scholarly journals Self-Assembling Tacrolimus Nanomicelles for Retinal Drug Delivery

Pharmaceutics ◽  
2020 ◽  
Vol 12 (11) ◽  
pp. 1072
Author(s):  
Vrinda Gote ◽  
Abhirup Mandal ◽  
Meshal Alshamrani ◽  
Dhananjay Pal
Keyword(s):  
Retinal Pigment Epithelium ◽  
Inflammatory Cytokines ◽  
Pigment Epithelium ◽  
Retinal Pigment ◽  
Age Related Macular Degeneration ◽  
Dependent Manner ◽  
Sodium Iodate ◽  
Cytotoxicity Studies ◽  
Pro Inflammatory Cytokines

Neovascular age-related macular degeneration (AMD) is characterized by an increase in reactive oxygen species (ROS) and pro-inflammatory cytokines in the retinal pigment epithelium cells. The primary purpose of this study was the development of a clear, tacrolimus nanomicellar formulation (TAC-NMF) for AMD. The optimized formulation had a mean diameter of 15.41 nm, a zeta potential of 0.5 mV, and an entrapment efficiency of 97.13%. In-vitro cytotoxicity studies revealed the dose-dependent cytotoxicity of TAC-NMF on various ocular cell lines, such as human retinal pigment epithelium (D407), monkey retinal choroidal endothelial (RF/6A) cells, and human corneal epithelium (CCL 20.2) cells. Cellular uptake and in-vitro distribution studies using flow cytometry and confocal microscopy, respectively, indicated an elevated uptake of TAC-NMF in a time-dependent manner. Biocompatibility assay using macrophage RAW 264.7 cell line resulted in low production of inflammatory cytokines such as IL-6, IL-1β and TNF-α after treatment with TAC-NMF. There was a decrease in ROS in D407 cells pre-treated with sodium iodate (ROS inducing agent) after treating with TAC-NMF and tacrolimus drug. Similarly, there was a reduction in the pro-inflammatory cytokines and VEGF-A in D407 cells pretreated with sodium iodate. This indicates that TAC-NMF could lower pro-inflammatory cytokines and ROS commonly seen in AMD.

scholarly journals Clinical-grade stem cell–derived retinal pigment epithelium patch rescues retinal degeneration in rodents and pigs

2019 ◽  
Vol 11 (475) ◽  
pp. eaat5580 ◽  
Author(s):  
Ruchi Sharma ◽  
Vladimir Khristov ◽  
Aaron Rising ◽  
Balendu Shekhar Jha ◽  
Roba Dejene ◽  
...  
Keyword(s):  
Stem Cell ◽  
Retinal Pigment Epithelium ◽  
Pigment Epithelium ◽  
Retinal Pigment ◽  
Age Related Macular Degeneration ◽  
Clinical Grade ◽  
Functional Validation ◽  
Age Related

Considerable progress has been made in testing stem cell–derived retinal pigment epithelium (RPE) as a potential therapy for age-related macular degeneration (AMD). However, the recent reports of oncogenic mutations in induced pluripotent stem cells (iPSCs) underlie the need for robust manufacturing and functional validation of clinical-grade iPSC-derived RPE before transplantation. Here, we developed oncogenic mutation-free clinical-grade iPSCs from three AMD patients and differentiated them into clinical-grade iPSC-RPE patches on biodegradable scaffolds. Functional validation of clinical-grade iPSC-RPE patches revealed specific features that distinguished transplantable from nontransplantable patches. Compared to RPE cells in suspension, our biodegradable scaffold approach improved integration and functionality of RPE patches in rats and in a porcine laser-induced RPE injury model that mimics AMD-like eye conditions. Our results suggest that the in vitro and in vivo preclinical functional validation of iPSC-RPE patches developed here might ultimately be useful for evaluation and optimization of autologous iPSC-based therapies.

scholarly journals Lutein-Loaded, Biotin-Decorated Polymeric Nanoparticles Enhance Lutein Uptake in Retinal Cells

