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The generation of induced pluripotent stem cells for macular degeneration as a drug screening platform: identification of curcumin as a protective agent for retinal pigment epithelial cells against oxidative stress.

Chang YC, Chang WC, Hung KH, Yang DM, Cheng YH, Liao YW, Woung LC, Tsai CY, Hsu CC, Lin TC, Liu JH, Chiou SH, Peng CH, Chen SJ - Front Aging Neurosci (2014)

Bottom Line: These patient-derived RPEs with the AMD-associated background (AMD-RPEs) exhibited reduced antioxidant ability, compared with normal RPE cells.Among several screened candidate drugs, curcumin caused most significant reduction of ROS in AMD-RPEs.Curcumin represented an ideal drug that can effectively restore the neuronal functions in AMD patient-derived RPE cells, rendering this drug an effective option for macular degeneration therapy and an agent against aging-associated oxidative stress.

View Article: PubMed Central - PubMed

Affiliation: Department of Medical Research and Education, Taipei Veterans General Hospital Taipei, Taiwan ; School of Medicine, Institute of Pharmacology, National Yang-Ming University Taipei, Taiwan ; Department of Ophthalmology, Taipei Veterans General Hospital Taipei, Taiwan.

ABSTRACT
Age-related macular degeneration (AMD) is one retinal aging process that may lead to irreversible vision loss in the elderly. Its pathogenesis remains unclear, but oxidative stress inducing retinal pigment epithelial (RPE) cells damage is perhaps responsible for the aging sequence of retina and may play an important role in macular degeneration. In this study, we have reprogrammed T cells from patients with dry type AMD into induced pluripotent stem cells (iPSCs) via integration-free episomal vectors and differentiated them into RPE cells that were used as an expandable platform for investigating pathogenesis of the AMD and in-vitro drug screening. These patient-derived RPEs with the AMD-associated background (AMD-RPEs) exhibited reduced antioxidant ability, compared with normal RPE cells. Among several screened candidate drugs, curcumin caused most significant reduction of ROS in AMD-RPEs. Pre-treatment of curcumin protected these AMD-RPEs from H2O2-induced cell death and also increased the cytoprotective effect against the oxidative stress of H2O2 through the reduction of ROS levels. In addition, curcumin with its versatile activities modulated the expression of many oxidative stress-regulating genes such as PDGF, VEGF, IGFBP-2, HO1, SOD2, and GPX1. Our findings indicated that the RPE cells derived from AMD patients have decreased antioxidative defense, making RPE cells more susceptible to oxidative damage and thereby leading to AMD formation. Curcumin represented an ideal drug that can effectively restore the neuronal functions in AMD patient-derived RPE cells, rendering this drug an effective option for macular degeneration therapy and an agent against aging-associated oxidative stress.

No MeSH data available.


Related in: MedlinePlus

A schematic illustrations of interrelations between curcumin and processes of AMD pathogenesis. AMD is a complex chronic neurodegenerative disease associated with many environmental, lifestyle, aging, and genetic factors. Oxidative stress and ROS production play a pivotal role in AMD pathogenesis. Curcumin has remarkable efficacy in ameliorating neurodegenerative, protecting AMD-RPEs from H2O2-induced ROS and cell death, and the modulating several oxidative stress-regulating genes that may inhibit cellular inflammatory responses and protects AMD-RPEs against oxidative stress. These evidences indicated curcumin may be potentially effective therapeutic means to treat AMD.
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Figure 7: A schematic illustrations of interrelations between curcumin and processes of AMD pathogenesis. AMD is a complex chronic neurodegenerative disease associated with many environmental, lifestyle, aging, and genetic factors. Oxidative stress and ROS production play a pivotal role in AMD pathogenesis. Curcumin has remarkable efficacy in ameliorating neurodegenerative, protecting AMD-RPEs from H2O2-induced ROS and cell death, and the modulating several oxidative stress-regulating genes that may inhibit cellular inflammatory responses and protects AMD-RPEs against oxidative stress. These evidences indicated curcumin may be potentially effective therapeutic means to treat AMD.

