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Suresh Kumar Subbiah - One of the best experts on this subject based on the ideXlab platform.
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mitigation of Sodium Iodate induced cytotoxicity in retinal pigment epithelial cells in vitro by transgenic erythropoietin expressing mesenchymal stem cells
Frontiers in Cell and Developmental Biology, 2021Co-Authors: Avin Eehwan Koh, Suresh Kumar Subbiah, Aisha Farhana, Mohammad Khursheed Alam, Pooi Ling MokAbstract:Mesenchymal stem cells (MSC) have shown promise in restoring the vision of patients in clinical trials. However, this therapeutic effect is not observed in every treated patient and is possibly due to the inefficacies of cell delivery and high cell death following transplantation. Utilizing erythropoietin can significantly enhance the regenerative properties of MSCs and hence improve retinal neuron survivability in oxidative stress. Hence, this study aimed to investigate the efficacy of conditioned medium (CM) obtained from transgenic human erythropoietin-expressing MSCs (MSC EPO ) in protecting human retinal pigment epithelial cells from Sodium Iodate (NaIO3)-induced cell death. Human MSC and MSC EPO were first cultured to obtain conditioned media (CM). The IC50 of NaIO3 in the ARPE-19 culture was then determined by an MTT assay. After that, the efficacy of both MSC-CM and MSC-CM EPO in ARPE-19 cell survival were compared at 24 and 48 h after NaIO3 treatment with MTT. The treatment effects on mitochondrial membrane potential was then measured by a JC-1 flow cytometric assay. The MTT results indicated a corresponding increase in cell survivability (5-58%) in the ARPE-19 cell cultures. In comparison to MSC-CM, the use of conditioned medium collected from the MSC-CM EPO further enhanced the rate of ARPE-19 survivability at 24 h (P < 0.05) and 48 h (P < 0.05) in the presence of NaIO3. Furthermore, more than 90% were found viable with the JC-1 assay after MSC-CM EPO treatment, showing a positive implication on the mitochondrial dynamics of ARPE-19. The MSC-CM EPO provided an enhanced mitigating effect against NaIO3-induced ARPE-19 cell death over that of MSC-CM alone during the early phase of the treatment, and it may act as a future therapy in treating retinal degenerative diseases.
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human dental pulp stem cells dpscs therapy in rescuing photoreceptors and establishing a Sodium Iodate induced retinal degeneration rat model
Tissue Engineering and Regenerative Medicine, 2021Co-Authors: Chenshen Lam, Hiba Amer Alsaeedi, Avin Eehwan Koh, Mohd Hairul Nizam Harun, Angela Ng Min Hwei, Pooi Ling Mok, Chi D Luu, Then Kong Yong, Suresh Kumar SubbiahAbstract:Different methods have been used to inject stem cells into the eye for research. We previously explored the intravitreal route. Here, we investigate the efficacy of intravenous and subretinal-transplanted human dental pulp stem cells (DPSCs) in rescuing the photoreceptors of a Sodium Iodate-induced retinal degeneration model. Three groups of Sprague Dawley rats were used: intervention, vehicle group and negative control groups (n = 6 in each). Intravenous injection of 60 mg/kg Sodium Iodate (day 0) induced retinal degeneration. On day 4 post-injection of Sodium Iodate, the rats in the intervention group received intravenous DPSC and subretinal DPSC in the right eye; rats in the vehicle group received subretinal Hank’s balance salt solution and intravenous normal saline; while negative control group received nothing. Electroretinogram (ERG) was performed to assess the retinal function at day 0 (baseline), day 4, day 11, day 18, day 26, and day 32. By the end of the study at day 32, the rats were euthanized, and both their enucleated eyes were sent for histology. No significant difference in maximal ERG a-wave (p = 0.107) and b-wave, (p = 0.153) amplitude was seen amongst the experimental groups. However, photopic 30 Hz flicker amplitude of the study eye showed significant differences in the 3 groups (p = 0.032). Within the intervention group, there was an improvement in 30 Hz flicker ERG response of all 6 treated right eyes, which was injected with subretinal DPSC; while the 30 Hz flicker ERG of the non-treated left eyes remained flat. Histology showed improved outer nuclear layer thickness in intervention group; however, findings were not significant compared to the negative and vehicle groups. Combination of subretinal and intravenous injection of DPSCs may have potential to rescue cone function from a NaIO3-induced retinal injury model.
Avin Eehwan Koh - One of the best experts on this subject based on the ideXlab platform.
