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Weiwei X, Jingxi L, Erti G, Xinrun Z, Yifei H. Inhibition of lens-induced myopia in guinea pigs using a far-induced infrared ray material. Front Med (Lausanne) 2025; 12:1545099. [PMID: 40231076 PMCID: PMC11994589 DOI: 10.3389/fmed.2025.1545099] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2024] [Accepted: 03/10/2025] [Indexed: 04/16/2025] Open
Abstract
Purpose Numerous studies have demonstrated a close relationship between choroidal thickness (ChT), sclera/choroidal hypoxia, and the onset and progression of myopia. Far-infrared (FIR) therapy is a traditional method used to enhance microcirculation. In this study, we estimated the effectiveness of FIR in myopia control and explored its underlying mechanisms. Furthermore, we compared the efficacy of FIR from two different sources in controlling myopia. Methods Guinea pigs were divided into three groups, all of which underwent minus lens induction for 4 weeks. Two of the groups received simultaneous FIR intervention, either from a FIR radiator (FIRR) lamp or from an innovative FIR material (FIRM). Refraction, axial length (AL), ChT, and levels of hypoxia-labeled pimonidazole in the choroid and sclera were measured. Results Both FIRR and FIRM inhibited increases in refraction and AL and attenuate the decrease in ChT. They also mitigated choroidal and scleral hypoxia. Compared to FIRR, FIRM demonstrated a greater effect on myopia control and hypoxia attenuation. However, the difference in AL reduction between the two FIR sources was not statistically significant. Conclusion FIR effectively controls myopia, and the innovative FIR material may represent a breakthrough in myopia management in the near future.
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Affiliation(s)
- Xu Weiwei
- Department of Ophthalmology, The Chinese PLA General Hospital, Beijing, China
| | - Liu Jingxi
- National Research Institute for Family Planning, Beijing, China
| | - Guoji Erti
- National Research Institute for Family Planning, Beijing, China
| | - Zhou Xinrun
- School of Medicine, Nankai University, Tianjin, China
| | - Huang Yifei
- Department of Ophthalmology, The Chinese PLA General Hospital, Beijing, China
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2
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Kong M, Li J, Jin R, Zhang Y, You J, Wang N, Tong N. Lycium barbarum polysaccharide alleviates H 2O 2-induced premature senescence by downregulating miRNA-34a-5p in ARPE-19 cells. Cell Stress Chaperones 2025; 30:130-142. [PMID: 40112947 PMCID: PMC12002617 DOI: 10.1016/j.cstres.2025.03.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2025] [Revised: 03/12/2025] [Accepted: 03/14/2025] [Indexed: 03/22/2025] Open
Abstract
The premature senescence of retinal pigment epithelium (RPE) plays a significant role in the development of age-related macular degeneration. This study aimed to investigate the potential protective effect of Lycium barbarum polysaccharide (LBP) against H2O2-induced premature senescence and to elucidate the underlying mechanisms. The ARPE-19 cell line was subjected to H2O2 exposure to create a model of premature senescence. The modulation of microRNA-34a-5p expression was accomplished using antagomir and agomir, as assessed by quantitative real-time polymerase chain reaction. The senescence model was successfully established by treating cells with 200 μM H2O2 for 2 hours daily over a span of three consecutive days. This oxidative stress resulted in a notable increase in the proportion of senescence-associated beta-galactosidase-positive cells, reaching 33.5%, without significant alterations in cell viability or apoptosis. In the ARPE-19 cells undergoing premature senescence, there was a marked increase in reactive oxygen species (ROS) production and malondialdehyde levels, coupled with a significant decrease in the activity of total superoxide dismutase, glutathione peroxidase, and catalase. Additionally, microRNA-34a-5p was found to be overexpressed in these cells. Treatment with LBP alleviated H2O2-induced premature senescence, diminished the overexpression of microRNA-34a-5p, and suppressed ROS production. Moreover, the incubation with ago-34a reversed the protective effect of LBP in ARPE-19 cells. In conclusion, the overexpression of microRNA-34a-5p contributes to the H2O2-induced premature senescence of ARPE-19 cells. LBP appears to mitigate this premature senescence, at least in part, by downregulating microRNA-34a-5p expression and reducing oxidative stress.
