In Vivo Imaging of Retinal Oxidative Stress Using a Reactive Oxygen Species–Activated Fluorescent Probe

Prunty, Megan; Aung, Moe H.; Hanif, Adam M.; Allen, Rachael S; Chrenek, Micah A; Boatright, Jeffrey H; Thulé, Peter M.; Kundu, Kousik; Murthy, Niren; Pardue, Machelle T.

doi:10.1167/iovs.15-16810

Cited by 35 publications

(31 citation statements)

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“…Understanding the exact link between oxidative stress and ECM in the context of BAV aortopathy may lead to the discovery of new therapeutic targets to prevent and/or delay aneurysm formation and/or rupture in patients with BAV. In addition, with the development of imaging methods allowing for in vivo detection of oxidative stress, 45–47 our work may support the need to design new diagnostic tools that would utilize oxidative stress as a marker of BAV aortopathy.…”

Section: Discussionmentioning

confidence: 91%

Elevated oxidative stress in the aortic media of patients with bicuspid aortic valve

Billaud

Phillippi

Kotlarczyk

et al. 2017

The Journal of Thoracic and Cardiovascular Surgery

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Objective Congenital bicuspid aortic valve (BAV) is distinctly associated with the development of ascending aortopathy in adulthood, portending risk of both ascending aortic aneurysm and dissection. Our previous work implicated deficiency in oxidative stress response as a mediator of the BAV-associated aortopathy. We hypothesize that reactive oxygen species generation invokes elevated local oxidative tissue damage in ascending aorta of patients with BAV. Methods Ascending aortic specimens were obtained from patients undergoing elective aortic replacement and/or aortic valve replacement and during heart transplant operations. Levels of superoxide anion were measured via high-pressure liquid chromatography–based detection of 2-hydroxyethidium in aortic specimens. Lipid peroxidation and enzymatic activity of superoxide dismutase and peroxidase were quantified in aortic specimens. Results Superoxide anion production was elevated in aortic specimens from patients with nonaneurysmal BAV (n = 59) compared with specimens from patients with the morphologically normal tricuspid aortic valve (TAV, n = 38). Total superoxide dismutase activity was similar among aortic specimens from patients with TAV versus BAV (n = 27 and 26, respectively), whereas peroxidase activity was increased in aortic specimens from patients with BAV compared with specimens from patients with TAV (n = 14 for both groups). Lipid peroxidation was elevated in aortic specimens from BAV patients compared with TAV patients (n = 14 and 11, respectively). Conclusions Superoxide anion accumulation and increased lipid peroxidation demonstrate that, despite increased peroxidase activity, the ascending aortopathy of patients with BAV involves oxidative stress. In addition, the absence of increased superoxide dismutase activity in BAV specimens indicates a deficiency in antioxidant defense. This suggests that the characteristic smooth muscle cell loss observed in BAV aortopathy may be a consequence of superoxidemediated cell damage.

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Section: Discussionmentioning

confidence: 91%

Elevated oxidative stress in the aortic media of patients with bicuspid aortic valve

Billaud

Phillippi

Kotlarczyk

et al. 2017

The Journal of Thoracic and Cardiovascular Surgery

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“…Quest MRI offers advantages compared to other imaging methods that report on oxidative stress in vivo (52,55,57,(75)(76)(77)(78)(79). These other methods involve exogenously administered contrast agents that bind to free radicals (spin traps) and/or require highly specialized equipment (e.g., ref.…”

Section: Discussionmentioning

confidence: 99%

“…52). Thus, their potential clinical application is likely limited because, for example, of a combination of lack of U.S. Food and Drug Administration approval for the contrast agent, difficulty of the contrast agent crossing blood-brain/retina barriers, concerns about how disease may alter contrast agent pharmacokinetics, and possible modifications to endogenous neuronal redox signaling due to binding of free radicals (55,57,(75)(76)(77)(78)(79)(80). However, Quest MRI does not require injection of a contrast agent or require specialized equipment, and Food and Drug Administration-approved antioxidants can be used for the confirmatory quench.…”

