bims-mideyd 2024-08-25 papers

Free Radic Biol Med. 2024 Aug 20. pii: S0891-5849(24)00616-6. [Epub ahead of print]

Gastrodin ameliorates oxidative stress-induced RPE damage by facilitating autophagy and phagocytosis through PPARα-TFEB/CD36 signal pathway.

Chaojuan Wen, Xinyue Yu, Jingya Zhu, Jingshu Zeng, Xielan Kuang, Youao Zhang, ShiYu Tang, Qingqiong Zhang, Jianhua Yan, Huangxuan Shen.

Age-related macular degeneration (AMD), the leading cause of irreversible blindness in the elderly, is primarily characterized by the degeneration of the retinal pigment epithelium (RPE). However, effective therapeutic options for dry AMD are currently lacking, necessitating further exploration into preventive and pharmaceutical interventions. This study aimed to investigate the protective effects of gastrodin on RPE cells exposed to oxidative stress. We constructed an in vitro oxidative stress model of 4-hydroxynonenal (4-HNE) and performed RNA-seq, and demonstrated the protective effect of gastrodin through mouse experiments. Our findings reveal that gastrodin can inhibit 4-HNE-induced oxidative stress, effectively improving the mitochondrial and lysosomal dysfunction of RPE cells. We further elucidated that gastrodin promotes autophagy and phagocytosis through activating the PPARα-TFEB/CD36 signaling pathway. Interestingly, these outcomes were corroborated in a mouse model, in which gastrodin maintained retinal integrity and reduced RPE disorganization and degeneration under oxidative stress. The accumulation of LC3B and SQSTM1 in mouse RPE-choroid was also reduced. Moreover, activating PPARα and downstream pathways to restore autophagy and phagocytosis, thereby countering RPE injury from oxidative stress. In conclusion, this study demonstrated that gastrodin maintains the normal function of RPE cells by reducing oxidative stress, enhancing their phagocytic function, and restoring the level of autophagic flow. These findings suggest that gastrodin is a novel formulation with potential applications in the development of AMD disease.

Keywords: Age-related macular degeneration (AMD); Autophagy; Gastrodin; Oxidative stress; Phagocytosis

DOI: https://doi.org/10.1016/j.freeradbiomed.2024.08.023

JCI Insight. 2024 Jul 16. pii: e177231. [Epub ahead of print]9(16):

Evaluating precision medicine approaches for gene therapy in patient-specific cellular models of Bietti crystalline dystrophy.

Yao Li, Richard R Yang, Yong-Shi Li, Chun-Wei Hsu, Laura A Jenny, Yang Kong, Merry Zc Ruan, Janet R Sparrow, Stephen H Tsang.

Patient-specific induced pluripotent stem cell-derived (iPSC-derived) cell lines allow for therapies to be tailored to individual patients, increasing therapeutic precision and efficiency. Bietti crystalline dystrophy (BCD) is a rare blinding disease estimated to affect about 67,000 individuals worldwide. Here, we used iPSC-derived retinal pigment epithelium (iRPE) cells from patients with BCD to evaluate adeno-associated virus-mediated (AAV-mediated) gene augmentation therapy strategies. We found that BCD iRPE cells were vulnerable to blue light-induced oxidative stress and that cellular phenotype can be quantified using 3 robust biomarkers: reactive oxygen species (ROS), 4-hydroxy 2-nonenal (4-HNE) levels, and cell death rate. Additionally, we demonstrated that AAV-mediated gene therapy can significantly reduce light-induced cell death in BCD iRPE cells. This is the first proof-of-concept study to our knowledge to show that AAV-CYP4V2 gene therapy can be used to treat light-induced RPE damage in BCD. Furthermore, we observed significant variability in cellular phenotypes among iRPE from patients with BCD of divergent mutations, which outlined genotype-phenotype correlations in BCD patient-specific cell disease models. Our results reveal that patient-specific iRPE cells retained personalized responses to AAV-mediated gene therapy. Therefore, this approach can advance BCD therapy and set a precedent for precision medicine in other diseases, emphasizing the necessity for personalization in healthcare to accommodate individual diversity.

Keywords: Gene therapy; Genetic diseases; Ophthalmology; Therapeutics; iPS cells

DOI: https://doi.org/10.1172/jci.insight.177231

Exp Eye Res. 2024 Aug 14. pii: S0014-4835(24)00272-0. [Epub ahead of print] 110051

HIF-1α-dependent regulation of angiogenic factor expression in Müller cells by mechanical stimulation.

Tadahiko Ogata, Atsushige Ashimori, Fumiaki Higashijima, Ayano Sakuma, Waka Hamada, Junki Sunada, Ren Aoki, Masanori Mikuni, Kenichiro Hayashi, Takuya Yoshimoto, Makiko Wakuta, Shinichiro Teranishi, Manami Ohta, Kazuhiro Kimura.