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transplanted erythropoietin expressing mesenchymal stem cells promote pro survival gene expression and protect photoreceptors from Sodium Iodate induced cytotoxicity in a retinal degeneration model
Frontiers in Cell and Developmental Biology, 2021Co-Authors: Avin Eehwan Koh, Chenshen Lam, Hiba Amer Alsaeedi, Mohd Hairul Nizam Harun, Munirah Binti Abd Rashid, Hazlita Mohd Isa, Aisha Farhana, Kong Yong Then, Maelynn Catherine Bastion, Mohammad Khursheed AlamAbstract:Mesenchymal stem cells (MSC) are highly regarded as a potential treatment for retinal degenerative disorders like retinitis pigmentosa and age-related macular degeneration. However, donor cell heterogeneity and inconsistent protocols for transplantation have led to varied outcomes in clinical trials. We previously showed that genetically-modifying MSCs to express erythropoietin (MSCEPO) improved its regenerative capabilities in vitro. Hence, in this study, we sought to prove its potential in vivo by transplanting MSCsEPO in a rat retinal degeneration model and analyzing its retinal transcriptome using RNA-Seq. Firstly, MSCsEPO were cultured and expanded before being intravitreally transplanted into the Sodium Iodate-induced model. After the procedure, electroretinography (ERG) was performed bi-weekly for 30 days. Histological analyses were performed after the ERG assessment. The retina was then harvested for RNA extraction. After mRNA-enrichment and library preparation, paired-end RNA-Seq was performed. Salmon and DESeq2 were used to process the output files. The generated dataset was then analyzed using over-representation (ORA), functional enrichment (GSEA), and pathway topology analysis tools (SPIA) to identify enrichment of key pathways in the experimental groups. The results showed that the MSCEPO-treated group had detectable ERG waves (P <0.05), which were indicative of successful phototransduction. The stem cells were also successfully detected by immunohistochemistry 30 days after intravitreal transplantation. An initial over-representation analysis revealed a snapshot of immune-related pathways in all the groups but was mainly overexpressed in the MSC group. A subsequent GSEA and SPIA analysis later revealed enrichment in a large number of biological processes including phototransduction, regeneration, and cell death (P adj <0.05). Based on these pathways, a set of pro-survival gene expressions were extracted and tabulated. This study provided an in-depth transcriptomic analysis on the MSCEPO-treated retinal degeneration model as well as a profile of pro-survival genes that can be used as candidates for further genetic enhancement studies on stem cells.
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mitigation of Sodium Iodate induced cytotoxicity in retinal pigment epithelial cells in vitro by transgenic erythropoietin expressing mesenchymal stem cells
Frontiers in Cell and Developmental Biology, 2021Co-Authors: Avin Eehwan Koh, Suresh Kumar Subbiah, Aisha Farhana, Mohammad Khursheed Alam, Pooi Ling MokAbstract:Mesenchymal stem cells (MSC) have shown promise in restoring the vision of patients in clinical trials. However, this therapeutic effect is not observed in every treated patient and is possibly due to the inefficacies of cell delivery and high cell death following transplantation. Utilizing erythropoietin can significantly enhance the regenerative properties of MSCs and hence improve retinal neuron survivability in oxidative stress. Hence, this study aimed to investigate the efficacy of conditioned medium (CM) obtained from transgenic human erythropoietin-expressing MSCs (MSC EPO ) in protecting human retinal pigment epithelial cells from Sodium Iodate (NaIO3)-induced cell death. Human MSC and MSC EPO were first cultured to obtain conditioned media (CM). The IC50 of NaIO3 in the ARPE-19 culture was then determined by an MTT assay. After that, the efficacy of both MSC-CM and MSC-CM EPO in ARPE-19 cell survival were compared at 24 and 48 h after NaIO3 treatment with MTT. The treatment effects on mitochondrial membrane potential was then measured by a JC-1 flow cytometric assay. The MTT results indicated a corresponding increase in cell survivability (5-58%) in the ARPE-19 cell cultures. In comparison to MSC-CM, the use of conditioned medium collected from the MSC-CM EPO further enhanced the rate of ARPE-19 survivability at 24 h (P < 0.05) and 48 h (P < 0.05) in the presence of NaIO3. Furthermore, more than 90% were found viable with the JC-1 assay after MSC-CM EPO treatment, showing a positive implication on the mitochondrial dynamics of ARPE-19. The MSC-CM EPO provided an enhanced mitigating effect against NaIO3-induced ARPE-19 cell death over that of MSC-CM alone during the early phase of the treatment, and it may act as a future therapy in treating retinal degenerative diseases.