Section: Discussionmentioning

confidence: 99%

In vivoimaging of prodromal hippocampus CA1 subfield oxidative stress in models of Alzheimer disease and Angelman syndrome

et al. 2017

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Hippocampus oxidative stress is considered pathogenic in neurodegenerative diseases, such as Alzheimer disease (AD), and in neurodevelopmental disorders, such as Angelman syndrome (AS). Yet clinical benefits of antioxidant treatment for these diseases remain unclear because conventional imaging methods are unable to guide management of therapies in specific hippocampus subfields that underlie abnormal behavior. Excessive production of paramagnetic free radicals in nonhippocampus brain tissue can be measured as a greater-than-normal 1/ that is quenchable with antioxidant as measured by quench-assisted (Quest) MRI. Here, we further test this approach in phantoms, and we present proof-of-concept data in models of AD-like and AS hippocampus oxidative stress that also exhibit impaired spatial learning and memory. AD-like models showed an abnormal gradient along the CA1 dorsal-ventral axis of excessive free radical production as measured by Quest MRI, and redox-sensitive calcium dysregulation as measured by manganese-enhanced MRI and electrophysiology. In the AS model, abnormally high free radical levels were observed in dorsal and ventral CA1. Quest MRI is a promising paradigm for bridging brain subfield oxidative stress and behavior in animal models and in human patients to better manage antioxidant therapy in devastating neurodegenerative and neurodevelopmental diseases.-Berkowitz, B. A., Lenning, J., Khetarpal, N., Tran, C., Wu, J. Y., Berri, A. M., Dernay, K., Haacke, E. M., Shafie-Khorassani, F., Podolsky, R. H., Gant, J. C., Maimaiti, S., Thibault, O., Murphy, G. G., Bennett, B. M., Roberts, R. imaging of prodromal hippocampus CA1 subfield oxidative stress in models of Alzheimer disease and Angelman syndrome.

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“…Accurate reactive oxygen species (ROS) quantification and characterization plays an important role in the investigation of metabolism [1,2], inflammatory responses [3,4], the pathogenesis of the disease [5,6], treatment monitoring [7][8][9] [10] and potentially provides prognostic information [11]. Currently, standard ROS measurement uses various molecular indicators such as dichlorofluorescein, a fluorescent probe that reacts intracellularly with peroxidase, or CellROX, a fluorogenic probe for measuring oxidative stress in live cells and tissue [12][13][14]. However, due to challenges with administration and potential toxicity molecular ROS probes may not be suitable for in-vivo use [12].…”

Section: Introductionmentioning

confidence: 99%

Non-invasive real-time imaging of reactive oxygen species (ROS) using multispectral auto-fluorescence imaging technique: a novel tool for redox biology

Habibalahi¹,

Moghari

Campbell

et al. 2020

Preprint

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AbstractDetecting reactive oxygen species (ROS) that play a critical role as redox modulators and signalling molecules in biological systems currently requires invasive methods such as ROS - specific indicators for imaging and quantification. We developed a non-invasive, real-time, label-free imaging technique for assessing the level of ROS in live cells and thawed cryopreserved tissues that is compatible with in-vivo imaging. The technique is based on autofluorescence multispectral imaging (AFMI) carried out in an adapted fluorescence microscope with an expanded number of spectral channels spanning specific excitation (365 nm-495 nm) and emission (420 nm-700 nm) wavelength ranges. We established a strong quantitative correlation between the spectral information obtained from AFMI and the level of ROS obtained from CellROX staining. The results were obtained in several cell types (HeLa, PANC1 and mesenchymal stem cells) and in live kidney tissue. Additioanly, two spectral regimes were considered: with and without UV excitation (wavelengths > 400 nm); the latter being suitable for UV-sensitive systems such as the eye. Data were analyzed by linear regression combined with an optimization method of swarm intelligence. This allowed the calibration of AFMI signals to the level of ROS with excellent correlation (R= 0.84, p=0.00) in the entire spectral range and very good correlation (R= 0.78, p=0.00) in the limited, UV-free spectral range. We also developed a strong classifier which allowed us to distinguish moderate and high levels of ROS in these two regimes (AUC= 0.91 in the entire spectral range and AUC = 0.78 for UV-free imaging). These results indicate that ROS in cells and tissues can be imaged non-invasively, which opens the way to future clinical applications in conditions where reactive oxygen species are known to contribute to progressive disease such as in ophthalmology, diabetes, kidney disease, cancer and neurodegenerative diseases.

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In Vivo Imaging of Retinal Oxidative Stress Using a Reactive Oxygen Species–Activated Fluorescent Probe

Abstract: Hydrocyanine-800CW detects retinal ROS in vivo and shows potential as a novel biomarker for ROS levels in ophthalmic diseases.

Cited by 35 publications

References 50 publications

Elevated oxidative stress in the aortic media of patients with bicuspid aortic valve

Elevated oxidative stress in the aortic media of patients with bicuspid aortic valve

In vivoimaging of prodromal hippocampus CA1 subfield oxidative stress in models of Alzheimer disease and Angelman syndrome

Non-invasive real-time imaging of reactive oxygen species (ROS) using multispectral auto-fluorescence imaging technique: a novel tool for redox biology

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