bims-mideyd 2023-01-08 papers

ACS Nano. 2023 Jan 03.

Repeated Topical Administration of 3 nm Cerium Oxide Nanoparticles Reverts Disease Atrophic Phenotype and Arrests Neovascular Degeneration in AMD Mouse Models.

Anna Badia, Anna Duarri, Anna Salas, Jordi Rosell, Joana Ramis, Muriel Freixanet Gusta, Eudald Casals, Miguel A Zapata, Victor Puntes, Josep García-Arumí.

Increased oxidative stress in the retina and retinal pigment epithelium is implicated in age-related macular degeneration (AMD). Antioxidant cerium oxide nanoparticles (CeO2NPs) have been used to treat degenerative retinal pathologies in animal models, although their delivery route is not ideal for chronic patient treatment. In this work, we prepared a formulation for ocular topical delivery that contains small (3 nm), nonaggregated biocompatible CeO2NPs. In vitro results indicate the biocompatible and protective character of the CeO2NPs, reducing oxidative stress in ARPE19 cells and inhibiting neovascularization related to pathological angiogenesis in both HUVEC and in in vitro models of neovascular growth. In the in vivo experiments, we observed the capacity of CeO2NPs to reach the retina after topical delivery and a subsequent reversion of the altered retinal transcriptome of the retinal degenerative mouse model DKOrd8 toward that of healthy control mice, together with signs of decreased inflammation and arrest of degeneration. Furthermore, CeO2NP eye drops' treatment reduced laser-induced choroidal neovascular lesions in mice by lowering VEGF and increasing PEDF levels. These results indicate that CeO2NP eye drops are a beneficial antioxidant and neuroprotective treatment for both dry and wet forms of AMD disease.

Keywords: age-related macular degeneration; cerium oxide nanoparticles; eye-drops; immunomodulation; retina

DOI: https://doi.org/10.1021/acsnano.2c05447

Mol Vis. 2022 ;28 441-450

Lipoxin A4 alleviates inflammation in Aspergillus fumigatus-stimulated human corneal epithelial cells by Nrf2/HO-1 signaling pathway.

Xudong Peng, Xiaojia Zhu, Junjie Luan, Jing Lin, Yingxue Zhang, Qian Wang, Guiqiu Zhao.

Purpose: To investigate the therapeutic effect of lipoxin A4 (LXA4) on Aspergillus fumigatus (A. fumigatus)-stimulated human corneal epithelial cells (HCECs).
Methods: The cell counting kit-8 (CCK-8) was performed in HCECs to evaluate the toxicity of LXA4. A cell scratch test was used to assess the impact of LXA4 on the migration of HCECs. Enzyme-linked immunosorbent assay (ELISA), quantitative real-time polymerase chain reaction (qRT-PCR), and western blot were applied to examine the expression of inflammatory mediators in A. fumigatus-stimulated HCECs. The nuclear factor erythroid 2-related factor 2 (Nrf2) nuclear translocation and expression in HCECs were detected by immunofluorescence staining.
Results: LXA4 at 0-10 nmol·L-1 (nM) had no significant cytotoxic effect on HCECs. LXA4 at a concentration of 1 nM and 10 nM significantly promoted the migration rate of HCECs. The mRNA and protein levels of pro-inflammatory mediators, including IL-1β, TNF-α, and IL-6, were remarkably lower in the LXA4-treated group. LXA4 promoted the expression of Nrf2 and heme oxygenase 1 (HO-1) in A. fumigatus-stimulated HCECs compared with the PBS control group. Pretreatment with brusatol (BT, Nrf2 inhibitor) or Zine Protoporphyrin (Znpp, HO-1 inhibitor) receded the anti-inflammatory ability of LXA4.
Conclusions: LXA4 plays a protective role in A. fumigatus-stimulated HCECs by inhibiting the expression of pro-inflammatory mediators through the Nrf2/HO-1 signaling pathway.

Mol Vis. 2022 ;28 451-459

Psychological stress induces moderate pathology in the ganglion cell layer in mice.

Dandan Zhang, Nannan Sun, Congcong Guo, Jun Hui Lee, Jiamin Zhang, Zhenni Zhao, Xiaowei Yu, Ying Han, Jian Ge, Zhigang Fan.

Purpose: Primary open-angle glaucoma (POAG) is a condition with unclear pathogenesis. Researchers have observed an increased incidence of young Chinese POAG patients who manifest significant psychological stress while their intraocular pressure (IOP) is normal or close to normal; we hypothesize that psychological stress may play a causal role in initiating POAG.
Methods: Twenty-four male C57BL/6 mice were included and divided randomly into two groups. A chronic unpredictable mild stress (CUMS) mouse model was established to evaluate the effect of psychological stress on glaucoma-related retinal pathologies. Body weight and IOP were recorded weekly. At 5 weeks after the CUMS procedure, a behavior test, serum corticosterone level, retinal nerve fiber layer (RNFL) thickness, retinal ganglion cell (RGC) number and neurotrophic factor expression were evaluated and compared between the CUMS group and the control group.
Results: CUMS exposure induced depression-like behaviors, lighter body weight, and increased serum corticosterone levels in mice. RNFL thinning and neural cell loss in the ganglion cell layer (GCL) were observed in CUMS mice without significant IOP elevation. Decreased mRNA expression and protein levels of neurotropic factors in retinas of CUMS mice were observed, especially brain-derived neurotrophic factor (BDNF).
Conclusions: The CUMS mouse model demonstrated that psychological stress induced glaucoma-like changes in the retinas of CUMS mice. The mechanism by which psychological stress induces retina defects may be due to a reduced expression of retinal neurotropic factors. Thus, we conclude that psychological stress is causally associated with POAG.