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human dental pulp stem cells dpscs therapy in rescuing photoreceptors and establishing a Sodium Iodate induced retinal degeneration rat model
Tissue Engineering and Regenerative Medicine, 2021Co-Authors: Chenshen Lam, Hiba Amer Alsaeedi, Avin Eehwan Koh, Mohd Hairul Nizam Harun, Angela Ng Min Hwei, Pooi Ling Mok, Chi D Luu, Then Kong Yong, Suresh Kumar SubbiahAbstract:Different methods have been used to inject stem cells into the eye for research. We previously explored the intravitreal route. Here, we investigate the efficacy of intravenous and subretinal-transplanted human dental pulp stem cells (DPSCs) in rescuing the photoreceptors of a Sodium Iodate-induced retinal degeneration model. Three groups of Sprague Dawley rats were used: intervention, vehicle group and negative control groups (n = 6 in each). Intravenous injection of 60 mg/kg Sodium Iodate (day 0) induced retinal degeneration. On day 4 post-injection of Sodium Iodate, the rats in the intervention group received intravenous DPSC and subretinal DPSC in the right eye; rats in the vehicle group received subretinal Hank’s balance salt solution and intravenous normal saline; while negative control group received nothing. Electroretinogram (ERG) was performed to assess the retinal function at day 0 (baseline), day 4, day 11, day 18, day 26, and day 32. By the end of the study at day 32, the rats were euthanized, and both their enucleated eyes were sent for histology. No significant difference in maximal ERG a-wave (p = 0.107) and b-wave, (p = 0.153) amplitude was seen amongst the experimental groups. However, photopic 30 Hz flicker amplitude of the study eye showed significant differences in the 3 groups (p = 0.032). Within the intervention group, there was an improvement in 30 Hz flicker ERG response of all 6 treated right eyes, which was injected with subretinal DPSC; while the 30 Hz flicker ERG of the non-treated left eyes remained flat. Histology showed improved outer nuclear layer thickness in intervention group; however, findings were not significant compared to the negative and vehicle groups. Combination of subretinal and intravenous injection of DPSCs may have potential to rescue cone function from a NaIO3-induced retinal injury model.
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retinal degeneration rat model a study on the structural and functional changes in the retina following injection of Sodium Iodate
Journal of Photochemistry and Photobiology B-biology, 2019Co-Authors: Avin Eehwan Koh, Chenshen Lam, Hiba Amer Alsaeedi, Mohd Hairul Nizam Harun, Chi D Luu, Munirah Binti Abd Rashid, Muhamad Fakhri Bin Mohd Saleh, Suresh Kumar, Hazlita Mohd Isa, Sue Ngein LeowAbstract:Abstract Retinal disorders account for a large proportion of ocular disorders that can lead to visual impairment or blindness, and yet our limited knowledge in the pathogenesis and choice of appropriate animal models for new treatment modalities may contribute to ineffective therapies. Although genetic in vivo models are favored, the variable expressivity and penetrance of these heterogeneous disorders can cause difficulties in assessing potential treatments against retinal degeneration. Hence, an attractive alternative is to develop a chemically-induced model that is both cost-friendly and standardizable. Sodium Iodate is an oxidative chemical that is used to simulate late stage retinitis pigmentosa and age-related macular degeneration. In this study, retinal degeneration was induced through systemic administration of Sodium Iodate (NaIO3) at varying doses up to 80 mg/kg in Sprague-Dawley rats. An analysis on the visual response of the rats by electroretinography (ERG) showed a decrease in photoreceptor function with NaIO3 administration at a dose of 40 mg/kg or greater. The results correlated with the TUNEL assay, which revealed signs of DNA damage throughout the retina. Histomorphological analysis also revealed extensive structural lesions throughout the outer retina and parts of the inner retina. Our results provided a detailed view of NaIO3-induced retinal degeneration, and showed that the administration of 40 mg/kg NaIO3 was sufficient to generate disturbances in retinal function. The pathological findings in this model reveal a degenerating retina, and can be further utilized to develop effective therapies for RPE, photoreceptor, and bipolar cell regeneration.
Chi Pui Pang - One of the best experts on this subject based on the ideXlab platform.