Pharmaceutics ◽  
2020 ◽  
Vol 12 (9) ◽  
pp. 798 ◽  
Author(s):  
Pradeep Kumar Bolla ◽  
Vrinda Gote ◽  
Mahima Singh ◽  
Manan Patel ◽  
Bradley A. Clark ◽  
...  
Keyword(s):  
Polymeric Nanoparticles ◽  
Pigment Epithelium ◽  
Retinal Pigment ◽  
In Vitro Release ◽  
Age Related Macular Degeneration ◽  
Scanning Calorimetry ◽  
Retinal Cells ◽  
Age Related ◽  
Cytotoxicity Studies

Age related macular degeneration (AMD) is one of the leading causes of visual loss and is responsible for approximately 9% of global blindness. It is a progressive eye disorder seen in elderly people (>65 years) mainly affecting the macula. Lutein, a carotenoid, is an antioxidant, and has shown neuroprotective properties in the retina. However, lutein has poor bioavailability owing to poor aqueous solubility. Drug delivery to the posterior segment of the eye is challenging due to the blood–retina barrier. Retinal pigment epithelium (RPE) expresses the sodium-dependent multivitamin transporter (SMVT) transport system which selectively uptakes biotin by active transport. In this study, we aimed to enhance lutein uptake into retinal cells using PLGA–PEG–biotin nanoparticles. Lutein loaded polymeric nanoparticles were prepared using O/W solvent-evaporation method. Particle size and zeta potential (ZP) were determined using Malvern Zetasizer. Other characterizations included differential scanning calorimetry, FTIR, and in-vitro release studies. In-vitro uptake and cytotoxicity studies were conducted in ARPE-19 cells using flow cytometry and confocal microscopy. Lutein was successfully encapsulated into PLGA and PLGA–PEG–biotin nanoparticles (<250 nm) with uniform size distribution and high ZP. The entrapment efficiency of lutein was ≈56% and ≈75% for lutein-loaded PLGA and PLGA–PEG–biotin nanoparticles, respectively. FTIR and DSC confirmed encapsulation of lutein into nanoparticles. Cellular uptake studies in ARPE-19 cells confirmed a higher uptake of lutein with PLGA–PEG–biotin nanoparticles compared to PLGA nanoparticles and lutein alone. In vitro cytotoxicity results confirmed that the nanoparticles were safe, effective, and non-toxic. Findings from this study suggest that lutein-loaded PLGA–PEG–biotin nanoparticles can be potentially used for treatment of AMD for higher lutein uptake.

scholarly journals Efficacy of Ethanol Extract ofFructus lyciiand Its Constituents Lutein/Zeaxanthin in Protecting Retinal Pigment Epithelium Cells against Oxidative Stress:In VivoandIn VitroModels of Age-Related Macular Degeneration

2013 ◽  
Vol 2013 ◽  
pp. 1-10 ◽  
Author(s):  
Xinrong Xu ◽  
Li Hang ◽  
Binglin Huang ◽  
Yuanhua Wei ◽  
Shizhong Zheng ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Retinal Pigment Epithelium ◽  
Macular Degeneration ◽  
Pigment Epithelium ◽  
Retinal Pigment ◽  
Ethanol Extract ◽  
Age Related Macular Degeneration ◽  
Age Related ◽  
Fructus Lycii

Age-related macular degeneration (AMD) is a major cause of blindness worldwide. Oxidative stress plays a large role in the pathogenesis of AMD. The present study was to evaluate the effects ofFructus lyciiethanol extract on AMD in mice and to investigate whether combination of lutein and zeaxanthin, two carotenoid pigments inFructus lycii, could protect human retinal pigment epithelial ARPE-19 cells treated with hydrogen peroxide (H2O2)in vitro. We found that severe sediment beneath retinal pigment epithelium and thickened Bruch membrane occurred in AMD mice. However,Fructus lyciiethanol extract improved the histopathologic changes and decreased the thickness of Bruch membrane. Furthermore, the gene and protein expression of cathepsin B and cystatin C was upregulated in AMD mice but was eliminated byFructus lyciiethanol extract. Investigationsin vitroshowed that ARPE-19 cell proliferation was suppressed by H2O2. However, lutein/zeaxanthin not only stimulated cell proliferation but also abrogated the enhanced expression of MMP-2 and TIMP-1 in H2O2-treated ARPE-19 cells. These data collectively suggested thatFructus lyciiethanol extract and its active components lutein/zeaxanthin had protective effects on AMDin vivoandin vitro, providing novel insights into the beneficial role ofFructus lyciifor AMD therapy.