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Affiliation(s)
- Meng Kong
- School of Medicine, Qingdao University, 266001, Qingdao, China; Department of Ophthalmology, Qingdao Municipal Hospital, 266001, Qingdao, China
| | - Jingwen Li
- School of Medicine, Qingdao University, 266001, Qingdao, China; Department of Ophthalmology, Qingdao Municipal Hospital, 266001, Qingdao, China
| | - Rong Jin
- Department of Ophthalmology, Qingdao Municipal Hospital, 266001, Qingdao, China; Department of Pediatrics, Affiliated Hospital of Qingdao University, 266001, Qingdao, China
| | - Yi Zhang
- School of Medicine, Qingdao University, 266001, Qingdao, China; Department of Ophthalmology, Qingdao Municipal Hospital, 266001, Qingdao, China
| | - Jia You
- Department of Ophthalmology, Qingdao Municipal Hospital, 266001, Qingdao, China; Department of Ophthalmology, Qingdao Central Hospital, 266001, Qingdao, China
| | - Nan Wang
- School of Medicine, Qingdao University, 266001, Qingdao, China; Department of Ophthalmology, Qingdao Municipal Hospital, 266001, Qingdao, China
| | - Nianting Tong
- School of Medicine, Qingdao University, 266001, Qingdao, China; Department of Ophthalmology, Qingdao Municipal Hospital, 266001, Qingdao, China.
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Fan Q, Song X, Li M, Xu Q, Yan C, Li H, Qu Y. Neutrophils promote laser-induced choroidal neovascularization by increasing pro-inflammatory cytokines secretion and cell cycle arrest in retinal pigment epithelium. Int Immunopharmacol 2025; 145:113735. [PMID: 39642572 DOI: 10.1016/j.intimp.2024.113735] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2024] [Revised: 11/25/2024] [Accepted: 11/26/2024] [Indexed: 12/09/2024]
Abstract
Inflammation is hypothesized to have essential functions in the development of wet age-related macular degeneration (AMD). Polymorphonuclear neutrophils (PMNs), recognized as major players in inflammation, are typically the first leukocytes to be recruited to an inflammatory site. Previous studies have identified neutrophil aggregates in the lesion site of the choroidal neovascularization model, and systemic depletion of neutrophils in adult mice is associated with reduced choroidal neovascularization (CNV) area, suggesting a pivotal role of PMNs in CNV pathogenesis. Here, we investigate the role of neutrophils in promoting CNV, a key feature of wet AMD. The malfunction and demise of retinal pigment epithelium cells are essential elements in CNV pathogenesis. Our hypothesis posits that neutrophils exacerbate CNV by influencing pro-inflammatory cytokines secreted by retinal pigment epithelium (RPE) cells. Using in vivo laser-induced CNV models with mice and in vitro experiments with the human ARPE-19 cell line, we demonstrated that co-culturing neutrophils with ARPE-19 cells induces an increase in pro-inflammatory cytokines and leads to S-phase cell cycle arrest, potentially through the induction of double-strand breaks (DSBs). Further exploration of this interaction revealed a potential pathway involving reactive oxygen species (ROS) and microRNA-23a, wherein PMNs induce DSBs by initiating the downregulation of LB1 via microRNA-23a. Additionally, we found that dHL-60 cell line could serve as a substitute for primary PMNs, highlighting its potential as a valuable tool in experimental models involving interactions with retinal cells. Our findings underscore the significant role of neutrophils in CNV pathogenesis, providing insights into potential therapeutic targets for wet AMD.
