bims-mideyd 2023-01-22 papers

bims-mideyd

Biomed News

on Mitochondrial dysfunction in eye diseases

Issue of 2023–01–22
nine papers selected by
Rajalekshmy “Raji” Shyam, Indiana University Bloomington

Lycium barbarum Polysaccharides Regulating miR-181/Bcl-2 Decreased Autophagy of Retinal Pigment Epithelium with Oxidative Stress.
Dimethyl Fumarate Protects Retinal Pigment Epithelium from Blue Light-Induced Oxidative Damage via the Nrf2 Pathway.
Self-Healing Alginate Hydrogel Formed by Dynamic Benzoxaborolate Chemistry Protects Retinal Pigment Epithelium Cells against Oxidative Damage.
Protective effects of Panax ginseng berry extract on blue light-induced retinal damage in ARPE-19 cells and mouse retina.
Single cell RNA sequencing reveals transcriptional changes of human choroidal and retinal pigment epithelium cells during fetal development, in healthy adult and intermediate age-related macular degeneration.
P2X7 Is Involved in the Mouse Retinal Degeneration via the Coordinated Actions in Different Retinal Cell Types.
HIF2α activation and mitochondrial deficit due to iron chelation cause retinal atrophy.
Ascorbic acid protects retinal pigment epithelial cells from high glucose by inhibiting the NF-κB signal pathway through MALAT1/IGF2BP3 axis.
Inflammation of the retinal pigment epithelium drives early-onset photoreceptor degeneration in Mertk-associated retinitis pigmentosa.

Oxid Med Cell Longev. 2023 ;2023 9554457

Lycium barbarum Polysaccharides Regulating miR-181/Bcl-2 Decreased Autophagy of Retinal Pigment Epithelium with Oxidative Stress.

Yi-Jing Yang, Ying Wang, Ying Deng, Xiao-Qing Liu, Jing Lu, Jun Peng, Jie Li, Ya-Sha Zhou, Hui-An Zhu, Bo Li, Yu-Hui Qin, Qing-Hua Peng.

Disturbed structure and dysfunction of the retinal pigment epithelium (RPE) lead to degenerative diseases of the retina. Excessive accumulation of reactive oxygen species (ROS) in the RPE is thought to play an important role in RPE dysfunction and degeneration. Autophagy is a generally low-activity degradation process of cellular components that increases significantly when high levels of oxidative stress are present. Agents with antioxidant properties may decrease autophagy and provide protection against RPE dysfunction and damage caused by ROS. Lycium barbarum polysaccharide (LBP) has been widely studied as an antioxidant and cell-protective agent. Therefore, we designed this study to investigate the effects of LBP, which inhibits miR-181, on autophagy in retinal pigment epithelium (RPE) with oxidative stress in vitro and in vivo. In the current study, we found that the highly expressed miR-181 downregulated the expression of Bcl-2 in hydrogen peroxide- (H2O2-) induced ARPE-19 cells, resulting in an increase in ROS, apoptosis, and autophagy flux. LBP inhibited the expression of miR-181, decreased the levels of ROS, apoptosis, and autophagy flux, and increased cell viability in H2O2-induced ARPE-19 cells, suggesting that LBP provides protection against oxidative damage in ARPE-19 cells. We also found that LBP decreased RPE atrophy and autophagy flux in rd10 mice. Taken together, the results showed that LBP has a protective effect for RPE under oxidative stress by inhibiting miR-181 and affecting the Bcl-2/Beclin1 autophagy signaling pathway.

DOI: https://doi.org/10.1155/2023/9554457
Antioxidants (Basel). 2022 Dec 26. pii: 45. [Epub ahead of print]12(1):

Dimethyl Fumarate Protects Retinal Pigment Epithelium from Blue Light-Induced Oxidative Damage via the Nrf2 Pathway.

Hideyuki Shimizu, Kei Takayama, Kazuhisa Yamada, Ayana Suzumura, Tomohito Sato, Yoshiaki Nishio, Masataka Ito, Hiroaki Ushida, Koji M Nishiguchi, Masaru Takeuchi, Hiroki Kaneko.

  The purpose of this study is to investigate the protective effect of dimethyl fumarate (DMF), the methyl-ester of fumaric acid, against blue-light (BL) exposure in retinal pigment epithelial (RPE) cells. ARPE-19 cells, a human RPE cell line, were cultured with DMF followed by exposure to BL. Reactive oxygen species (ROS) generation, cell viability, and cell death rate were determined. Real-time polymerase chain reaction and Western blotting were performed to determine the change in nuclear factor (erythroid-derived)-like 2 (NRF2) expression. Twenty-seven inflammatory cytokines in the supernatant of culture medium were measured. BL exposure induced ROS generation in ARPE-19 cells, which DMF alleviated in a concentration-dependent manner. BL exposure increased the ARPE-19 cell death rate, which DMF alleviated. BL exposure induced ARPE-19 cell apoptosis, again alleviated by DMF. Under BL exposure, DMF increased the NRF2 mRNA level and promoted NRF2 expression in the nucleus. BL also strongly increased interleukin (IL)-1β and fibroblast growth factor (FGF) expression. BL strongly induced RPE cell damage with apoptotic change while DMF mainly reduced inflammation in BL-induced RPE damage, resulting in blockade of cell death. DMF has a protective effect in RPE cells against BL exposure via activation of the NRF2 pathway.

