bims-mideyd 2022-04-10 papers

Oxid Med Cell Longev. 2022 ;2022 5851315

Ming-Mu-Di-Huang-Pill Activates SQSTM1 via AMPK-Mediated Autophagic KEAP1 Degradation and Protects RPE Cells from Oxidative Damage.

Xi Chen, Yujie Zhu, Xiaoqing Shi, Jing Zuo, Tianming Hu, Hao Wu, Ying Xia, Wei Shi, Wei Wei.

Oxidative stress and diminished autophagy in the retinal pigment epithelium (RPE) play crucial roles in the pathogenesis of age-related macular degeneration (AMD). Enhancing autophagy has recently been identified as an important strategy to protect RPE cells from oxidative damage. Ming-Mu-Di-Huang-Pill (MMDH pill) is a traditional herbal medicine used to treat AMD, and its molecular mechanism is not well understood. The aim of the present study was to investigate whether the MMDH pill relieved acute oxidative damage by activating autophagy in an in vitro and in vivo model of sodium iodate (NaIO3). The results showed that NaIO3 induced cell death and inhibited proliferation. The MMDH pill increased cell viability, restored the activities of antioxidant enzymes, and reduced reactive oxygen species (ROS) fluorescence intensity. The MMDH pill mediated Kelch-like ECH-associated protein 1 (Keap1) degradation and decreased oxidative damage, which was blocked in autophagy inhibitor (chloroquine) or sequestosome-1 (SQSTM1) siRNA-treated RPE cells. Furthermore, we indicated that the MMDH pill could promote adenosine monophosphate-activated protein kinase (AMPK) phosphorylation and autophagy adaptor-SQSTM1 expression, which could stimulate autophagic degradation of Keap1. In addition, the MMDH pill increased nuclear factor (erythroid-derived 2)-like 2 (Nrf2) nuclear translocation in a SQSTM1-dependent manner and induced the expression of the downstream antioxidant factors heme oxygenase-1 (HO-1) and nicotinamide adenine dinucleotide phosphate quinone dehydrogenase 1 (NQO1). In conclusion, MMDH pill plays a protective role in relieving NaIO3-induced oxidative stress by activating the AMPK/SQSTM1/Keap1 pathway. The MMDH pill may be useful to treat AMD by maintaining redox homeostasis and autophagy.

DOI: https://doi.org/10.1155/2022/5851315

Oxid Med Cell Longev. 2022 ;2022 3955748

Decorin Protects Retinal Pigment Epithelium Cells from Oxidative Stress and Apoptosis via AMPK-mTOR-Regulated Autophagy.

Xinyi Xie, Duo Li, Yuqing Cui, Tianhua Xie, Jiping Cai, Yong Yao.

Age-related macular degeneration (AMD) is the leading cause of irreversible visual loss among the elderly worldwide with unidentified pathogenesis and limited therapeutic options. Oxidative stress-induced damage to the retinal pigment epithelium (RPE) is central in the development and progression of AMD. Decorin (DCN), a small leucine-rich proteoglycan, possesses powerful antifibrotic, anti-inflammatory, and antiangiogenic properties. DCN has also been reported to serve a cytoprotective role in various cell types, but its protective effects against H2O2-induced oxidative stress and apoptosis in ARPE-19 cells remain unclear. In this study, we showed that DCN significantly attenuated the increase in cell viability loss, apoptosis rate, and reactive oxygen species (ROS) levels in ARPE-19 cells induced by H2O2. Furthermore, DCN activated the AMPK/mTOR pathway to promote autophagy while genetic inhibition of autophagy-related gene 5 (ATG5) hindered autophagic process and diminished the protective role of DCN against oxidative stress in ARPE-19 cells. Collectively, these results suggest that DCN could protect RPE cells from H2O2-induced oxidative stress and apoptosis via autophagy promotion, thus providing the therapeutic potential for AMD prevention and treatment.

DOI: https://doi.org/10.1155/2022/3955748

Gene Ther. 2022 Apr 06.

Gene therapy restores mitochondrial function and protects retinal ganglion cells in optic neuropathy induced by a mito-targeted mutant ND1 gene.

Yuan Liu, Jeremy D Eastwood, Diego E Alba, Sindhu Velmurugan, Ning Sun, Vittorio Porciatti, Richard K Lee, William W Hauswirth, John Guy, Hong Yu.

Therapies for genetic disorders caused by mutated mitochondrial DNA are an unmet need, in large part due barriers in delivering DNA to the organelle and the absence of relevant animal models. We injected into mouse eyes a mitochondrially targeted Adeno-Associated-Virus (MTS-AAV) to deliver the mutant human NADH ubiquinone oxidoreductase subunit I (hND1/m.3460 G > A) responsible for Leber's hereditary optic neuropathy, the most common primary mitochondrial genetic disease. We show that the expression of the mutant hND1 delivered to retinal ganglion cells (RGC) layer colocalizes with the mitochondrial marker PORIN and the assembly of the expressed hND1 protein into host respiration complex I. The hND1-injected eyes exhibit hallmarks of the human disease with progressive loss of RGC function and number, as well as optic nerve degeneration. We also show that gene therapy in the hND1 eyes by means of an injection of a second MTS-AAV vector carrying wild-type human ND1 restores mitochondrial respiratory complex I activity, the rate of ATP synthesis and protects RGCs and their axons from dysfunction and degeneration. These results prove that MTS-AAV is a highly efficient gene delivery approach with the ability to create mito-animal models and has the therapeutic potential to treat mitochondrial genetic diseases.

DOI: https://doi.org/10.1038/s41434-022-00333-6

Cell Death Dis. 2022 Apr 09. 13(4): 323

Angiotensin II related glial cell activation and necroptosis of retinal ganglion cells after systemic hypotension in glaucoma.

Soo Ji Jeon, Jungbin Huh, Eojin Jeong, Chan Kee Park, Hae Young Lopilly Park.

The purpose of this study was to design an animal model mimicking glaucoma with hemodynamic instability and to identify involvement of angiotensin II (AngII) and associated changes of the retina. Systemic hypotension was induced in Sprague-Dawley rats by oral hydrochlorothiazide administration. Rats were sacrificed at 4, 8, and 12-week time points. AngII and receptor levels were examined in the serum and retina. To examine the relationship between glia activation and associated RGC death, biochemical analysis of GFAP, Iba-1, and necroptosis associated factors such as TNFα, receptor-interacting protein (RIP) 1, 3, and inactive caspase 8 were explored. To investigate the difference in RGC death mechanism, JNK inhibitor or RIP3 inhibitor were given intraperitoneally to rats with ocular hypertension and systemic hypotension both to identify the pathway mainly involved. AngII and receptors were increased in the serum and retina of systemic hypotensive rat. At 4, 8, and 12 weeks after hypotension induction, glial activation was increased as indicated by GFAP and Iba-1 staining. TNFα, RIP3 were elevated. and downregulation of inactive caspase 8 was apparent in the retina of hypotensive rat. Electron microscopy revealed that necroptosis of RGC was gradually increased after systemic hypotension. Following intraperitoneal JNK inhibitor or RIP3 inhibitor administration, RGC loss was attenuated in systemic hypotensive rats but not in ocular hypertensive rats. In conclusion, AngII is involved in glial activation and associated RGC necroptosis following systemic hypotension. This pathway represents a novel and distinct cell death mechanism when compared to that involved in elevated intraocular pressure.

DOI: https://doi.org/10.1038/s41419-022-04762-4