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Affiliation(s)
- Qian Fan
- Department of Geriatrics, Qilu Hospital of Shandong University, Jinan, Shandong Province, China; Department of Ophthalmology, Qilu Hospital of Shandong University, Jinan, Shandong Province, China; Jinan Clinical Research Center for Geriatric Medicine (202132001), Jinan, Shandong Province, China
| | - Xian Song
- Department of Geriatrics, Qilu Hospital of Shandong University, Jinan, Shandong Province, China
| | - Mengyao Li
- Department of Geriatrics, Qilu Hospital of Shandong University, Jinan, Shandong Province, China; Jinan Clinical Research Center for Geriatric Medicine (202132001), Jinan, Shandong Province, China
| | - Qian Xu
- Department of Geriatrics, Qilu Hospital of Shandong University, Jinan, Shandong Province, China
| | - Chenfei Yan
- Department of Geriatrics, Qilu Hospital of Shandong University, Jinan, Shandong Province, China
| | - Haiming Li
- Department of Geriatrics, Qilu Hospital of Shandong University, Jinan, Shandong Province, China
| | - Yi Qu
- Department of Geriatrics, Qilu Hospital of Shandong University, Jinan, Shandong Province, China; Department of Ophthalmology, Qilu Hospital of Shandong University, Jinan, Shandong Province, China; Jinan Clinical Research Center for Geriatric Medicine (202132001), Jinan, Shandong Province, China.
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Wang Y, Gao S, Cao F, Yang H, Lei F, Hou S. Ocular immune-related diseases: molecular mechanisms and therapy. MedComm (Beijing) 2024; 5:e70021. [PMID: 39611043 PMCID: PMC11604294 DOI: 10.1002/mco2.70021] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2024] [Revised: 10/05/2024] [Accepted: 10/31/2024] [Indexed: 11/30/2024] Open
Abstract
Ocular immune-related diseases, represent a spectrum of conditions driven by immune system dysregulation, include but not limit to uveitis, diabetic retinopathy, age-related macular degeneration, Graves' ophthalmopathy, etc. The molecular and cellular mechanisms underlying these diseases are typically dysfunctioned immune responses targeting ocular tissues, resulting in inflammation and tissue damage. Recent advances have further elucidated the pivotal role of different immune responses in the development, progression, as well as management of various ocular immune diseases. However, there is currently a relative lack of connection between the cellular mechanisms and treatments of several immune-related ocular diseases. In this review, we discuss recent findings related to the immunopathogenesis of above-mentioned diseases. In particular, we summarize the different types of immune cells, inflammatory mediators, and associated signaling pathways that are involved in the pathophysiology of above-mentioned ophthalmopathies. Furthermore, we also discuss the future directions of utilizing anti-inflammatory regime in the management of these diseases. This will facilitate a better understanding of the pathogenesis of immune-related ocular diseases and provide new insights for future treatment approaches.
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Affiliation(s)
- Yakun Wang
- The First Affiliated Hospital of Chongqing Medical UniversityChongqingChina
- Beijing Institute of OphthalmologyBeijing Tongren Eye CenterBeijing Tongren Hospital, Beijing Ophthalmology & Visual Sciences Key Laboratory, Capital Medical UniversityBeijingChina
| | - Shangze Gao
- Beijing Institute of OphthalmologyBeijing Tongren Eye CenterBeijing Tongren Hospital, Beijing Ophthalmology & Visual Sciences Key Laboratory, Capital Medical UniversityBeijingChina
| | - Fan Cao
- Beijing Institute of OphthalmologyBeijing Tongren Eye CenterBeijing Tongren Hospital, Beijing Ophthalmology & Visual Sciences Key Laboratory, Capital Medical UniversityBeijingChina
| | - Hui Yang
- Beijing Institute of OphthalmologyBeijing Tongren Eye CenterBeijing Tongren Hospital, Beijing Ophthalmology & Visual Sciences Key Laboratory, Capital Medical UniversityBeijingChina
| | - Fengyang Lei
- Beijing Institute of OphthalmologyBeijing Tongren Eye CenterBeijing Tongren Hospital, Beijing Ophthalmology & Visual Sciences Key Laboratory, Capital Medical UniversityBeijingChina
| | - Shengping Hou
- Beijing Institute of OphthalmologyBeijing Tongren Eye CenterBeijing Tongren Hospital, Beijing Ophthalmology & Visual Sciences Key Laboratory, Capital Medical UniversityBeijingChina
