynitrite as a macrophage-derived cytotoxin against internalized Trypanosoma cruzi, could also explain the transient activation of pro-oxidant enzymes such as NOS2 observed in the presence of carnosine.…”

Section: Discussionsupporting

confidence: 94%

Carnosine Protects Macrophages against the Toxicity of Aβ1-42 Oligomers by Decreasing Oxidative Stress

et al. 2021

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Carnosine (β-alanyl-L-histidine) is a naturally occurring endogenous peptide widely distributed in excitable tissues such as the brain. This dipeptide has well-known antioxidant, anti-inflammatory, and anti-aggregation activities, and it may be useful for treatment of neurodegenerative disorders such as Alzheimer’s disease (AD). In this disease, peripheral infiltrating macrophages play a substantial role in the clearance of amyloid beta (Aβ) peptides from the brain. Correspondingly, in patients suffering from AD, defects in the capacity of peripheral macrophages to engulf Aβ have been reported. The effects of carnosine on macrophages and oxidative stress associated with AD are consequently of substantial interest for drug discovery in this field. In the present work, a model of stress induced by Aβ1-42 oligomers was investigated using a combination of methods including trypan blue exclusion, microchip electrophoresis with laser-induced fluorescence, flow cytometry, fluorescence microscopy, and high-throughput quantitative real-time PCR. These assays were used to assess the ability of carnosine to protect macrophage cells, modulate oxidative stress, and profile the expression of genes related to inflammation and pro- and antioxidant systems. We found that pre-treatment of RAW 264.7 macrophages with carnosine counteracted cell death and apoptosis induced by Aβ1-42 oligomers by decreasing oxidative stress as measured by levels of intracellular nitric oxide (NO)/reactive oxygen species (ROS) and production of peroxynitrite. This protective activity of carnosine was not mediated by modulation of the canonical inflammatory pathway but instead can be explained by the well-known antioxidant and free-radical scavenging activities of carnosine, enhanced macrophage phagocytic activity, and the rescue of fractalkine receptor CX3CR1. These new findings obtained with macrophages challenged with Aβ1-42 oligomers, along with the well-known multimodal mechanism of action of carnosine in vitro and in vivo, substantiate the therapeutic potential of this dipeptide in the context of AD pathology.

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Section: Discussionsupporting

confidence: 94%

Carnosine Protects Macrophages against the Toxicity of Aβ1-42 Oligomers by Decreasing Oxidative Stress

et al. 2021

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“…In this way, a mouse model for acute inflammation was established according to the literature. 37,38 The mice were divided into two groups; one was administered with pure saline intraperitoneally (i.p.) as a control, while the other was injected i.p.…”

Section: Introductionmentioning

confidence: 99%

Protein encapsulation: a new approach for improving the capability of small-molecule fluorogenic probes

et al. 2020

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“…Fluorescent sensors derived from small molecules have been based on cleavable side chains derived from p -hydroxyphenol and p -hydroxyaniline, 6 p -aminophenol, 7–9 p -aminophenyl-trifluoromethylbutanone, 10, 11 boronates, 12 indoles, 13 and other functional groups such as polymethines. 14 In some cases, these sensors have been targeted to intracellular mitochondria 15–19 and lysosomes. 20 Reversible 16, 21 and genetically-encoded 22 fluorescent sensors have also been described.…”

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confidence: 99%

Targeting Fluorescent Sensors to Endoplasmic Reticulum Membranes Enables Detection of Peroxynitrite During Cellular Phagocytosis

2018

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Peroxynitrite is a highly reactive oxidant derived from superoxide and nitric oxide. In normal vertebrate physiology, some phagocytes deploy this oxidant as a cytotoxin against foreign pathogens. To provide a new approach for detection of endogenous cellular peroxynitrite, we synthesized fluorescent sensors targeted to membranes of the endoplasmic reticulum (ER). The very high surface area of these membranes, approximately 30 times greater than the cellular plasma membrane, was envisioned as a vast intracellular platform for the display of sensors to transient reactive species. By linking an ER-targeted profluorophore to reactive phenols, sensors were designed to be cleaved by peroxynitrite and release a highly fluorescent ER-associated rhodol. Studies of kinetics in aqueous buffer revealed a linear free energy relationship where electron-donating substituents accelerate this reaction. However, in living cells, the efficiency of detection of endogenous cellular peroxynitrite was directly proportional to association with ER membranes. By incorporating a 2,6-dimethylphenol to accelerate the reaction and enhance this subcellular targeting, endogenous peroxynitrite in living RAW 264.7 macrophage cells could be readily detected after addition of antibody-opsonized tentagel microspheres, without additional stimulation, a process undetectable with other known fluorescent sensors. This approach provides uniquely sensitive tools for studies of transient reactive species in living mammalian cells.

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Molecular visualizing and quantifying immune-associated peroxynitrite fluxes in phagocytes and mouse inflammation model

Cited by 62 publications

References 39 publications

Carnosine Protects Macrophages against the Toxicity of Aβ1-42 Oligomers by Decreasing Oxidative Stress

Carnosine Protects Macrophages against the Toxicity of Aβ1-42 Oligomers by Decreasing Oxidative Stress

Protein encapsulation: a new approach for improving the capability of small-molecule fluorogenic probes

Targeting Fluorescent Sensors to Endoplasmic Reticulum Membranes Enables Detection of Peroxynitrite During Cellular Phagocytosis

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