Mentions: The generation of ROS has been considered to have harmful consequences, and has been thought to be a major factor in aging and disease (Handa, 2012). RPE cells are particularly susceptible to oxidative stress, high oxygen tension, lifelong light illumination, and phagocytosis. Therefore, in accordance with the decrease of antioxidative enzymes in RPE cells with age, oxidative stress is thought to play a critical role in the pathogenesis of macular degeneration (Beatty et al., 2000). There is no effective drug or strategy to improve AMD debilitating visual disease. Therefore, the elucidation of its underlying pathogenesis and the development of novel therapies for macular degeneration are urgently needed. Curcumin is widely used in traditional Chinese medicine because of its multifaceted beneficial effects, including anticancer, antioxidant, and neuroprotective properties (Anand et al., 2007; Aggarwal and Harikumar, 2009). In addition, curcumin has shown remarkable efficacy in ameliorating neurodegenerative disorders (Aggarwal and Harikumar, 2009; Jiang et al., 2013) and RPE cell death induced by light or oxidative insults (Mandal et al., 2009; Woo et al., 2012). The efficacy of curcumin has been attributed to the upregulation of oxidative stress defense enzymes (Woo et al., 2012) and the activation of several cellular regulatory proteins that inhibit cellular inflammatory responses and protection (Sreejayan and Rao, 1997; Mandal et al., 2009; Woo et al., 2012). Among several dietary supplements for retinal protection and natural antioxidant compounds, we identified curcumin as a potent agent that can prevent AMD-RPEs from H2O2-induced cell death and ROS production. In addition, inflammation and angiogenesis have been implicated in the pathogenesis of AMD. Production of cytokines and ROS leads to further RPE and photoreceptor damage. Based on our data, curcumin with its pleiotropic activities can modulate the expression of many oxidative stress regulatory proteins such as PDGF, VEGF, IGFBP-2, HO1, SOD2, and GPX1, which in turn inhibit cellular inflammatory responses and protect RPE cells. Although the mechanisms of curcumin that improved RPE functions in AMD-RPEs were not fully elucidated, our data indicated that, at least in part, a potent ROS scavenging effect was involved in this curcumin-mediated cytoprotection (Figure 7). The in vivo therapeutic potential of curcumin for the treatment of AMD should be examined in animal models in future studies.


The generation of induced pluripotent stem cells for macular degeneration as a drug screening platform: identification of curcumin as a protective agent for retinal pigment epithelial cells against oxidative stress.

Chang YC, Chang WC, Hung KH, Yang DM, Cheng YH, Liao YW, Woung LC, Tsai CY, Hsu CC, Lin TC, Liu JH, Chiou SH, Peng CH, Chen SJ - Front Aging Neurosci (2014)

A schematic illustrations of interrelations between curcumin and processes of AMD pathogenesis. AMD is a complex chronic neurodegenerative disease associated with many environmental, lifestyle, aging, and genetic factors. Oxidative stress and ROS production play a pivotal role in AMD pathogenesis. Curcumin has remarkable efficacy in ameliorating neurodegenerative, protecting AMD-RPEs from H2O2-induced ROS and cell death, and the modulating several oxidative stress-regulating genes that may inhibit cellular inflammatory responses and protects AMD-RPEs against oxidative stress. These evidences indicated curcumin may be potentially effective therapeutic means to treat AMD.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4117985&req=5

