bims-mideyd 2022-01-16 papers

Cell Signal. 2022 Jan 06. pii: S0898-6568(22)00004-3. [Epub ahead of print] 110244

High glucose induced inflammation is inhibited by copper chelation via rescuing mitochondrial fusion protein 2 in retinal pigment epithelial cells.

M Aloysius Dhivya, K N Sulochana, S R Bharathi Devi.

Altered trace element homeostasis is associated with diabetic complications, and studies have shown elevated copper levels in the serum of individuals with type 1 & 2 diabetes. Copper chelation has been shown to be beneficial by preventing or reversing diabetic organ damage and developing as a new treatment strategy for treating diabetic complications. Diabetic retinopathy is the major vision-threatening complication of diabetes. Recent studies have reported copper to be elevated in the serum of patients with diabetic retinopathy. Here in this study, we attempt to unravel the role of copper chelator penicillamine in retinal pigment epithelial cells exposed to high glucose (HG) and copper as a model for diabetic retinopathy. We have found that high glucose by itself and along with copper alters the mitochondrial morphology, reduces the expression of the mitochondrial fusion protein 2 (MFN2), and induces endoplasmic reticulum (ER) stress and inflammation. Copper chelation with penicillamine reduced all these changes in mitochondria, thereby rescuing the cells from mitochondrial damage and inflammation.

Keywords: Copper transporter 1; High glucose; Mitofusion 2; Retinal pigment epithelial cells

DOI: https://doi.org/10.1016/j.cellsig.2022.110244

Drug Dev Res. 2022 Jan 11.

Mitoquinone intravitreal injection ameliorates retinal ischemia-reperfusion injury in rats involving SIRT1/Notch1/NADPH axis.

Dongyong Tang, Xin Liu, Jun Chen.

Retinal ischemia-reperfusion injury (RIRI) is an important pathological process of many ocular diseases. Mitoquinone (MitoQ), a mitochondrial targeted antioxidant, is a potential compound for therapeutic development of RIRI. This study observed the effect of MitoQ on RIRI, and further explored its possible molecular mechanism. Temporary increase in intraocular pressure was used to establish rat model of RIRI to observe the effect of MitoQ treatment on retinal function, pathological injury, oxidative stress, inflammation and apoptosis. Immunohistochemistry and Western blot were used to detect expressions of cleaved caspase 3, B cell leukemia/lymphoma 2 associated X (Bax), nicotinamide adenine dinucleotide phosphate oxidase (NOX1), NOX4, cleaved-Notch 1, hairy and enhancer of split 1 (Hes1), and sirtuin 1 (SIRT 1) in retina were detected by immunohistochemistry and Western blot. MitoQ treatment significantly improved retinal function and pathological injury, inhibited the over-production of reactive oxygen species, increased the expression of superoxide dismutase 1 (SOD 1), suppressed the releases of inflammatory cytokines, and inhibited retinal cells apoptosis. MitoQ also down-regulated the expressions of cleaved caspase 3, Bax, NOX 1, NOX 4, cleaved-Notch 1, and Hes 1, increased the expression of SIRT 1 protein and its activity. These effects were significantly reversed by SIRT1 inhibitor EX527. Our data suggests that MitoQ, as a potentially effective drug for improving RIRI, may act through the SIRT1/Notch1/NADPH signal axis.

Keywords: Mitoquinone; ROS; SIRT 1; inflammation; mitochondria injury; notch 1; retinal ischemia-reperfusion injury

DOI: https://doi.org/10.1002/ddr.21911

J Biophotonics. 2022 Jan 12. e2916

Near infrared spectroscopy reveals instability in retinal mitochondrial metabolism and haemodynamics with blue light exposure at environmental levels.

Pardis Kaynezhad, Robert Fosbury, Chris Hogg, Ilias Tachtsidis, Sobha Sivaprasad, Glen Jeffery.

Blue light (~400-470nm) is considered potentially detrimental to the retina but is present in natural environmental light. Mitochondrial density is highest in the retina, and they exhibit a prominent optical absorption around 420nm arising from the Soret band of their porphyrins, including in cytochrome-c-oxidase in their respiratory chain. We examine the impact of continuous 420nm at environmental energy levels on retinal mitochondrial metabolism and haemodynamics in vivo in real time using broadband near-infrared spectroscopy. 1h environmental exposure to 420nm induces significant metabolic instability in retinal mitochondria and blood signals, which continues for up to 1h post blue exposure. Porphyrins are important in mitochondrial adenosine triphosphate (ATP) production and cytochrome-c-oxidase is a key part of the electron transport chain through which this is achieved. Hence, environmental 420nm likely restricts respiration and ATP production that may impact on retinal function. This article is protected by copyright. All rights reserved.