Mechanical stress regulates various biological processes in cells, tissues, and organs as well as contributes to the pathogenesis of various diseases. The retina is subjected to mechanical stress imposed by intraocular pressure as well as by retinal hemorrhage and edema. Responses to mechanical stress have been studied in retinal pigment epithelial cells and Müller cells of the retina, with the former cells having been found to undergo a stress-induced increase in the expression of vascular endothelial growth factor (VEGF), which plays a key role in physiological and pathological angiogenesis in the retina. We here examined the effects of stretch stimulation on the expression of angiogenic factors in cultured human Müller cells. Reverse transcription and quantitative PCR analysis revealed that expression of the VEGF-A gene was increased by such stimulation in Müller cells, whereas that of the angiopoietin 1 gene was decreased. An enzyme-linked immunosorbent assay showed that stretch stimulation also increased VEGF secretion from these cells. Expression of the transcription factor HIF-1α (hypoxia-inducible factor-1α) was increased at both mRNA and protein levels by stretch stimulation, and the HIF-1α inhibitor CAY10585 prevented the effects of mechanical stress on VEGF-A gene expression and VEGF secretion. Furthermore, RNA-sequencing analysis showed that the expression of angiogenesis-related pathway genes was upregulated by stretch stimulation. Our results thus suggest that mechanical stress induces VEGF production in Müller cells in a manner dependent on HIF-1α, and that HIF-1α is therefore a potential therapeutic target for conditions such as diabetic retinopathy, age-related macular degeneration, and retinal vein occlusion.

Keywords: Angiogenesis; Angiopoietin 1 (ANG1); Mechanical stimulation; Müller cell; Retina; Vascular endothelial growth factor (VEGF)

DOI: https://doi.org/10.1016/j.exer.2024.110051

Int J Ophthalmol. 2024 ;17(8): 1531-1544

NLRP3 and autophagy in retinal ganglion cell inflammation in age-related macular degeneration: potential therapeutic implications.

Xiao-Li Wang, Yun-Xia Gao, Qiong-Zhen Yuan, Ming Zhang.

Retinal degenerative diseases were a large group of diseases characterized by the primary death of retinal ganglion cells (RGCs). Recent studies had shown an interaction between autophagy and nucleotide-binding oligomerization domain-like receptor 3 (NLRP3) inflammasomes, which may affect RGCs in retinal degenerative diseases. The NLRP3 inflammasome was a protein complex that, upon activation, produces caspase-1, mediating the apoptosis of retinal cells and promoting the occurrence and development of retinal degenerative diseases. Upregulated autophagy could inhibit NLRP3 inflammasome activation, while inhibited autophagy can promote NLRP3 inflammasome activation, which leaded to the accelerated emergence of drusen and lipofuscin deposition under the neurosensory retina. The activated NLRP3 inflammasome could further inhibit autophagy, thus forming a vicious cycle that accelerated the damage and death of RGCs. This review discussed the relationship between NLRP3 inflammasome and autophagy and its effects on RGCs in age-related macular degeneration, providing a new perspective and direction for the treatment of retinal diseases.

Keywords: NLRP3 inflammasome; age-related macular degeneration; autophagy; retinal degeneration; retinal ganglion cells

DOI: https://doi.org/10.18240/ijo.2024.08.20

Biochim Biophys Acta Mol Cell Res. 2024 Aug 17. pii: S0167-4889(24)00159-9. [Epub ahead of print] 119816

Activation of retinoid X receptors protects retinal neurons and pigment epithelial cells from BMAA-induced death.

Tamara B Soto, Paula E Tenconi, Edgardo D Buzzi, Leonardo Dionisio, Melina V Mateos, Nora P Rotstein, Guillermo Spitzmaul, Luis E Politi, Olga L German.

Exposure to the non-protein amino acid cyanotoxin β-N-methylamino-L-alanine (BMAA), released by cyanobacteria found in many water reservoirs has been associated with neurodegenerative diseases. We previously demonstrated that BMAA induced cell death in both retina photoreceptors (PHRs) and amacrine neurons by triggering different molecular pathways, as activation of NMDA receptors and formation of carbamate-adducts was only observed in amacrine cell death. We established that activation of Retinoid X Receptors (RXR) protects retinal cells, including retina pigment epithelial (RPE) cells from oxidative stress-induced apoptosis. We now investigated the mechanisms underlying BMAA toxicity in these cells and those involved in RXR protection. BMAA addition to rat retinal neurons during early development in vitro increased reactive oxygen species (ROS) generation and polyADP ribose polymers (PAR) formation, while pre-treatment with serine (Ser) before BMAA addition decreased PHR death. Notably, RXR activation with the HX630 agonist prevented BMAA-induced death in both neuronal types, reducing ROS generation, preserving mitochondrial potential, and decreasing TUNEL-positive cells and PAR formation. This suggests that BMAA promoted PHR death by substituting Ser in polypeptide chains and by inducing polyADP ribose polymerase activation. BMAA induced cell death in ARPE-19 cells, a human epithelial cell line; RXR activation prevented this death, decreasing ROS generation and caspase 3/7 activity. These findings suggest that RXR activation prevents BMAA harmful effects on retinal neurons and RPE cells, supporting this activation as a broad-spectrum strategy for treating retina degenerations.

Keywords: BMAA; Inflammatory response; Photoreceptors; Retinal pigment epithelial cells; Retinoid X receptors; Survival

DOI: https://doi.org/10.1016/j.bbamcr.2024.119816