Keywords:  NRF2 pathway; age-related macular degeneration; blue-light; dimethyl fumarate; nuclear factor (erythroid-derived)-like 2; oxidative stress; retinal pigment epithelium

DOI:  https://doi.org/10.3390/antiox12010045
Gels. 2022 Dec 29. pii: 24. [Epub ahead of print]9(1):

Self-Healing Alginate Hydrogel Formed by Dynamic Benzoxaborolate Chemistry Protects Retinal Pigment Epithelium Cells against Oxidative Damage.

Minhua Liu, Yate Huang, Chunwen Tao, Weijia Yang, Junrong Chen, Li Zhu, Tonghe Pan, Ravin Narain, Kaihui Nan, Yangjun Chen.

  Oxidative stress is considered as a major factor causing retinal pigment epithelium (RPE) dysfunction and finally leading to retinal diseases such as age-related macular degeneration (AMD). Developing hydrogels for RPE cell delivery, especially those with antioxidant feature, is emerging as a promising approach for AMD treatment. Herein, a readily prepared antioxidant alginate-based hydrogel was developed to serve as a cytoprotective agent for RPE cells against oxidative damage. Alg-BOB was synthesized via conjugation of benzoxaborole (BOB) to the polysaccharide backbone. Hydrogels were formed through self-crosslinking of Alg-BOB based on benzoxaborole-diol complexation. The resulting hydrogel showed porous micro-structure, pH dependent mechanical strength and excellent self-healing, remolding, and injectable properties. Moreover, the hydrogel exhibited excellent cytocompatibility and could efficiently scavenge reactive oxygen species (ROS) to achieve an enhanced viability of ARPE-19 cells under oxidative condition. Altogether, our study reveals that the antioxidant Alg-BOB hydrogel represents an eligible candidate for RPE delivery and AMD treatment.

Keywords:  alginate; dynamic crosslinking; oxidative stress; retinal pigment epithelium; self-healing hydrogel

DOI:  https://doi.org/10.3390/gels9010024
J Ginseng Res. 2023 Jan;47(1): 65-73

Protective effects of Panax ginseng berry extract on blue light-induced retinal damage in ARPE-19 cells and mouse retina.

Hye Mi Cho, Sang Jun Lee, Se-Young Choung.

   Background: Age-related macular degeneration (AMD) is a significant visual disease that induces impaired vision and irreversible blindness in the elderly. However, the effects of ginseng berry extract (GBE) on the retina have not been studied. Therefore, this study aimed to investigate the protective effects of GBE on blue light (BL)-induced retinal damage and elucidate its underlying mechanisms in human retinal pigment epithelial cells (ARPE-19 cells) and Balb/c retina.
Methods: To investigate the effects and underlying mechanisms of GBE on retinal damage in vitro, we performed cell viability assay, pre-and post-treatment of sample, reactive oxygen species (ROS) assay, quantitative real-time PCR (qRT-PCR), and western immunoblotting using A2E-laden ARPE-19 cells with BL exposure. In addition, Balb/c mice were irradiated with BL to induce retinal degeneration and orally administrated with GBE (50, 100, 200 mg/kg). Using the harvested retina, we performed histological analysis (thickness of retinal layers), qRT-PCR, and western immunoblotting to elucidate the effects and mechanisms of GBE against retinal damage in vivo.
Results: GBE significantly inhibited BL-induced cell damage in ARPE-19 cells by activating the SIRT1/PGC-1α pathway, regulating NF-kB translocation, caspase 3 activation, PARP cleavage, expressions of apoptosis-related factors (BAX/BCL-2, LC3-Ⅱ, and p62), and ROS production. Furthermore, GBE prevented BL-induced retinal degeneration by restoring the thickness of retinal layers and suppressed inflammation and apoptosis via regulation of NF-kB and SIRT1/PGC-1α pathway, cleavage of caspase 3 and PARP, and expressions of apoptosis-related factors in vivo.
Conclusions: GBE could be a potential agent to prevent dry AMD and progression to wet AMD.