Keywords: Blue light; Cytochrome-c-oxidase; Environmental light; Mitochondria; Near-Infrared Spectroscopy

DOI: https://doi.org/10.1002/jbio.202100283

Oxid Med Cell Longev. 2022 ;2022 4328116

Lipopolysaccharide Enhances Genotoxicity by Activating GADD45G and NF-κB in Human Corneal Epithelial Cells.

Ramachandran Samivel, Umadevi Subramanian, Adnan Ali Khan, Omar Kirat, Ali Masmali, Turki Almubrad, Saeed Akhtar.

As the prevalence of microbial keratitis increases, it creates an environment conducive to genotoxicity response. A potential connection between growth arrest and DNA-damage-inducible 45 gamma (GADD45G) gene expression has not been proven in the corneal epithelial cells. The aim of this study was to determine whether lipopolysaccharide (LPS) enhances genotoxicity, DNA damage, and inflammatory responses in human corneal epithelial cells (HCECs) in vitro. In a set of parameters, cytotoxicity, reactive oxygen species, mitochondrial membrane potential, DNA damage, inflammatory response, and apoptosis were assessed. LPS (1, 5, and 10 μg/mL) treated HCECs were increased reactive oxygen species formation, mitochondrial membrane depolarization, and genotoxicity in a concentration-dependent manner. Similarly, NF-κB, PARP1, and TP53 were also overexpressed in the LPS treated HCECs. 24 hours after LPS induction, micronucleus scoring, and proapoptotic factors were also increased. Among them, the GADD45G, NF-κB, and γH2AX were overexpressed both on the mRNA and protein levels in LPS (10 μg/mL) treated HCECs. In our study, we show that the GADD45G signaling can trigger genotoxic instability in HCECs exposed to LPS. Therefore, understanding the factors contributing to infectious keratitis, such as GADD45G, NF-κB, and γH2AX signaling, may help to develop antigenotoxic and anti-inflammatory therapies for corneal dystrophy and epithelial cell remodeling.

DOI: https://doi.org/10.1155/2022/4328116

Materials (Basel). 2021 Dec 30. pii: 269. [Epub ahead of print]15(1):

What Is the Cause of Toxicity of Silicone Oil?

Ying Chen, Yan Lam Ip, Liangyu Zhou, Pik Yi Li, Yee Mei Chan, Wai Ching Lam, Kenneth Kai Wang Li, David H Steel, Yau Kei Chan.

PURPOSE: To investigate the toxicity of the low-molecular-weight components (LMWCs) in ophthalmic silicone oils (SilOils) on retinal cell lines.
METHODS: The toxicity of six types of LMWCs were studied and compared with conventional SilOil 1000 cSt. In vitro cytotoxic tests of LMWCs, in both liquid and emulsified forms, on three retinal cell lines (Müller cells (rMC-1), photoreceptor cells (661W) and retinal pigment epithelial cells (ARPE-19)) were conducted using a transwell cell culturing system. The morphology and viability of cells were assessed by light microscopy and Cell Counting Kit-8 (CCK-8) assay at different time points (6, 24 and 72 h). The ARPE-19 apoptotic pathway was investigated by Mitochondrial Membrane Potential/Annexin V Apoptosis Kit at different time points (6, 24 and 72 h).
RESULTS: Apart from dodecamethylpentasiloxane (L5), all liquid LMWCs showed varying degrees of acute cytotoxicity on retinal cell lines within 72 h. Emulsified LMWCs showed comparable cytotoxicity with liquid LMWCs on retinal cell lines. Cyclic LMWCs, octamethylcyclotetrasiloxane (D4) and decamethylcyclopentasiloxane (D5) had significantly higher cytotoxicity when compared with their linear counterparts decamethyltetrasiloxane (L4) and L5 with similar molecular formula. Using ARPE-19 cells as an example, we showed that LMWCs induce the apoptosis of retinal cells.
CONCLUSIONS: Most LMWCs, in both liquid and emulsified forms, can induce acute cytotoxicity. In addition, cyclic LMWCs are suspected to have higher cytotoxicity than their linear counterparts. Therefore, LMWCs are suspected to be the main cause of the long-term toxicity of ophthalmic SilOil, due to their toxicity and propensity to cause ophthalmic SilOil to emulsify. The amount of LMWCs should be considered as the paramount parameter when referring to the quality of SilOil.

Keywords: Müller cell (rMC-1); emulsification; low-molecular-weight component (LMWC); photoreceptor cell (661W); polydimethylsiloxane; retinal toxicity

DOI: https://doi.org/10.3390/ma15010269