Figure 7: A schematic illustrations of interrelations between curcumin and processes of AMD pathogenesis. AMD is a complex chronic neurodegenerative disease associated with many environmental, lifestyle, aging, and genetic factors. Oxidative stress and ROS production play a pivotal role in AMD pathogenesis. Curcumin has remarkable efficacy in ameliorating neurodegenerative, protecting AMD-RPEs from H2O2-induced ROS and cell death, and the modulating several oxidative stress-regulating genes that may inhibit cellular inflammatory responses and protects AMD-RPEs against oxidative stress. These evidences indicated curcumin may be potentially effective therapeutic means to treat AMD.
Mentions: The generation of ROS has been considered to have harmful consequences, and has been thought to be a major factor in aging and disease (Handa, 2012). RPE cells are particularly susceptible to oxidative stress, high oxygen tension, lifelong light illumination, and phagocytosis. Therefore, in accordance with the decrease of antioxidative enzymes in RPE cells with age, oxidative stress is thought to play a critical role in the pathogenesis of macular degeneration (Beatty et al., 2000). There is no effective drug or strategy to improve AMD debilitating visual disease. Therefore, the elucidation of its underlying pathogenesis and the development of novel therapies for macular degeneration are urgently needed. Curcumin is widely used in traditional Chinese medicine because of its multifaceted beneficial effects, including anticancer, antioxidant, and neuroprotective properties (Anand et al., 2007; Aggarwal and Harikumar, 2009). In addition, curcumin has shown remarkable efficacy in ameliorating neurodegenerative disorders (Aggarwal and Harikumar, 2009; Jiang et al., 2013) and RPE cell death induced by light or oxidative insults (Mandal et al., 2009; Woo et al., 2012). The efficacy of curcumin has been attributed to the upregulation of oxidative stress defense enzymes (Woo et al., 2012) and the activation of several cellular regulatory proteins that inhibit cellular inflammatory responses and protection (Sreejayan and Rao, 1997; Mandal et al., 2009; Woo et al., 2012). Among several dietary supplements for retinal protection and natural antioxidant compounds, we identified curcumin as a potent agent that can prevent AMD-RPEs from H2O2-induced cell death and ROS production. In addition, inflammation and angiogenesis have been implicated in the pathogenesis of AMD. Production of cytokines and ROS leads to further RPE and photoreceptor damage. Based on our data, curcumin with its pleiotropic activities can modulate the expression of many oxidative stress regulatory proteins such as PDGF, VEGF, IGFBP-2, HO1, SOD2, and GPX1, which in turn inhibit cellular inflammatory responses and protect RPE cells. Although the mechanisms of curcumin that improved RPE functions in AMD-RPEs were not fully elucidated, our data indicated that, at least in part, a potent ROS scavenging effect was involved in this curcumin-mediated cytoprotection (Figure 7). The in vivo therapeutic potential of curcumin for the treatment of AMD should be examined in animal models in future studies.

Bottom Line: These patient-derived RPEs with the AMD-associated background (AMD-RPEs) exhibited reduced antioxidant ability, compared with normal RPE cells.Among several screened candidate drugs, curcumin caused most significant reduction of ROS in AMD-RPEs.Curcumin represented an ideal drug that can effectively restore the neuronal functions in AMD patient-derived RPE cells, rendering this drug an effective option for macular degeneration therapy and an agent against aging-associated oxidative stress.

View Article: PubMed Central - PubMed

Affiliation: Department of Medical Research and Education, Taipei Veterans General Hospital Taipei, Taiwan ; School of Medicine, Institute of Pharmacology, National Yang-Ming University Taipei, Taiwan ; Department of Ophthalmology, Taipei Veterans General Hospital Taipei, Taiwan.

ABSTRACT
Age-related macular degeneration (AMD) is one retinal aging process that may lead to irreversible vision loss in the elderly. Its pathogenesis remains unclear, but oxidative stress inducing retinal pigment epithelial (RPE) cells damage is perhaps responsible for the aging sequence of retina and may play an important role in macular degeneration. In this study, we have reprogrammed T cells from patients with dry type AMD into induced pluripotent stem cells (iPSCs) via integration-free episomal vectors and differentiated them into RPE cells that were used as an expandable platform for investigating pathogenesis of the AMD and in-vitro drug screening. These patient-derived RPEs with the AMD-associated background (AMD-RPEs) exhibited reduced antioxidant ability, compared with normal RPE cells. Among several screened candidate drugs, curcumin caused most significant reduction of ROS in AMD-RPEs. Pre-treatment of curcumin protected these AMD-RPEs from H2O2-induced cell death and also increased the cytoprotective effect against the oxidative stress of H2O2 through the reduction of ROS levels. In addition, curcumin with its versatile activities modulated the expression of many oxidative stress-regulating genes such as PDGF, VEGF, IGFBP-2, HO1, SOD2, and GPX1. Our findings indicated that the RPE cells derived from AMD patients have decreased antioxidative defense, making RPE cells more susceptible to oxidative damage and thereby leading to AMD formation. Curcumin represented an ideal drug that can effectively restore the neuronal functions in AMD patient-derived RPE cells, rendering this drug an effective option for macular degeneration therapy and an agent against aging-associated oxidative stress.

No MeSH data available.


Related in: MedlinePlus