scholarly journals Tracking the Transplanted Neurosphere in Retinal Pigment Epithelium Degeneration Model

2021 ◽  
Vol 12 (4) ◽  
pp. 523-532
Author(s):  
Hamid Aboutaleb Kadkhodaeian1 ◽  
◽  
Amir Salati ◽  
Mojtaba Ansari ◽  
Vajihe Taghdiri Nooshabadi ◽  
...  
Keyword(s):  
Stem Cells ◽  
Retinal Pigment Epithelium ◽  
Pigment Epithelium ◽  
Retinal Pigment ◽  
Study Data ◽  
Age Related Macular Degeneration ◽  
Sodium Iodate ◽  
Neural Lineage ◽  
Age Related ◽  
Stromal Stem Cells

Introduction: Retinal Pigment Epithelium (RPE) layer deterioration is a leading cause of Age-Related Macular Degeneration (AMD), i.e., the most significant reason for irreversible blindness. The present study aimed to track the Neurosphere-Derived (NS) from Bone Marrow Stromal Stem Cells (BMSCs) grafted into the sub-retinal space (destruction of the RPE layer by sodium iodate). Methods: RPE degeneration model was performed using the injection of 5% sodium iodate performed in the retro-orbital sinus of Wistar rats. BMSCs were extracted from the examined rat femur and induced into NS, using EGF, bFGF, and B27. BrdU-NS labeled cells were transplanted into the sub-retinal space. For detecting BMSCs and NS markers, immunocytochemistry was performed. Moreover, immunohistochemical was conducted for tracking the transplanted cells in the RPE and sensory retina. Results: The immunocytochemistry of BMSCs cells displayed the expression of mesenchymal stem cells markers (CD90; 99%±1), CD166 (98%±2), CD44 (99%±1). Additionally, the expression of neural lineage markers in NS, such as SOX2, OCT4, Nanog, Nestin, and Neurofilaments (68, 160, 200) revealed the differentiation from BMSCs. Tracking BrdU-NS labeled suggested these aggregations in most layers of the retina. Conclusion: Our study data indicated that BMSCs derived neurosphere had the potential to migrate in injured retinal and integrate into the neurosensory retina. These data can be useful in finding safe cells for replacement therapy in AMD.

scholarly journals Spermidine Oxidation-Mediated Degeneration of Retinal Pigment Epithelium in Rats

2017 ◽  
Vol 2017 ◽  
pp. 1-13 ◽  
Author(s):  
Koji Ohashi ◽  
Masaaki Kageyama ◽  
Katsuhiko Shinomiya ◽  
Yukie Fujita-Koyama ◽  
Shin-ichiro Hirai ◽  
...  
Keyword(s):  
Cell Death ◽  
Retinal Pigment Epithelium ◽  
Amine Oxidase ◽  
Morphological Changes ◽  
Pigment Epithelium ◽  
Retinal Pigment ◽  
Age Related Macular Degeneration ◽  
In Vivo Model ◽  
Dependent Manner ◽  
Age Related

Retinal pigment epithelium (RPE) degeneration is a crucial event in dry age-related macular degeneration and gyrate atrophy. The polyamine spermidine has been shown to induce RPE cell death in vitro. The present study aimed to establish a novel in vivo model of spermidine-induced RPE degeneration and to determine whether spermidine-induced RPE cell death involves oxidative mechanisms. In this study, spermidine caused ARPE-19 cell death in a concentration-dependent manner. This effect was prevented by removal of serum from the culture medium or treatment with amine oxidase inhibitors, N-acetylcysteine (NAC), or aldehyde dehydrogenase (ALDH). Intravitreal injection of spermidine into rats significantly increased the permeability of the blood-retinal barrier and decreased the amplitudes of scotopic electroretinogram a- and b-waves. Histological analysis revealed that spermidine induced vacuolation, atrophy, and dropout of RPE cells, leading to the disruption of photoreceptor outer segments. Simultaneous intravitreal administration of NAC and ALDH with spermidine prominently inhibited the functional and morphological changes induced by spermidine. In conclusion, this study demonstrated that the intravitreal administration of spermidine induced RPE cell dysfunction and death followed by photoreceptor degeneration in rats. These effects of spermidine are thought to be mediated by oxidative stress and a toxic aldehyde generated during spermidine oxidation.