Keywords:  A2E; ARPE-19 cells; Age-related macular degeneration; Blue light exposure; Panax ginseng berry

DOI:  https://doi.org/10.1016/j.jgr.2022.04.002
Hum Mol Genet. 2023 Jan 16. pii: ddad007. [Epub ahead of print]

Single cell RNA sequencing reveals transcriptional changes of human choroidal and retinal pigment epithelium cells during fetal development, in healthy adult and intermediate age-related macular degeneration.

Joseph Collin, Megan S R Hasoon, Darin Zerti, Sarah Hammadi, Birthe Dorgau, Lucy Clarke, David Steel, Rafiqul Hussain, Jonathan Coxhead, Steven Lisgo, Rachel Queen, Majlinda Lako.

  Age related macular degeneration (AMD) is the most prevalent cause of blindness in the developed world. Vision loss in the advanced stages of the disease is caused by atrophy of retinal photoreceptors, overlying retinal pigment epithelium (RPE) and choroidal endothelial cells (CECs). The molecular events that underline the development of these cell types from in utero to adult as well as the progression to intermediate and advanced stages AMD are not yet fully understood. We performed single cell RNA-Sequencing (Seq) of human fetal and adult RPE-choroidal tissues, profiling in detail all the cell types and elucidating cell type specific proliferation, differentiation, and immunomodulation events that occur up to midgestation. Our data demonstrate that progression from the fetal to adult state is characterised by an increase in expression of genes involved in the oxidative stress response and detoxification from heavy metals, suggesting a better defence against oxidative stress in the adult RPE-choroid tissue. Single cell comparative transcriptional analysis between a patient with intermediate AMD and an unaffected subject revealed a reduction in the number of RPE and melanocytes in the macular region of the AMD patient. Together these findings may suggest a macular loss of RPE cells and melanocytes in the AMD patients, but given the complex processing of tissues required for single cell RNA-Seq which is prone to technical artefacts, these findings need to be validated by additional techniques in a larger number of AMD patients and controls.

Keywords:  embryonic and fetal eyeretinal pigment epitheliumchoroidchoroid endothelial cellsmelanocytespericytessmooth muscle cellsSchwann cellssingle cell RNA-Seqage related macular degeneration (AMD)

DOI:  https://doi.org/10.1093/hmg/ddad007
Antioxidants (Basel). 2023 Jan 06. pii: 141. [Epub ahead of print]12(1):

P2X7 Is Involved in the Mouse Retinal Degeneration via the Coordinated Actions in Different Retinal Cell Types.

Ponarulselvam Sekar, George Hsiao, Yuan-Shen Chen, Wan-Wan Lin, Chi-Ming Chan.

  Adenosine triphosphate (ATP) released from dying cells with high concentrations is sensed as a danger signal by the P2X7 receptor. Sodium iodate (NaIO3) is an oxidative toxic agent, and its retinal toxicity has been used as the model of dry age-related macular degeneration (AMD). In this study, we used NaIO3-treated mice and cultured retinal cells, including BV-2 microglia, 661W photoreceptors, rMC1 Müller cells and ARPE-19 retinal epithelial cells, to understand the pathological action of P2X7 in retinal degeneration. We found that NaIO3 can significantly decrease the photoreceptor function by reducing a-wave and b-wave amplitudes in electroretinogram (ERG) analysis. Optical coherence tomography (OCT) analysis revealed the degeneration of retinal epithelium and ganglion cell layers. Interestingly, P2X7-/- mice were protected from the NaIO3-induced retinopathy and inflammatory NLRP3, IL-1β and IL-6 gene expression in the retina. Hematoxylin and eosin staining indicated that the retinal epithelium was less deteriorated in P2X7-/- mice compared to the WT group. Although P2X7 was barely detected in 661W, rMC1 and ARPE-19 cells, its gene and protein levels can be increased after NaIO3 treatment, leading to a synergistic cytotoxicity of BzATP [2'(3')-O-(4-benzoylbenzoyl)adenosine-5'-triphosphate tri(triethyleneammonium)salt] and NaIO3 administration in ARPE-19 cells. In conclusion, the paracrine action of the ATP/P2X7 axis via cell-cell communication is involved in NaIO3-induced retinal injury. Our results show that P2X7 antagonist might be a potential therapy in inflammation-related retinal degeneration.

Keywords:  P2X7; microglia; photoreceptors; retinopathy; sodium iodate

DOI:  https://doi.org/10.3390/antiox12010141
EMBO Mol Med. 2023 Jan 16. e16525

HIF2α activation and mitochondrial deficit due to iron chelation cause retinal atrophy.

Yang Kong, Pei-Kang Liu, Yao Li, Nicholas D Nolan, Peter M J Quinn, Chun-Wei Hsu, Laura A Jenny, Jin Zhao, Xuan Cui, Ya-Ju Chang, Katherine J Wert, Janet R Sparrow, Nan-Kai Wang, Stephen H Tsang.

