Rapamycin Removes Damaged Mitochondria and Protects Human Trabecular Meshwork (TM-1) Cells from Chronic Oxidative Stress

He, Jing; Zhang, Shao Dan; Qu, Yang; Wang, Hai Lin; Tham, Clement C.; Pang, Chi Pui; Chu, Wai Kit

doi:10.1007/s12035-019-1559-5

Cited by 29 publications

(24 citation statements)

References 37 publications

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“…On the other hand, the aged retina is characterized by increased levels of reactive oxygen species (ROS), impaired autophagy, excessive energy consumption, and DNA damage, all of which contribute to the degeneration of RPE cells and link to AMD pathogenesis [48,49]. Besides, autophagy is not only linked to AMD but also to glaucoma, since dysregulation of autophagy can harm the outflow path of the trabecular meshwork, whereas promotion of autophagy via rapamycin treatment may have a cytoprotective effect upon oxidative stress [50].…”

Section: Autophagy and Oxidative Stressmentioning

confidence: 99%

The Relevance of Oxidative Stress in the Pathogenesis and Therapy of Retinal Dystrophies

2020

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Retinal cell survival requires an equilibrium between oxygen, reactive oxygen species, and antioxidant molecules that counteract oxidative stress damage. Oxidative stress alters cell homeostasis and elicits a protective cell response, which is most relevant in photoreceptors and retinal ganglion cells, neurons with a high metabolic rate that are continuously subject to light/oxidative stress insults. We analyze how the alteration of cellular endogenous pathways for protection against oxidative stress leads to retinal dysfunction in prevalent (age-related macular degeneration, glaucoma) as well as in rare genetic visual disorders (Retinitis pigmentosa, Leber hereditary optic neuropathy). We also highlight some of the key molecular actors and discuss potential therapies using antioxidants agents, modulators of gene expression and inducers of cytoprotective signaling pathways to treat damaging oxidative stress effects and ameliorate severe phenotypic symptoms in multifactorial and rare retinal dystrophies.

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Section: Autophagy and Oxidative Stressmentioning

confidence: 99%

The Relevance of Oxidative Stress in the Pathogenesis and Therapy of Retinal Dystrophies

2020

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“…Another research showed that mTORC1 improved mitochondrial biogenesis and metabolism through transcription factors YY-1 and PGC-1a (Cunningham et al, 2007). Moreover, RAP significantly induced autophagy, and suppressed oxidative stress as well as apoptosis, possibly via eliminating injured mitochondria (He et al, 2019).…”

Section: Discussionmentioning

confidence: 99%

Protective Effects of Rapamycin on Trabecular Meshwork Cells in Glucocorticoid-Induced Glaucoma Mice

Zhu

Zeng

et al. 2020

Front. Pharmacol.

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Glucocorticoid-induced glaucoma (GIG) is a chronic optic neuropathy caused by systemic or topical glucocorticoid (GC) treatment, which could eventually lead to permanent vision loss. To investigate the protective effects of rapamycin (RAP) on the trabecular cells during the development of GIG in mice, the effects of RAP on intraocular pressure (IOP), trabecular ultrastructure, and retinal ganglion cells (RGCs) were examined in C57BL/6J female mice treated with dexamethasone acetate (Dex-Ace). The expression of a-actin in trabecular tissue was detected by immunofluorescence, and the autophagic activity of trabecular cells and the expression of GIG-related myocilin and a-actin were detected by immunoblotting. Our results indicated that Dex-Ace significantly increased IOP at the end of the third week (p < 0.05), while RAP treatment neutralized this elevation of IOP by Dex-Ace. Dex-Ace treatment significantly decreased the RGC numbers (p < 0.05), while synchronous RAP treatment kept the number comparable to control. The outer sheath of elastic fibers became thicker and denser, and the mitochondria of lesions increased in Dex-Ace-treated groups at 4 weeks, while no significant change was observed in the RAP-treated trabecular tissues. Dex-Ace induced myocilin, a-actin, Beclin-1, and LC3-II/ LC-I ratio, and lowered p62, while synchronous RAP treatment further activated autophagy and neutralized the induction of myocilin and a-actin. Our studies suggested that RAP protected trabecular meshwork cells by further inducing autophagy way from damages of GC treatment.

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“…92,95 Downstream mTOR signalling has been shown to be disrupted in human glaucomatous TM compared to nonglaucomatous TM in vitro, 96 and there is evidence that rapamycin is protective against rotenone-induced TM oxidative stress. 97 However, a case series of human volunteers with ocular hypertension, normotensive glaucoma and healthy controls found no significant differences in mTOR signalling in the bloodstream. 98 The role of mTOR and its modulation in glaucoma thus appears to be complex, likely in part due to the multifactorial nature of the condition and in part to the multiple and complex actions of the pathway.…”

Section: Glaucomamentioning

confidence: 98%

“…Downstream mTOR signalling has been shown to be disrupted in human glaucomatous TM compared to non‐glaucomatous TM in vitro, 96 and there is evidence that rapamycin is protective against rotenone‐induced TM oxidative stress 97 . However, a case series of human volunteers with ocular hypertension, normotensive glaucoma and healthy controls found no significant differences in mTOR signalling in the bloodstream 98 …”

Section: Mtor In Diseases Of the Optic Nervementioning

confidence: 99%

Metabolic pathways in context: mTOR signalling in the retina and optic nerve ‐ A review

Yao

Wijngaarden

2020

Clinical Exper Ophthalmology

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The mechanistic target of rapamycin (mTOR) signalling network plays a key role in growth and development, autophagy, metabolism, inflammation as well as ageing, and it is therefore important in ocular health and disease. mTOR dysregulation has been identified in a range of conditions, including age-related macular degeneration, diabetic retinopathy, retinitis pigmentosa, traumatic optic neuropathy and glaucoma. Experimental modulation of the pathway has contributed to the understanding of these diseases and offers the potential for new avenues of therapy. This review discusses the mTOR pathway and its role in health and in diseases of the retina and optic nerve.

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Rapamycin Removes Damaged Mitochondria and Protects Human Trabecular Meshwork (TM-1) Cells from Chronic Oxidative Stress

Cited by 29 publications

References 37 publications

The Relevance of Oxidative Stress in the Pathogenesis and Therapy of Retinal Dystrophies

The Relevance of Oxidative Stress in the Pathogenesis and Therapy of Retinal Dystrophies

Protective Effects of Rapamycin on Trabecular Meshwork Cells in Glucocorticoid-Induced Glaucoma Mice

Metabolic pathways in context: mTOR signalling in the retina and optic nerve ‐ A review

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