scholarly journals Grp78 alleviates sodium iodate-induced retinal cell injury in vivo and in vitro

2021 ◽  
Author(s):  
Jiang Shuang ◽  
Guo Yongpeng ◽  
Yi Ning ◽  
Li Hongdan ◽  
Liu Hua
Keyword(s):  
Retinal Pigment Epithelium ◽  
Cell Injury ◽  
Morphological Changes ◽  
Pigment Epithelium ◽  
Retinal Pigment ◽  
Retinal Cell ◽  
Sodium Iodate ◽  
Retinal Injury

AbstractObjectiveGlucose-regulated protein 78 (Grp78) has been regarded as a main member of the endoplasmic reticulum proteins, Grp78 could protect cells from apoptosis under stress conditions. However, whether Grp78 could protect retinal pigment epithelium (RPE) cells from oxidative injury and then protect retinas from morphological changes and functional abnormalities remain undetermined. Here, we try to explore the effect of Grp78 on retinal cell injury induced by sodium iodate in vivo and in vitro.MethodsTo investigate whether Grp78 has a protective effect on RPE injury in vitro, human retinal pigment epithelium (ARPE-19) cells were treated with sodium iodate. The cell proliferation, morphology, apoptosis and ROS production assays were detected. In vivo, We established sodium iodate-induced retinal injury model in mice by intravenous injection of sodium iodate into tail vein. After that, we examined the morphology and function of retina in mice by fundus photography, OCT and ERG. Finally, we removed the retina of mice for histological examination.ResultsGrp78 significantly inhibited sodium iodate-induced reactive oxygen species (ROS), and decreased apoptosis of RPE in vitro. Furthermore, Grp78 significantly decreased the apoptosis of retinal cells in vivo, resulting in the inhibition of morphological changes of retina, and improving the function of retina. The underlying mechanisms included inhibited caspase3 and Nos, and increased expression of Bcl2, thereby protecting RPE from SI-induced ROS and apoptosis.ConclusionGrp78 could reduce the injury of retinal cells induced by sodium iodate in vitro and in vivo. These findings suggested Grp78 may become a new therapeutic target for retinal injury in clinical practice.

scholarly journals The Effect of Lycium barbarum Polysaccharides on Pyroptosis-Associated Amyloid β1-40 Oligomers-Induced Adult Retinal Pigment Epithelium 19 Cell Damage

2020 ◽  
Vol 21 (13) ◽  
pp. 4658 ◽  
Author(s):  
Ming Yang ◽  
Kwok-Fai So ◽  
Amy Cheuk Yin Lo ◽  
Wai Ching Lam
Keyword(s):  
Retinal Pigment Epithelium ◽  
Cell Viability ◽  
Pigment Epithelium ◽  
Retinal Pigment ◽  
Morphological Characteristics ◽  
Age Related Macular Degeneration ◽  
Dependent Manner ◽  
Lycium Barbarum ◽  
Age Related ◽  
Lycium Barbarum Polysaccharides

