Solubilized ubiquinol for preserving corneal function

Naguib, Youssef W.; Saha, Sanjib; Skeie, Jessica M.; Acri, Timothy M.; Ebeid, Kareem; Abdel-Rahman, Somaya A.; Kesh, Sandeep; Schmidt, Gregory A.; Nishimura, Darryl; Banas, Jeffrey A.; Zhu, Min; Greiner, Mark A.; Salem, Aliasger K.

doi:10.1016/j.biomaterials.2021.120842

Cited by 16 publications

(14 citation statements)

References 66 publications

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“…Due to the scarcity of surgical FECD tissue samples, we utilized an established TCF4 expanded repeat CEC line derived from an FECD patient (F35T), human TCF4 expanded repeat primary CEC lines from FECD patients, and a control CEC line (HCEC-B4G12) for additional experiments. As oxidative stress is highly implicated in FECD pathogenesis, we first recapitulated our and others work (3, 10, 12, 33, 62) by showing that TCF4 expanded repeat F35T cells had a higher basal ROS (p < 0.0001, Fig. 2A-B ) and basal mitochondrial superoxide concentration (p < 0.0001, Fig.…”

Section: Resultssupporting

confidence: 65%

“…Ubiquinol is an endogenous antioxidant that is converted from coenzyme Q10 via ferroptosis suppressor protein 1 (FSP1) and provides some degree of protection against ferroptosis and lipid peroxidation (97). Previously, we developed a highly dispersible solubilized ubiquinol that showed significant protection against lipid peroxidation and ferroptosis in a dose-dependent manner in donor corneal endothelial cells (30). Herein, we treated both cell types with solubilized ubiquinol at different concentrations of 1, 10, 50, and 100 µM to examine its efficacy in preventing lipid peroxidation in a dose-dependent manner.…”

Section: Resultsmentioning

confidence: 99%

“…Next, in order to identify potential therapeutic options for FECD, we evaluated several pharmacological compounds known to protect against lipid peroxidation, iron overload, and ferroptosis, including solubilized ubiquinol (33), ferroptosis inhibitor ferrostatin-1, antioxidant N-acetyl cysteine (NAC), and iron-chelator deferoxamine (DFO). Strikingly, after 24 hours of RSL3 treatment, solubilized ubiquinol outperformed all other tested compounds in reducing lipid peroxidation and preventing cell death in both cell lines ( Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Of note, GPX4 levels are lower than controls in FECD surgical samples, indicating that FECD increases susceptibility to ferroptosis (31, 32). A possible role for ferroptosis in FECD has been postulated but not investigated to account for the increased susceptibility to oxidative damage and lipid peroxidation (4, 33). In addition to increased ROS-mediated lipid peroxidation and decreased GPX4 functioning, altered iron metabolism is required for ferroptosis to occur (34, 35).…”

Section: Introductionmentioning

confidence: 99%

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TCF4trinucleotide repeat expansions and UV irradiation increase susceptibility to ferroptosis in Fuchs endothelial corneal dystrophy

Saha

Skeie

Schmidt

et al. 2022

Preprint

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Fuchs endothelial corneal dystrophy (FECD), a progressive polygenic disease that causes degeneration of the corneal endothelium, is the leading indication for corneal transplantation in the U.S. Characteristically, loss of corneal endothelial cells and formation of degenerative extracellular guttae result in failure to maintain appropriate corneal hydration through active ion pumping to counter the passive leakage of aqueous humor. FECD pathogenesis is linked to oxidative stress and environmental exposure to ultraviolet A (UVA), and impaired endogenous response to oxidative stress is common to the disease across multiple genotypes. UV irradiation is also known to cause cellular damage by ferroptosis, a nonapoptotic oxidative cell death resulting from iron-mediated lipid peroxidation. Although a possible role for ferroptosis in FECD has been postulated to account for the increased susceptibility to oxidative damage and lipid peroxidation, this has not been explored systematically. In this study, we investigated the roles of genetic background and UVA exposure in causing lipid membrane damage and endothelial cell degeneration in FECD. We first sought clinical evidence of iron-mediated lipid peroxidation in surgical samples obtained from FECD patients undergoing endothelial keratoplasty, and found increased levels of cytosolic ferrous iron (Fe2+) and evidence of lipid peroxidation were present in end-stage diseased tissues compared with healthy human donor corneas. Next, using immortalized (F35T) and primary cell cultures modeling the TCF4 intronic trinucleotide repeat expansion genotype, we found that alterations in gene and protein expression involved in ferroptosis were conserved in both cell culture and tissue models of FECD disease compared to controls, including elevated levels of the ferroptosis-specific marker transferrin receptor 1. F35T immortalized cells showed significantly higher basal lipid peroxidation than control HCEC-B4G12 cells, indicating higher susceptibility to ferroptosis attributable to genetic background. Then, we tested the impact of physiologically relevant doses of UVA irradiation on F35T cell cultures and found increased cytosolic Fe2+ iron levels indicating a role for ferroptosis in FECD disease progression. Finally, we tested the effects of inhibitory ferroptosis molecules. We found that F35T cells were more prone to RSL3 induced ferroptosis than healthy controls with deferoxamine chelation which indicated increased susceptibility in FECD cells, and cell death could be prevented after experimentally-induced ferroptosis using solubilized antioxidant ubiquinol indicating a role for anti-ferroptosis therapies. This investigation demonstrates that FECD genetic background and UVA exposure contribute to basal and incidental iron-mediated lipid peroxidation and cell death in FECD, and provides the basis for future investigations of ferroptosis-mediated oxidative damage and disease progression in FECD.

