bims-mideyd 2022-11-06 papers

Cureus. 2022 Sep;14(9): e29583

Hrishikesh Vyawahare, Pranaykumar Shinde.

The greatest global root of irremediable amaurosis in the venerable is age-related macular degeneration (AMD), a complex eye condition. Clinically, AMD is characterized as being in an early stage to late stage and initially affects the macula, which is the center of the retina (advanced AMD). Age-related cellular and metabolic imbalance are made worse by the creation of excessive amounts of free radical species, which causes mitochondrial malfunction. As a result, in AMD-affected eyes, the deprivation of melanocytes, confection, and eventually atrophy within the retinal tissue are caused by the continued proliferation of oxidative stress caused by systemic antioxidant capacity depletion. In the urbanized, industrialized world, age-related macular degeneration (AMD) is one of the major causes of central vision loss in the older age group. Although several causes and mechanisms for the dysfunction and degeneration of the retinal pigment epithelium (RPE) have previously been identified, the condition's symptoms are still not fully understood. Etiopathogenesis is still not entirely understood. As a result, the RPE fails, allowing an accumulation of aberrant misfolded proteins, due to the loss of anatomical control over oppression, altered homeostasis, dysfunctional lipid homeostasis, and failure of mitochondria. Due to the multitude of interconnected processes, numerous complicated therapy combinations will probably be the best option to deliver the best visual outcomes; these combinations will vary depending on the kind and degree of the condition being treated. Undoubtedly, this will lead to the development of customized preventative medications and, hopefully, the revelation of a potential cure. All the mechanisms involved in the etiology of AMD should be continuously probed to create covariates for other contemporaneous or future problems.

Keywords: age-related macular degeneration; homeostasis; neuroinflammation; oxidative stress; proteostasis; retinal pigment epithelium (rpe)

DOI: https://doi.org/10.7759/cureus.29583

Discov Med. 2022 Jul-Aug;34(171):34(171): 33-43

Oxidative Stress-Responsive Small Extracellular Vesicles and MicroRNAs in Age-related Macular Degeneration: Biomarkers and Therapeutic Tools.

Zhongjing Lin, Ke Mao.

Age-related macular degeneration (AMD) is the main cause of blurred vision, and oxidative stress is a leading risk factor for AMD pathology. Small extracellular vesicles (EVs) are 50-90 nm membrane microvesicles (MVs) released by several cell types in a controlled fashion and they transfer from cell to cell to mediate disease progression. EVs encapsulate and transfer microRNAs (miRNA) to recipient cells. MiRNAs are small non-coding RNA molecules that inhibit expression and function of targeted mRNAs through miRNA/mRNA interactions in the conserved 3'UTR regions, and in this way they can modulate a variety of physiological and pathological processes. Dysregulation of EVs and their miRNAs cargo from retinal cells is believed to be correlated to a loss of cellular homeostasis and AMD pathology. This review investigates the association between oxidative stress, sEVs, miRNAs, and AMD pathogenesis, and the potential for discovering novel treatment targets for AMD.

Invest Ophthalmol Vis Sci. 2022 Nov 01. 63(12): 7

Pregabalin Mediates Retinal Ganglion Cell Survival From Retinal Ischemia/Reperfusion Injury Via the Akt/GSK3β/β-Catenin Signaling Pathway.

Jing Xu, Yuyan Guo, Qiong Liu, Hui Yang, Ming Ma, Jian Yu, Linjiang Chen, Chunlian Ou, Xiaohui Liu, Jing Wu.

Purpose: Progressive retinal ganglion cell (RGC) loss induced by retinal ischemia/reperfusion (RIR) injury leads to irreversible visual impairment. Pregabalin (PGB) is a promising drug for neurodegenerative diseases. However, with regard to RGC survival, its specific role and exact mechanism after RIR injury remain unclear. In this study, we sought to investigate whether PGB could protect RGCs from mitochondria-related apoptosis induced by RIR and explore the possible mechanisms.
Methods: C57BL/6J mice and primary RGCs were pretreated with PGB prior to ischemia/reperfusion modeling. The retinal structure and cell morphology were assessed by immunochemical assays and optical coherence tomography. CCK8 was used to assay cell viability, and an electroretinogram was performed to detect RGC function. Mitochondrial damage was assessed by a reactive oxygen species (ROS) assay kit and transmission electron microscopy. Western blot and immunofluorescence assays quantified the expression of proteins associated with the Akt/GSK3β/β-catenin pathway.
Results: Treatment with PGB increased the viability of RGCs in vitro. Consistently, PGB preserved the normal thickness of the retina, upregulated Bcl-2, reduced the ratio of cleaved caspase-3/caspase-3 and the expression of Bax in vivo. Meanwhile, PGB improved mitochondrial structure and prevented excessive ROS production. Moreover, PGB restored the amplitudes of oscillatory potentials and photopic negative responses following RIR. The mechanisms underlying its neuroprotective effects were attributed to upregulation of the Akt/GSK3β/β-catenin pathway. However, PGB-mediated neuroprotection was suppressed when using MK2206 (an Akt inhibitor), whereas it was preserved when treated with TWS119 (a GSK3β inhibitor).
Conclusions: PGB exerts a protective effect against RGC apoptosis induced by RIR injury, mediated by the Akt/GSK3β/β-catenin pathway.

DOI: https://doi.org/10.1167/iovs.63.12.7

Biol Pharm Bull. 2022 ;45(11): 1609-1615

Oxidative Stress Impairs Autophagy via Inhibition of Lysosomal Transport of VAMP8.

Yukiya Ohnishi, Daisuke Tsuji, Kohji Itoh.

Autophagy is a highly conserved intracellular degrading system and its dysfunction is considered related to the cause of neurodegenerative disorders. A previous study showed that the inhibition of endocytosis transport attenuates soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) protein transport to lysosomes and block autophagy. The other studies demonstrated oxidative stress, one of the inducers of neurodegenerative diseases inhibits endocytosis transport. Thus, we hypothesized that oxidative stress-induced endocytosis inhibition causes alteration of SNARE protein transport to lysosomes and impairs autophagy. Here, we demonstrated that oxidative stress inhibits endocytosis and decreased the lysosomal localization of VAMP8, one of the autophagy-related SNARE proteins in a human neuroblastoma cell line. Moreover, this oxidative stress induction blocked the autophagosome-lysosome fusion step. Since we also observed decreased lysosomal localization of VAMP8 and inhibition of autophagosome-lysosome fusion in endocytosis inhibitor-treated cells, oxidative stress may inhibit VAMP8 trafficking by suppressing endocytosis and impair autophagy. Our findings suggest that oxidative stress-induced inhibition of VAMP8 trafficking to lysosomes is associated with the development of neurodegenerative diseases due to the blocked autophagosome-lysosome fusion, and may provide a new therapeutic target for restoring the autophagic activity.

Keywords: autophagy; endocytosis; oxidative stress; soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) protein

DOI: https://doi.org/10.1248/bpb.b22-00131