bims-mideyd 2024-07-14 papers

Medicine (Baltimore). 2024 Jul 12. 103(28): e38908

Role of AMPK-regulated autophagy in retinal pigment epithelial cell homeostasis: A review.

Liangliang Zhou, Ya Mo, Haiyan Zhang, Mengdi Zhang, Jiayu Xu, Sumin Liang.

The retinal pigment epithelium (RPE) is a regularly arranged monolayer of cells in the outermost layer of the retina. It is crucial for transporting nutrients and metabolic substances in the retina and maintaining the retinal barrier. RPE dysfunction causes diseases related to vision loss. Thus, understanding the mechanisms involved in normal RPE function is vital. Adenosine monophosphate-activated protein kinase (AMPK) is an RPE energy sensor regulating various signaling and metabolic pathways to maintain cellular energetic homeostasis. AMPK activation is involved in multiple signaling pathways regulated by autophagy in the RPE, thereby protecting the cells from oxidative stress and slowing RPE degeneration. In this review, we attempt to broaden the understanding of the pathogenesis of RPE dysfunction by focusing on the role and mechanism of AMPK regulation of autophagy in the RPE. The correlation between RPE cellular homeostasis and role of AMPK was determined by analyzing the structure and mechanism of AMPK and its signaling pathway in autophagy. The protective effect of AMPK-regulated autophagy on the RPE for gaining insights into the regulatory pathways of RPE dysfunction has been discussed.

DOI: https://doi.org/10.1097/MD.0000000000038908

Int J Mol Med. 2024 Sep;pii: 76. [Epub ahead of print]54(3):

Triptonide protects retinal cells from oxidative damage via activation of Nrf2 signaling.

Jinjing Li, Jiajun Li, Yuan Cao, Jin Yuan, Yaming Shen, Linyi Lei, Keran Li.

Age‑related macular degeneration (AMD) is an ocular disease that threatens the visual function of older adults worldwide. Key pathological processes involved in AMD include oxidative stress, inflammation and choroidal vascular dysfunction. Retinal pigment epithelial cells and Müller cells are most susceptible to oxidative stress. Traditional herbal medicines are increasingly being investigated in the field of personalized medicine in ophthalmology. Triptonide (Tn) is a diterpene tricyclic oxide, the main active ingredient in the extract from the Chinese herbal medicinal plant Tripterygium wilfordii, and is considered an effective immunosuppressant and anti‑inflammatory drug. The present study investigated the potential beneficial role of Tn in retinal oxidative damage in order to achieve personalized treatment for early AMD. An oxidative stress model of retinal cells induced by H2O2 and a retinal injury model of mice induced by light and N‑Methyl‑D‑aspartic acid were constructed. In vitro, JC‑1 staining, flow cytometry and apoptosis assay confirmed that low concentrations of Tn effectively protected retinal cells from oxidative damage, and reverse transcription‑quantitative PCR and western blotting analyses revealed that Tn reduced the expression of retinal oxidative stress‑related genes and inflammatory factors, which may depend on the PI3K/AKT/mTOR‑induced Nrf2 signaling pathway. In vivo, by retinal immunohistochemistry, hematoxylin and eosin staining and electroretinogram assay, it was found that retinal function and structure improved and choroidal neovascularization was significantly inhibited after Tn pretreatment. These results suggested that Tn is an efficient Nrf2 activator, which can be expected to become a new intervention for diseases such as AMD, to inhibit retinal oxidative stress damage and pathological neovascularization.

Keywords: Keap1/Nrf2/ARE pathway; age‑related macular degeneration; inflammation; oxidative stress; retinal cells; triptonide

DOI: https://doi.org/10.3892/ijmm.2024.5400

Exp Eye Res. 2024 Jul 10. pii: S0014-4835(24)00220-3. [Epub ahead of print] 109999

RNASeq profiling of retinal pigment epithelial cells derived from induced pluripotent stem cells revealed 3 genes involved in lipid homeostasis in age-related macular degeneration.