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continuous exposure to non lethal doses of Sodium Iodate induces retinal pigment epithelial cell dysfunction
Scientific Reports, 2016Co-Authors: Xiaoyu Zhang, Sunon Chan, Marten E Brelen, Jian Xiong Wang, Kwok Ping Chan, Jasmine Sum Yee Yung, Di Cao, Yu Meng Wang, Shaodan Zhang, Chi Pui PangAbstract:Age-related macular degeneration (AMD), characterized by progressive degeneration of retinal pigment epithelium (RPE), is the major cause of irreversible blindness and visual impairment in elderly population. We previously established a RPE degeneration model using an acute high dose Sodium Iodate to induce oxidative stress. Here we report findings on a prolonged treatment of low doses of Sodium Iodate on human RPE cells (ARPE-19). RPE cells were treated continuously with low doses (2–10 mM) of Sodium Iodate for 5 days. Low doses (2–5 mM) of Sodium Iodate did not reduce RPE cell viability, which is contrasting to cell apoptosis in 10 mM treatment. These low doses are sufficient to retard RPE cell migration and reduced expression of cell junction protein ZO-1. Phagocytotic activity of RPE cells was attenuated by Sodium Iodate dose-dependently. Sodium Iodate also increased expression of FGF-2, but suppressed expression of IL-8, PDGF, TIMP-2 and VEGF. Furthermore, HTRA1 and epithelial-to-mesenchymal transition marker proteins were downregulated, whereas PERK and LC3B-II proteins were upregulated after Sodium Iodate treatment. These results suggested that prolonged exposure to non-lethal doses of oxidative stress induces RPE cell dysfunctions that resemble conditions in AMD. This model can be used for future drug/treatment investigation on AMD.
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green tea catechins are potent anti oxidants that ameliorate Sodium Iodate induced retinal degeneration in rats
Scientific Reports, 2016Co-Authors: Yaping Yang, Yolanda W Y Yip, Chi Pui Pang, Kwok Ping Chan, Yong Jie Qin, Kai On Chu, Wai Kit Chu, Sunon ChanAbstract:Green tea extracts exhibit anti-oxidative and anti-inflammatory actions in different disease conditions. We hypothesized that green tea extract and its catechin constituents ameliorate Sodium Iodate-induced retinal degeneration in rats by counteracting oxidative stress. In this study, adult Sprague-Dawley rats were intravenously injected with a single dose of Sodium Iodate. Green tea extract (GTE; Theaphenon-E) or combinations of its catechin constituents, including (-)-epigallocatechin gallate (EGCG), were administered intra-gastrically before injection. Live imaging analysis using confocal scanning laser ophthalmoscopy and spectral-domain optical coherence tomography showed a progressive increase of degenerating profile across the retinal surface and decrease in thickness of outer nuclear layer (ONL) at Day-14 of post-injection. These lesions were significantly ameliorated by Theaphenon-E and catechin combinations with EGCG. Catechins with exclusion of EGCG did not show obvious protective effect. Histological analyses confirmed that Theaphenon-E and catechins containing EGCG protect the retina by reducing ONL disruption. Retinal protective effects were associated with reduced expression of superoxide dismutase, glutathione peroxidase and caspase-3, and suppression of 8-iso-Prostaglandin F2α generation in the retina. In summary, GTE and its catechin constituents are potent anti-oxidants that offer neuroprotection to the outer retinal degeneration after Sodium Iodate insult, among which EGCG is the most active constituent.
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assessing Sodium Iodate induced outer retinal changes in rats using confocal scanning laser ophthalmoscopy and optical coherence tomography
Investigative Ophthalmology & Visual Science, 2014Co-Authors: Yaping Yang, Yolanda W Y Yip, Kasin Law, Sunon Chan, Chi Pui PangAbstract:PURPOSE Sodium Iodate induces RPE atrophy and photoreceptor degeneration, as seen in the pathogenesis of many retinal diseases. We investigated a new approach of analyzing retinal images using confocal scanning laser ophthalmoscopy (cSLO) that allows longitudinal assessment of Sodium Iodate-induced lesions in the retina of living rats. METHODS A single dose of Sodium Iodate (25-75 mg/kg) was given intravenously to adult Sprague-Dawley rats. Control animals were given normal saline or Sodium iodide. The retina was examined by cSLO and optical coherence tomography (OCT) in living rats, which were then killed for histologic assessments. RESULTS Confocal scanning laser ophthalmoscopy revealed the appearance of dark patchy blots in planar images of the retina 7 days after intravenous injection of Sodium Iodate (25-75 mg/kg). This finding coincided with the observations of degenerative changes in the outer retinal layers in OCT images and in histology of the retina. Further analyses showed a concomitant localization of degenerative profiles in histologic preparations of this retina, suggesting that the blots corresponded to the deteriorating photopigments and outer nuclear layer (ONL). In histologic sections, these degenerative profiles appeared as irregular folds or rosettes in the ONL. Quantitative analyses showed that the changes in blot number were dose dependent, which again coincided with results showing a dose-dependent lesion in the photopigment layer and ONL in histologic sections of the retina. CONCLUSIONS Sodium Iodate-induced degenerative changes can be assessed quantitatively and reliably by in vivo retinal imaging using cSLO in adult rats, allowing efficient evaluation of lesions in a large area of retina in longitudinal studies.