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Section: Resultssupporting

confidence: 65%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

TCF4trinucleotide repeat expansions and UV irradiation increase susceptibility to ferroptosis in Fuchs endothelial corneal dystrophy

Saha

Skeie

Schmidt

et al. 2022

Preprint

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“…In human corneal endothelial cells, Nrf2 loss induced a substantial increase in lipid peroxidation, causing ferroptosis, which was rescued by ferrostatin-1 [ 31 ]. Erastin/RSL3-induced ferroptosis in human corneal endothelial cells was rescued by complexed ubiquinol, which scavenges ROS and inhibits lipid peroxidation [ 102 ].…”

Section: Ferroptosis In Corneal Diseasesmentioning

confidence: 99%

Roles and Mechanisms of Regulated Necrosis in Corneal Diseases: Progress and Perspectives

Lin

Chen

Cissé

et al. 2022

Journal of Ophthalmology

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Regulated necrosis is defined as cell death characterized by loss of the cell membrane integrity and release of the cytoplasmic content. It contributes to the development and progression of some diseases, including ischemic stroke injury, liver diseases, hypertension, and cancer. Various forms of regulated necrosis, particularly pyroptosis, necroptosis, and ferroptosis, have been implicated in the pathogenesis of corneal disease. Regulated necrosis of corneal cells enhances inflammatory reactions in the adjacent corneal tissues, leading to recurrence and aggravation of corneal disease. In this review, we summarize the molecular mechanisms of pyroptosis, necroptosis, and ferroptosis in corneal diseases and discuss the roles of regulated necrosis in inflammation regulation, tissue repair, and corneal disease outcomes.

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Faster and Protective Wound Healing Mechanistic of Para‐Coumaric Acid Loaded Liver ECM Scaffold Cross‐linked with Acellular Marine Kelp

Arin

Rahaman

Farwa

et al. 2023

Adv Funct Materials

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Decellularized liver-derived extracellular matrix is a unique combination of a complex milieu of growth factors and proteins that stimulate biochemical, physical, and mechanical cues to the cells. However, the lack of mechanical strength hindering the applicability of extracellular matrix (ECM) is an outstanding challenge. Herein, to deal with this problem, decellularized kelp is introduced as a crosslinking material thereby strengthening the physical structure of ECM for its utilization as a wound-healing material. Consequently, a significant architectural change is observed in the ECM by forming a solid-shaped scaffold. Nevertheless, the hindrance of high pH is addressed by incorporating the acidic drug p-coumaric acid. To evaluate the innate regenerative abilities, the scaffolds are applied to rat excisional wounds. A remarkable wound healing capability is demonstrated by both the EK scaffolds, but a faster regeneration is achieved with only EK-20@cou. The speculated hypothesis is that the incorporation of p-coumaric acid can offer many additional bioactive benefits to the scaffold such as remarkable biocompatibility, antioxidant, and anti-bacterial properties that are deliberately supported by the in vitro results. In silico molecular simulations (MS) validated that p-Cou released from the EK-20@Cou scaffold is accountable for the observed extraordinary regenerative behavior as compared to EK-20(PW).

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Solubilized ubiquinol for preserving corneal function

Cited by 16 publications

References 66 publications

TCF4trinucleotide repeat expansions and UV irradiation increase susceptibility to ferroptosis in Fuchs endothelial corneal dystrophy

TCF4trinucleotide repeat expansions and UV irradiation increase susceptibility to ferroptosis in Fuchs endothelial corneal dystrophy

Roles and Mechanisms of Regulated Necrosis in Corneal Diseases: Progress and Perspectives

Faster and Protective Wound Healing Mechanistic of Para‐Coumaric Acid Loaded Liver ECM Scaffold Cross‐linked with Acellular Marine Kelp

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