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Almalki WH, Almujri SS. The impact of NF-κB on inflammatory and angiogenic processes in age-related macular degeneration. Exp Eye Res 2024; 248:110111. [PMID: 39326776 DOI: 10.1016/j.exer.2024.110111] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2024] [Revised: 09/09/2024] [Accepted: 09/23/2024] [Indexed: 09/28/2024]
Abstract
Age-related macular degeneration (AMD) is a prominent cause of vision loss, characterized by two different types, dry (atrophic) and wet (neovascular). Dry AMD is distinguished by the progressive deterioration of retinal cells, which ultimately causes a decline in vision. In contrast, wet AMD is defined by the abnormal development of blood vessels underneath the retina, leading to a sudden and severe vision impairment. The course of AMD is primarily driven by chronic inflammation and pathological angiogenesis, in which the NF-κB signaling pathway plays a crucial role. The activation of NF-κB results in the generation of pro-inflammatory cytokines, chemokines, and angiogenic factors like VEGF, which contribute to inflammation and the formation of new blood vessels in AMD. This review analyzes the intricate relationship between NF-κB signaling, inflammation, and angiogenesis in AMD and assesses the possibility of using NF-κB as a target for therapy. The evaluation involves a comprehensive examination of preclinical and clinical evidence that substantiates the effectiveness of NF-κB inhibitors in treating AMD by diminishing inflammation and pathological angiogenesis.
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Affiliation(s)
- Waleed Hassan Almalki
- Department of Pharmacology, College of Pharmacy, Umm Al-Qura University, Makkah, Saudi Arabia.
| | - Salem Salman Almujri
- Department of Pharmacology, College of Pharmacy, King Khalid University, Abha 61421, Aseer, Saudi Arabia
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Velaga SB, Alagorie AR, Emamverdi M, Ashrafkhorasani M, Habibi A, Nittala MG, Sing G, Haines J, Pericak-Vance MA, Stambolian D, Sadda SR. Alterations of the Ganglion Cell Complex in Age-Related Macular Degeneration: An Amish Eye Study Analysis. Am J Ophthalmol 2024; 265:80-87. [PMID: 38677638 DOI: 10.1016/j.ajo.2024.04.024] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2023] [Revised: 04/02/2024] [Accepted: 04/22/2024] [Indexed: 04/29/2024]
Abstract
PURPOSE To compare the ganglion cell complex (GCC) thickness in eyes with age-related macular degeneration (AMD) vs healthy controls in an elderly Amish population. DESIGN Prospective cross-sectional study. METHODS This is a post hoc analysis of the family-based prospective study of Amish subjects. Study subjects underwent imaging with the Cirrus HD-OCT (Carl Zeiss Meditec Inc) using a macular cube protocol of 512 × 128 scans (128 horizontal B-scans, each comprising 512 A-scans) over a 6 mm × 6 mm region centered on the fovea. The ganglion cell analysis algorithm calculated the GCC thickness by segmenting the outer boundaries of the retinal nerve fiber layer (RNFL) and inner plexiform layer (IPL) in all B-scans of the volume, with the region between these boundaries representing the combined thickness of the ganglion cell layer (GCL) and the IPL. A number of parameters were used to evaluate the GCC thickness: the average GCC thickness, minimum (lowest GCC thickness at a single meridian crossing the elliptical annulus), and sectoral (within each of 6 sectoral areas: superior, superotemporal, superonasal, inferior, inferonasal, and inferotemporal). The stage of AMD was graded on color fundus photographs in accordance with the Beckman Initiative for Macular Research classification system. RESULTS Of 1339 subjects enrolled in the Amish eye study, a total of 1294 eyes of 1294 subjects had all required imaging studies of sufficient quality and were included in the final analysis. Of these, 798 (62%) were female. Following age adjustment, the average GCC thickness was significantly (P < .001) thinner in AMD subjects (73.71 ± SD; 13.77 µm) compared to normals (77.97 ± 10.42 µm). An independent t test showed that the early AMD (75.03 ± 12.45 µm) and late AMD (61.64 ± 21.18 µm) groups (among which eyes with geographic atrophy [GA] had the lowest thickness, of 58.10 ± 20.27 µm) had a statistically significant lower GCC thickness compared to eyes without AMD. There was no significant differences in average GCC thickness between early AMD and intermediate AMD (76.36 ± 9.25 µm) eyes. CONCLUSIONS The GCC thickness in AMD eyes is reduced compared to normal eyes; however, the relationship is complex, with the greatest reduction in late AMD eyes (particularly eyes with GA) but no difference between early and intermediate AMD eyes.