  Iron accumulation causes cell death and disrupts tissue functions, which necessitates chelation therapy to reduce iron overload. However, clinical utilization of deferoxamine (DFO), an iron chelator, has been documented to give rise to systemic adverse effects, including ocular toxicity. This study provided the pathogenic and molecular basis for DFO-related retinopathy and identified retinal pigment epithelium (RPE) as the target tissue in DFO-related retinopathy. Our modeling demonstrated the susceptibility of RPE to DFO compared with the neuroretina. Intriguingly, we established upregulation of hypoxia inducible factor (HIF) 2α and mitochondrial deficit as the most prominent pathogenesis underlying the RPE atrophy. Moreover, suppressing hyperactivity of HIF2α and preserving mitochondrial dysfunction by α-ketoglutarate (AKG) protects the RPE against lesions both in vitro and in vivo. This supported our observation that AKG supplementation alleviates visual impairment in a patient undergoing DFO-chelation therapy. Overall, our study established a significant role of iron deficiency in initiating DFO-related RPE atrophy. Inhibiting HIF2α and rescuing mitochondrial function by AKG protect RPE cells and can potentially ameliorate patients' visual function.

Keywords:  HIF2α upregulation; RPE atrophy; iron deficiency; mitochondrial deficit; α-ketoglutarate

DOI:  https://doi.org/10.15252/emmm.202216525
Diabet Med. 2023 Jan 20. e15050

Ascorbic acid protects retinal pigment epithelial cells from high glucose by inhibiting the NF-κB signal pathway through MALAT1/IGF2BP3 axis.

Yanming Tian, Wubo Cheng, Haiyan Wang, Chengcheng Zeng, Xueyi Chen.

   BACKGROUND: Diabetic retinopathy (DR) is a common complication of diabetes with nocuous effects on patients' eye health, typically accompanies by excessive inflammation and oxidative stress. Insulin-like growth factor-2 messenger RNA-binding protein 3 (IGF2BP3) was engaged with inflammation, whereas its precise role in the DR process was unclear. And enhanced lncRNA metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) and decreased ascorbic acid (AA) were also found in DR. This study was to explore the regulatory role and mechanism of IGF2BP3, MALAT1, and AA in the high glucose (HG)-induced retinal pigment epithelial (RPE) cell injury.
METHODS: ARPE-19 cells were treated with HG to establish the in vitro RPE cell injury model. The mRNA and protein levels of the gene were evaluated by qRT-PCR or Western blot. Immunofluorescence detected the translocation condition of the p65 protein. Inflammatory factor levels were detected by ELISA assays. Apoptosis was detected by flow cytometry. The binding interaction of IGF2BP3 and MALAT1 was validated by RIP-qPCR assays.
RESULTS: In high glucose induced RPE cell injury, IGF2BP3 expression, inflammatory response and apoptosis were enhanced. Next, the IGF2BP3 activated the NF-κB signaling to promote the RPE cell injury development. MALAT1 could directly bind with IGF2BP3 and upregulate its expression. In addition, AA ameliorated the HG-induced RPE cell injury through the regulation of MALAT1.
CONCLUSION: Ascorbic acid ameliorated HG-induced RPE cell injury by repressing the NF-κB signaling pathway via modulating the MALAT1/IGF2BP3 axis.

Keywords:  Diabetic retinopathy; IGF2BP3; MALAT1; NF-κB signaling; ascorbic acid

DOI:  https://doi.org/10.1111/dme.15050
Sci Adv. 2023 Jan 20. 9(3): eade9459

Inflammation of the retinal pigment epithelium drives early-onset photoreceptor degeneration in Mertk-associated retinitis pigmentosa.

Maria E Mercau, Yemsratch T Akalu, Francesca Mazzoni, Gavin Gyimesi, Emily J Alberto, Yong Kong, Brian P Hafler, Silvia C Finnemann, Carla V Rothlin, Sourav Ghosh.

Severe, early-onset photoreceptor (PR) degeneration associated with MERTK mutations is thought to result from failed phagocytosis by retinal pigment epithelium (RPE). Notwithstanding, the severity and onset of PR degeneration in mouse models of Mertk ablation are determined by the hypomorphic expression or the loss of the Mertk paralog Tyro3. Here, we find that loss of Mertk and reduced expression/loss of Tyro3 led to RPE inflammation even before eye-opening. Incipient RPE inflammation cascaded to involve microglia activation and PR degeneration with monocyte infiltration. Inhibition of RPE inflammation with the JAK1/2 inhibitor ruxolitinib mitigated PR degeneration in Mertk-/- mice. Neither inflammation nor severe, early-onset PR degeneration was observed in mice with defective phagocytosis alone. Thus, inflammation drives severe, early-onset PR degeneration-associated with Mertk loss of function.

DOI: https://doi.org/10.1126/sciadv.ade9459