David R Hinton - One of the best experts on this subject based on the ideXlab platform.
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Sodium Iodate induced retinal degeneration new insights from an old model
Neural Regeneration Research, 2014Co-Authors: Ram Kannan, David R HintonAbstract:Studies on the selective retinal degeneration induced by Sodium Iodate (NaIO3) date back to 1941; Sorsby (1941) described the effect of intravenously injected NaIO3 solution on the rabbit retina. Since then, NaIO3-induced retinal degeneration has been described in different mammalian species including sheep, rabbit, rat and mouse with varying doses and routes of administration. At the present time, the murine NaIO3 model is the most widely used because it results in reproducible, patchy retinal degeneration (Figure 1) and can be studied in a wide variety of wild type and genetic knockout strains. Many studies reporting the pathologic changes in retinal structure at specific time points and electrophysiological changes in retinal function over time have followed (Franco et al., 2009; Redfern et al., 2011). More recently, the model has gained a resurgence of interest because of the ability to utilize high resolution in vivo imaging to study structural changes in the retina in live animals. Techniques such as spectral domain optical coherence tomography (OCT) and confocal scanning laser ophthalmoscopy (cSLO) allow longitudinal evaluation of retinal structure (Machalinska et al., 2014; Yang et al., 2014); thus making this model amenable to evaluation of novel therapeutic approaches to retinal degeneration such as cellular therapies.
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Sodium Iodate induced retinal degeneration new insights from an old model
Neural Regeneration Research, 2014Co-Authors: Ram Kannan, David R HintonAbstract:Studies on the selective retinal degeneration induced by Sodium Iodate (NaIO3) date back to 1941; Sorsby (1941) described the effect of intravenously injected NaIO3 solution on the rabbit retina. Since then, NaIO3-induced retinal degeneration has been described in different mammalian species including sheep, rabbit, rat and mouse with varying doses and routes of administration. At the present time, the murine NaIO3 model is the most widely used because it results in reproducible, patchy retinal degeneration (Figure 1) and can be studied in a wide variety of wild type and genetic knockout strains. Many studies reporting the pathologic changes in retinal structure at specific time points and electrophysiological changes in retinal function over time have followed (Franco et al., 2009; Redfern et al., 2011). More recently, the model has gained a resurgence of interest because of the ability to utilize high resolution in vivo imaging to study structural changes in the retina in live animals. Techniques such as spectral domain optical coherence tomography (OCT) and confocal scanning laser ophthalmoscopy (cSLO) allow longitudinal evaluation of retinal structure (Machalinska et al., 2014; Yang et al., 2014); thus making this model amenable to evaluation of novel therapeutic approaches to retinal degeneration such as cellular therapies. Figure 1 Fundus photograph of murine retina 3 weeks after intravenous injection of NaIO3 (129S6/SvTac strain). The sequence of events leading to retinal damage after NaIO3 administration has been extensively evaluated; however, comparisons of different studies is at times difficult because of differences in the source of NaIO3, methods of administration, animals (type, strain, and age) and time points analyzed after injection. A classic study using high dose NaIO3 (100 mg/kg) reported rapid and selective necrotic cell death of the retinal pigment epithelium (RPE; the layer of pigmented epithelial cells that support the function and survival of the photoreceptors) beginning 6 hours after injection (Kiuchi et al., 2002). Others have evaluated lower doses of NaIO3 treatment and found progressively increasing RPE damage from 15–35 mg/kg (Franco et al., 2009; Machalinska et al., 2014) but no discernible change at 10 mg/kg (Wang et al., 2014). The death of RPE is followed by terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL)-positive cell death of photoreceptors, presumably by apoptosis (Kiuchi et al., 2002). Recently, the mechanism of photoreceptor dysfunction and death has been questioned. Carido et al. (2014) demonstrated increased calpain activity, without any increase in caspase 3 activation, 3 days after NaIO3 injection, and suggested that NaIO3 may be triggering a TUNEL-positive, non-apoptotic cell death mechanism in photoreceptors. As well, others suggest a direct effect of NaIO3 on photoreceptors, with visual dysfunction and rapid suppression of photoreceptor genes noted with 20–30 mg/kg intravenous dose in adult C57BL/6J mice (Wang et al., 2014). The molecular mechanism of RPE damage that occurs after NaIO3 administration is thought to be mediated through