Transglutaminase 2 (TGase2) is a ubiquitously expressed enzyme that catalyzes irreversible post-translational modification of protein, forming cross-linked protein aggregates. We previously reported that intracellular TGase2 is activated by oxidative stress. To elucidate the functional role of TGase2 activation in cells under the oxidatively stressed condition, we identified the mediator that activates TGase2. In this study, we showed that low levels of oxidative stress trigger the release of TGFbeta, which subsequently activates TGase2 through the nuclear translocation of Smad3. Analysis of substrate proteins reveals that TGase2-mediated protein modification results in a decrease of protein solubility and a collapse of intermediate filament network, which leads to aggregation of proteins. We confirm these results using lens tissues from TGase2-deficient mice. Among several antioxidants tried, only N-acetylcysteine effectively inhibits TGFbeta-mediated activation of TGase2. These results indicate that TGFbeta mediates oxidative stress-induced protein aggregation through activation of TGase2 and suggest that the formation of protein aggregation may not be a passive process of self-assembly of oxidatively damaged proteins but may be an active cellular response to oxidative stress. Therefore, TGFbeta-TGase2 pathway may have implications for both the pathogenesis of age-related degenerative diseases and the development of pharmaceutics.
Diabetes is a disease condition characterized by a prolonged, high blood glucose level, which may lead to devastating outcomes unless properly managed. Here, we introduce a simple camera-based optical monitoring system (OMS) utilizing the nanoparticle embedded contact lens that produces color changes matching the tear glucose level without any complicated electronic components. Additionally, we propose an image processing algorithm that automatically optimizes the measurement accuracy even in the presence of image blurring, possibly caused by breathing, subtle movements, and eye blinking. As a result, using in vivo mouse models and human tear samples we successfully demonstrated robust correlations across the glucose concentrations measured by three different independent techniques, validating the quantitative efficacy of the proposed OMS. For its methodological simplicity and accessibility, our findings strongly support that the innovation offered by the OMS and processing algorithm would greatly facilitate the glucose monitoring procedure and improve the overall welfare of diabetes patients.
Pituitary adenoma patients do not always have ocular symptoms at their first presentation, even when optic chiasm compression and visual field deficits are present. Therefore, collaboration with an ophthalmologist is important when evaluating pituitary adenoma patients.
Noninvasive methods for monitoring diabetes are being developed to eliminate the need for invasive finger-prick testing. Here, we propose the noninvasive detection of tear glucose using contact lenses that contain cerium oxide nanoparticles (CNPs). We chemically conjugated CNPs with glucose oxidase (GOx) using poly(ethylene glycol) (PEG) (CNP-PEG-GOx). GOx oxidizes glucose into hydrogen peroxide, which rapidly (∼1 min) reduces colorless Ce 3+ to yellow Ce 4+ with high sensitivity (>0.1 mM). Then, the yellow CNP-PEG-GOx can be analyzed to quantify the glucose concentration using a smartphone equipped with an image-processing algorithm. The CNP-PEG-GOx-laden contact lenses had physical properties similar to those of commercially available contact lenses and were nontoxic to human corneal cells and endothelial cells. When the CNP-PEG-GOx-laden contact lenses were placed on the eyes of diabetic rabbits, it was possible to measure the tear glucose levels. Interestingly, the lenses successfully detected glucose in human tear specimens and distinguished the diabetes status of patients. These findings suggest that the CNP-PEG-GOx-laden contact lenses could be used along with a smartphone-based image-processing algorithm to noninvasively monitor human tear glucose.
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