Audrey Voisin, Amaury Pénaguin, Afsaneh Gaillard, Nicolas Leveziel.

Age-related macular degeneration (AMD) is characterized by visual impairment observed in elderly population. Two forms of the disease are generally described, the atrophic (AMDa) and exudative forms (AMDe). Up until now, no curative treatment is available for this disease. The retinal pigment epithelium (RPE) plays a central role in the pathogenesis of age-related macular degeneration. Here, involvement of RPE dysfunction in AMD onset and progression was analyzed by a comparison of transcriptome profiles of hiPSC-RPE derived from healthy individuals or individuals affected by AMDa or AMDe. The analysis highlighted almost 1000 genes differentially expressed between the three comparison groups. Among these genes, 33 genes were already known to be involved in AMD pathogenesis. To establish an AMD genetic signature, we focused on genes differentially expressed in both AMDa/e cell lines compared to control cells and focused on the three genes (ABCA1, RPN2, RB1CC1) that were related to lipidic homeostasis. Differences in level expression of these three genes are found not only in control and AMDa/e cell lines, but also between AMDa and AMDe populations.

Keywords: cell signaling; cholesterol; genomics; lipids; retina

DOI: https://doi.org/10.1016/j.exer.2024.109999

Int J Mol Sci. 2024 Jul 02. pii: 7271. [Epub ahead of print]25(13):

Genetic and Epigenetic Biomarkers Linking Alzheimer's Disease and Age-Related Macular Degeneration.

Snježana Kaštelan, Tamara Nikuševa-Martić, Daria Pašalić, Antonela Gverović Antunica, Danijela Mrazovac Zimak.

Alzheimer's disease (AD) represents a prominent neurodegenerative disorder (NDD), accounting for the majority of dementia cases worldwide. In addition to memory deficits, individuals with AD also experience alterations in the visual system. As the retina is an extension of the central nervous system (CNS), the loss in retinal ganglion cells manifests clinically as decreased visual acuity, narrowed visual field, and reduced contrast sensitivity. Among the extensively studied retinal disorders, age-related macular degeneration (AMD) shares numerous aging processes and risk factors with NDDs such as cognitive impairment that occurs in AD. Histopathological investigations have revealed similarities in pathological deposits found in the retina and brain of patients with AD and AMD. Cellular aging processes demonstrate similar associations with organelles and signaling pathways in retinal and brain tissues. Despite these similarities, there are distinct genetic backgrounds underlying these diseases. This review comprehensively explores the genetic similarities and differences between AMD and AD. The purpose of this review is to discuss the parallels and differences between AMD and AD in terms of pathophysiology, genetics, and epigenetics.

Keywords: Alzheimer’s disease; age-related macular degeneration; epigenetics; genetics; inflammation; oxidative stress; pathophysiology

DOI: https://doi.org/10.3390/ijms25137271

Front Transplant. 2023 ;2 1130086

A treatment within sight: challenges in the development of stem cell-derived photoreceptor therapies for retinal degenerative diseases.

Davinia Beaver, Ioannis Jason Limnios.

Stem cell therapies can potentially treat various retinal degenerative diseases, including age-related macular degeneration (AMD) and inherited retinal diseases like retinitis pigmentosa. For these diseases, transplanted cells may include stem cell-derived retinal pigmented epithelial (RPE) cells, photoreceptors, or a combination of both. Although stem cell-derived RPE cells have progressed to human clinical trials, therapies using photoreceptors and other retinal cell types are lagging. In this review, we discuss the potential use of human pluripotent stem cell (hPSC)-derived photoreceptors for the treatment of retinal degeneration and highlight the progress and challenges for their efficient production and clinical application in regenerative medicine.

Keywords: cell therapy; human pluripotent stem cells; photoreceptors; regenerative medicine; retinal degeneration; retinal organoids

DOI: https://doi.org/10.3389/frtra.2023.1130086