induction of oxidative stress. We have shown that murine RPE cultured in the presence of NaIO3 show accumulation of reactive oxygen species (ROS) that co-localizes with mitochondria (Zhou et al., 2014). These results suggest that future studies focused on therapy with antioxidants such as superoxide dismutase could be of considerable interest. With respect to signaling mechanisms, it is known that a rapid activation of AKT and reduction of RPE65 (a RPE-specific protein) occurs in mice subjected to oxidative stress. NaIO3-induced oxidative stress caused inactivation of PTEN and loss of its interactions with junctional proteins suggesting an important role for PTEN in normal RPE cell function as well in response to oxidative stimuli. Another target that has been recently suggested is Nrf2. Sachdeva et al. (2014) showed that Nrf2 signaling is impaired in the aging RPE when an oxidative insult with NaIO3 was imposed. Not only did the RPE of older mice (15 months) show impaired induction of Nrf2 as compared to young (2 months old) mice, they exhibited higher levels of superoxide anion and malondialdehyde. When Keap1, the negative regulator of Nrf2 was conditionally knocked down, the Nrf2 signaling and protection of RPE was restored. Our laboratory has presented evidence that the small heat shock protein αB crystallin protects the retina from NaIO3 induced retinal degeneration (Zhou et al., 2014). Low dose NaIO3 (20 mg/kg) injection in αB crystallin knockout mice augmented RPE cell death and subsequent retinal degeneration when compared to wild type control mice. Further, using cultured human RPE cells we showed that NaIO3 induced increased AKT phosphorylation and PPARγ expression in RPE cells which could be partially blocked by αB crystallin siRNA knockdown. Our findings suggest that αB crystallin plays a significant role in protection of NaIO3-induced oxidative stress and retinal degeneration in part through upregulation of AKT phosphorylation and PPARγ expression. We are currently evaluating the potential of αB crystallin or αB crystallin peptide nanoparticles as a therapeutic approach for treatment of retinal degeneration. The NaIO3 model has emerged as a valuable model to study RPE regeneration and cellular therapies in the retina. Machalinska et al. (2014) have shown that regeneration of the RPE occurs 3 months after induction of low dose Sodium Iodate induced retinal degeneration. Carido et al. (2014) transplanted human embryonic stem cell (hESC)-derived RPE cells 1 week after a single intravenous injection of NaIO3 (70 mg/kg) to mice. While NaIO3 injection caused severe RPE cell loss, photoreceptor degeneration and altered gene and protein expression in the inner nuclear layer (INL) and outer nucler layer (ONL) of the retina, transplantation of donor hESC-derived RPE cells formed extensive monolayers showing mature RPE cell morphology, organization and function. Furthermore, the transplanted RPE within these monolayers showed RPE-specific functions such as phagocytosis of host photoreceptor outer segments. In addition, hESC-derived RPE produced considerable collagen IV which is a component of the underlying Bruch membrane. Although most studies deal with hESC transplantation, the beneficial role of stem-cell derived neural progenitor cells to restore retinal degeneration in the NaIO3 model has also been reported recently (Amirpour et al., 2012). As well, after transplantation of rat mesenchymal stem cells (with and without erythropoietin gene modification) into the subretinal space of NaIO3 treated rats, the transplanted cells adopted RPE morphology and function 8 weeks after transplantation (Guan et al., 2013). Many investigators see considerable potential of the NaIO3 model for the study of novel therapies for geographic atrophy, a blinding complication of age-related macular degeneration (AMD) for which there is currently no effective treatment. While no animal model fully recapitulates each of the pathologic features found in the disorder, further refinement of the NaIO3 model to better mimic the defined geographic degeneration seen in AMD is underway in our lab and should represent a valuable advance. Finally, geographic atrophy is a slowly progressive disease occurring in an elderly population. The NaIO3 model is typically performed in young mice; it will be important to evaluate whether aging alters NaIO3 toxicity and sensitivity using older mice in various strains. The advent of high resolution imaging will allow longitudinal studies over extended periods of time and provides impetus for use of imaging endpoints for evaluation of preclinical efficacy of novel therapeutics for geographic atrophy. This work is supported in part by grants EY01545 and by core grant EY03040, the Arnold and Mabel Beckman Foundation, and an unrestricted grant to the Department of Ophthalmology from Research to Prevent Blindness Inc., New York, NY. We thank Dr. Parameswaran G. Sreekumar for the fundus images in Figure 1.