Age-related macular degeneration (AMD) is a sight-threatening disease with limited treatment options. We investigated whether amyloid β1-40 (Aβ1-40) could cause pyroptosis and evaluated the effects of Lycium barbarum polysaccharides (LBP) on Aβ1-40 oligomers-induced retinal pigment epithelium 19 (ARPE-19) damage, which is an in vitro AMD model. Aβ1-40 oligomers verified by Western blot were added to ARPE-19 cells with or without 24 h LBP treatment. Aβ1-40 oligomers significantly decreased ARPE-19 cell viability with obvious morphological changes under light microscopy. SEM revealed swollen cells with a bubbling appearance and ruptured cell membrane, which are morphological characteristics of pyroptosis. ELISA results showed increased expression of IL-1β and IL-18, which are the final products of pyroptosis. LBP administration for 24 h had no toxic effects on ARPE-19 cells and improved cell viability and morphology while disrupting Aβ1-40 oligomerization in a dose-dependent manner. Furthermore, Aβ1-40 oligomers up-regulated the cellular immunoreactivity of pyroptosis markers including NOD-like receptors protein 3 (NLRP3), caspase-1, and membrane N-terminal cleavage product of GSDMD (GSDMD-N), which could be reversed by LBP treatment. Taken together, this study showed that LBP effectively protects the Aβ1-40 oligomers-induced pyroptotic ARPE-19 cell damages by its anti-Aβ1-40 oligomerization properties and its anti-pyroptotic effects.

scholarly journals Inhibition of DUSP6 Activates Autophagy and Rescues the Retinal Pigment Epithelium in Sodium Iodate-Induced Retinal Degeneration Models In Vivo and In Vitro

Biomedicines ◽  
2022 ◽  
Vol 10 (1) ◽  
pp. 159
Author(s):  
Hao-Yu Tsai ◽  
Henkie Isahwan Ahmad Mulyadi Lai ◽  
Zhang-Yuan Chen ◽  
Tai-Chi Lin ◽  
Winnie Khor ◽  
...  
Keyword(s):  
Retinal Pigment Epithelium ◽  
Retinal Degeneration ◽  
Pigment Epithelium ◽  
Retinal Pigment ◽  
Autophagic Flux ◽  
Erk Pathway ◽  
Sodium Iodate ◽  
Autophagy Flux

Autophagy plays a protective role in the retinal pigment epithelium (RPE) by eliminating damaged organelles in response to reactive oxygen species (ROS). Dual-specificity protein phosphatase 6 (DUSP6), which belongs to the DUSP subfamily, works as a negative-feedback regulator of the extracellular signal-regulated kinase (ERK) pathway. However, the complex interplay between DUSP6 and autophagy induced by ROS in RPE is yet to be investigated. To investigate the relationship between DUSP6 and autophagy, we exposed the ARPE-19 cell line and C57BL/6N mice to sodium iodate (NaIO3) as an oxidative stress inducer. Our data showed that the inhibition of DUSP6 activity promotes autophagy flux through the ERK pathway via the upregulation of immunoblotting expression in ARPE-19 cells. Live imaging showed a significant increase in autophagic flux activities, which suggested the restoration autophagy after treatment with the DUSP6 inhibitor. Furthermore, the mouse RPE layer exhibited an irregular structure and abnormal deposits following NaIO3 injection. The retina layer was recovered after being treated with DUSP6 inhibitor; this suggests that DUSP6 inhibitor can rescue retinal damage by restoring the mouse retina’s autophagy flux. This study suggests that the upregulation of DUSP6 can cause autophagy flux malfunctions in the RPE. The DUSP6 inhibitor can restore autophagy induction, which may serve as a potential therapeutic approach for retinal degeneration disease.

High-voltage electron microscopy of subretinal scar formation

1992 ◽  
Vol 50 (1) ◽  
pp. 486-487
Author(s):  
G.E. Korte ◽  
M. Marko ◽  
G. Hageman
Keyword(s):  
Electron Microscopy ◽  
Monoclonal Antibody ◽  
Retinal Pigment Epithelium ◽  
Glial Cells ◽  
High Voltage ◽  
Pigment Epithelium ◽  
Retinal Pigment ◽  
Sodium Iodate ◽  
High Voltage Electron Microscopy ◽  
Voltage Electron

Sodium iodate iv. damages the retinal pigment epithelium (RPE) in rabbits. Where RPE does not regenerate (e.g., 1,2) Muller glial cells (MC) forma subretinal scar that replaces RPE. The MC response was studied by HVEM in 3D computer reconstructions of serial thick sections, made using the STEREC0N program (3), and the HVEM at the NYS Dept. of Health in Albany, NY. Tissue was processed for HVEM or immunofluorescence localization of a monoclonal antibody recognizing MG microvilli (4).

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