Myeloperoxidase (MPO) has paradoxically been found to be able to both activate matrix metalloproteinases (MMPs) as well as inhibit MMPs. However, these regulatory effects have not yet been observed in vivo, and it is unclear which pathway is relevant in vivo. We aim to track MPO regulation of MMP activity in living animals in neuroinflammation. Mice induced with experimental autoimmune encephalomyelitis (EAE), a mouse model of neuroinflammation and multiple sclerosis, were treated with either the MPO-specific inhibitor 4-aminobenzoic acid hydrazide or saline as control. Mice underwent concurrent magnetic resonance imaging (MRI) with the MPO-specific molecular imaging agent MPO-Gd and fluorescence molecular tomography (FMT) with the MMP-targeting agent MMPsense on day 12 after induction. Biochemical and histopathological correlations were performed. Utilizing concurrent MRI and FMT imaging, we found reduced MMP activity in the brain with MPO inhibition, demonstrating MPO activity positively regulates MMP activity in vivo. In vivo MMPSense activation and MMP-9 activity correlated with MPO-Gd lesion volume and disease severity. This was corroborated by in vitro assays and histopathological analyses that showed MMP activity and MMP-9 cells correlated with MPO activity and MPO cells. In conclusion, multimodal molecular imaging demonstrates for the first time MPO regulation of MMP activity in living animals. This approach could serve as a model to study the interactions of other biologically interesting molecules in living organisms.
Glioma is a highly heterogeneous and lethal tumor with an extremely poor prognosis. Through analysis of TCGA data, we identified that OLFML2A is a key promotor of gliomagenesis. However, the molecular function of OLFML2A and its underlying mechanism of action in glioma remain unclear. In this study, we found that OLFML2A expression was significantly upregulated in glioma specimens and positively correlated with pathological grades in glioma patients. Moreover, Kaplan–Meier survival analysis of TCGA data revealed that glioma patients with higher OLFML2A expression had shorter overall survival. Importantly, OLFML2A knockdown in glioma cells inhibited cell proliferation and promoted apoptosis. Mechanistically, OLFML2A downregulation inhibits Wnt/β-catenin signaling by upregulating amyloid precursor protein (APP) expression and reducing stabilized β-catenin levels, leading to the repression of MYC, CD44, and CSKN2A2 expression. Furthermore, OLFML2A downregulation suppressed the growth of transplanted glioma subcutaneously and intracranially by inhibiting Wnt/β-catenin pathway-dependent cell proliferation. By uncovering the oncogenic effects in human and rodent gliomas, our data support OLFML2A as a potential therapeutic target for glioma.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.