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protection of retina by αb crystallin in Sodium Iodate induced retinal degeneration
PLOS ONE, 2014Co-Authors: Peng Zhou, Ram Kannan, Christine Spee, Parameswaran G Sreekumar, Guorui Dou, David R HintonAbstract:Age-related macular degeneration (AMD) is a leading cause of blindness in the developed world. The retinal pigment epithelium (RPE) is a critical site of pathology in AMD and αB crystallin expression is increased in RPE and associated drusen in AMD. The purpose of this study was to investigate the role of αB crystallin in Sodium Iodate (NaIO3)-induced retinal degeneration, a model of AMD in which the primary site of pathology is the RPE. Dose dependent effects of intravenous NaIO3 (20-70 mg/kg) on development of retinal degeneration (fundus photography) and RPE and retinal neuronal loss (histology) were determined in wild type and αB crystallin knockout mice. Absence of αB crystallin augmented retinal degeneration in low dose (20 mg/kg) NaIO3-treated mice and increased retinal cell apoptosis which was mainly localized to the RPE layer. Generation of reactive oxygen species (ROS) was observed with NaIO3 in mouse and human RPE which increased further after αB crystallin knockout or siRNA knockdown, respectively. NaIO3 upregulated AKT phosphorylation and peroxisome proliferator–activator receptor–γ (PPARγ) which was suppressed after αB crystallin siRNA knockdown. Further, PPARγ ligand inhibited NaIO3-induced ROS generation. Our data suggest that αB crystallin plays a critical role in protection of NaIO3-induced oxidative stress and retinal degeneration in part through upregulation of AKT phosphorylation and PPARγ expression.
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Protection of Retina by aB Crystallin in Sodium Iodate Induced Retinal Degeneration
2014Co-Authors: Peng Zhou, Ram Kannan, Christine Spee, Parameswaran G Sreekumar, Guorui Dou, David R HintonAbstract:Age-related macular degeneration (AMD) is a leading cause of blindness in the developed world. The retinal pigment epithelium (RPE) is a critical site of pathology in AMD and aB crystallin expression is increased in RPE and associated drusen in AMD. The purpose of this study was to investigate the role of aB crystallin in Sodium Iodate (NaIO3)-induced retinal degeneration, a model of AMD in which the primary site of pathology is the RPE. Dose dependent effects of intravenous NaIO3 (20-70 mg/kg) on development of retinal degeneration (fundus photography) and RPE and retinal neuronal loss (histology) were determined in wild type and aB crystallin knockout mice. Absence of aB crystallin augmented retinal degeneration in low dose (20 mg/kg) NaIO3-treated mice and increased retinal cell apoptosis which was mainly localized to the RPE layer. Generation of reactive oxygen species (ROS) was observed with NaIO3 in mouse and human RPE which increased further after aB crystallin knockout or siRNA knockdown, respectively. NaIO3 upregulated AKT phosphorylation and peroxisome proliferator–activator receptor–c (PPARc) which was suppressed after aB crystallin siRNA knockdown. Further, PPARc ligand inhibited NaIO3-induced ROS generation. Our data suggest that aB crystallin plays a critical role in protection of NaIO3-induced oxidative stress and retinal degeneration in part through upregulation of AKT phosphorylatio
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enhanced retinal degeneration induced by Sodium Iodate in alphab crystallin knockout mice
The FASEB Journal, 2010Co-Authors: David R Hinton, Peng Zhou, Ram KannanAbstract:The aim of this study was to determine the effect of αB-crystallin knockout on Sodium Iodate (NaIO3)-induced retinal degeneration in mice. Time and dose dependent effects of intravenous NaIO3 (20–7...
Sunon Chan - One of the best experts on this subject based on the ideXlab platform.
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continuous exposure to non lethal doses of Sodium Iodate induces retinal pigment epithelial cell dysfunction
Scientific Reports, 2016Co-Authors: Xiaoyu Zhang, Sunon Chan, Marten E Brelen, Jian Xiong Wang, Kwok Ping Chan, Jasmine Sum Yee Yung, Di Cao, Yu Meng Wang, Shaodan Zhang, Chi Pui PangAbstract:Age-related macular degeneration (AMD), characterized by progressive degeneration of retinal pigment epithelium (RPE), is the major cause of irreversible blindness and visual impairment in elderly population. We previously established a RPE degeneration model using an acute high dose Sodium Iodate to induce oxidative stress. Here we report findings on a prolonged treatment of low doses of Sodium Iodate on human RPE cells (ARPE-19). RPE cells were treated continuously with low doses (2–10 mM) of Sodium Iodate for 5 days. Low doses (2–5 mM) of Sodium Iodate did not reduce RPE cell viability, which is contrasting to cell apoptosis in 10 mM treatment. These low doses are sufficient to retard RPE cell migration and reduced expression of cell junction protein ZO-1. Phagocytotic activity of RPE cells was attenuated by Sodium Iodate dose-dependently. Sodium Iodate also increased expression of FGF-2, but suppressed expression of IL-8, PDGF, TIMP-2 and VEGF. Furthermore, HTRA1 and epithelial-to-mesenchymal transition marker proteins were downregulated, whereas PERK and LC3B-II proteins were upregulated after Sodium Iodate treatment. These results suggested that prolonged exposure to non-lethal doses of oxidative stress induces RPE cell dysfunctions that resemble conditions in AMD. This model can be used for future drug/treatment investigation on AMD.
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green tea catechins are potent anti oxidants that ameliorate Sodium Iodate induced retinal degeneration in rats
Scientific Reports, 2016Co-Authors: Yaping Yang, Yolanda W Y Yip, Chi Pui Pang, Kwok Ping Chan, Yong Jie Qin, Kai On Chu, Wai Kit Chu, Sunon ChanAbstract:Green tea extracts exhibit anti-oxidative and anti-inflammatory actions in different disease conditions. We hypothesized that green tea extract and its catechin constituents ameliorate Sodium Iodate-induced retinal degeneration in rats by counteracting oxidative stress. In this study, adult Sprague-Dawley rats were intravenously injected with a single dose of Sodium Iodate. Green tea extract (GTE; Theaphenon-E) or combinations of its catechin constituents, including (-)-epigallocatechin gallate (EGCG), were administered intra-gastrically before injection. Live imaging analysis using confocal scanning laser ophthalmoscopy and spectral-domain optical coherence tomography showed a progressive increase of degenerating profile across the retinal surface and decrease in thickness of outer nuclear layer (ONL) at Day-14 of post-injection. These lesions were significantly ameliorated by Theaphenon-E and catechin combinations with EGCG. Catechins with exclusion of EGCG did not show obvious protective effect. Histological analyses confirmed that Theaphenon-E and catechins containing EGCG protect the retina by reducing ONL disruption. Retinal protective effects were associated with reduced expression of superoxide dismutase, glutathione peroxidase and caspase-3, and suppression of 8-iso-Prostaglandin F2α generation in the retina. In summary, GTE and its catechin constituents are potent anti-oxidants that offer neuroprotection to the outer retinal degeneration after Sodium Iodate insult, among which EGCG is the most active constituent.
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assessing Sodium Iodate induced outer retinal changes in rats using confocal scanning laser ophthalmoscopy and optical coherence tomography
Investigative Ophthalmology & Visual Science, 2014Co-Authors: Yaping Yang, Yolanda W Y Yip, Kasin Law, Sunon Chan, Chi Pui PangAbstract:PURPOSE Sodium Iodate induces RPE atrophy and photoreceptor degeneration, as seen in the pathogenesis of many retinal diseases. We investigated a new approach of analyzing retinal images using confocal scanning laser ophthalmoscopy (cSLO) that allows longitudinal assessment of Sodium Iodate-induced lesions in the retina of living rats. METHODS A single dose of Sodium Iodate (25-75 mg/kg) was given intravenously to adult Sprague-Dawley rats. Control animals were given normal saline or Sodium iodide. The retina was examined by cSLO and optical coherence tomography (OCT) in living rats, which were then killed for histologic assessments. RESULTS Confocal scanning laser ophthalmoscopy revealed the appearance of dark patchy blots in planar images of the retina 7 days after intravenous injection of Sodium Iodate (25-75 mg/kg). This finding coincided with the observations of degenerative changes in the outer retinal layers in OCT images and in histology of the retina. Further analyses showed a concomitant localization of degenerative profiles in histologic preparations of this retina, suggesting that the blots corresponded to the deteriorating photopigments and outer nuclear layer (ONL). In histologic sections, these degenerative profiles appeared as irregular folds or rosettes in the ONL. Quantitative analyses showed that the changes in blot number were dose dependent, which again coincided with results showing a dose-dependent lesion in the photopigment layer and ONL in histologic sections of the retina. CONCLUSIONS Sodium Iodate-induced degenerative changes can be assessed quantitatively and reliably by in vivo retinal imaging using cSLO in adult rats, allowing efficient evaluation of lesions in a large area of retina in longitudinal studies.