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Affiliation(s)
- Swetha Bindu Velaga
- From the Doheny Eye Institute (S.B.V., A.R.A., M.E., M.A., A.H., M.G.N., G.S., S.R.S.), University of California-Los Angeles, Los Angeles, California, USA; Department of Ophthalmology (S.B.V., A.R.A., M.E., M.A., A.H., M.G.N., S.R.S.), David Geffen School of Medicine at UCLA, Los Angeles, CA, USA
| | - Ahmed Roshdy Alagorie
- From the Doheny Eye Institute (S.B.V., A.R.A., M.E., M.A., A.H., M.G.N., G.S., S.R.S.), University of California-Los Angeles, Los Angeles, California, USA; Department of Ophthalmology (S.B.V., A.R.A., M.E., M.A., A.H., M.G.N., S.R.S.), David Geffen School of Medicine at UCLA, Los Angeles, CA, USA; Department of Ophthalmology (A.R.A.), Faculty of Medicine, Tanta University, Tanta, Egypt
| | - Mehdi Emamverdi
- From the Doheny Eye Institute (S.B.V., A.R.A., M.E., M.A., A.H., M.G.N., G.S., S.R.S.), University of California-Los Angeles, Los Angeles, California, USA; Department of Ophthalmology (S.B.V., A.R.A., M.E., M.A., A.H., M.G.N., S.R.S.), David Geffen School of Medicine at UCLA, Los Angeles, CA, USA
| | - Maryam Ashrafkhorasani
- From the Doheny Eye Institute (S.B.V., A.R.A., M.E., M.A., A.H., M.G.N., G.S., S.R.S.), University of California-Los Angeles, Los Angeles, California, USA; Department of Ophthalmology (S.B.V., A.R.A., M.E., M.A., A.H., M.G.N., S.R.S.), David Geffen School of Medicine at UCLA, Los Angeles, CA, USA
| | - Abbas Habibi
- From the Doheny Eye Institute (S.B.V., A.R.A., M.E., M.A., A.H., M.G.N., G.S., S.R.S.), University of California-Los Angeles, Los Angeles, California, USA; Department of Ophthalmology (S.B.V., A.R.A., M.E., M.A., A.H., M.G.N., S.R.S.), David Geffen School of Medicine at UCLA, Los Angeles, CA, USA
| | - Muneeswar Gupta Nittala
- From the Doheny Eye Institute (S.B.V., A.R.A., M.E., M.A., A.H., M.G.N., G.S., S.R.S.), University of California-Los Angeles, Los Angeles, California, USA; Department of Ophthalmology (S.B.V., A.R.A., M.E., M.A., A.H., M.G.N., S.R.S.), David Geffen School of Medicine at UCLA, Los Angeles, CA, USA
| | - Gagan Sing
- From the Doheny Eye Institute (S.B.V., A.R.A., M.E., M.A., A.H., M.G.N., G.S., S.R.S.), University of California-Los Angeles, Los Angeles, California, USA; Department of Ophthalmology (S.B.V., A.R.A., M.E., M.A., A.H., M.G.N., S.R.S.), David Geffen School of Medicine at UCLA, Los Angeles, CA, USA
| | - Jonathan Haines
- Department of Population & Quantitative Health Sciences (J.H.), Case Western Reserve University, Cleveland, Ohio, USA; Institute for Computational Biology (J.H.), Case Western Reserve University, Cleveland, Ohio, USA
| | - Margaret A Pericak-Vance
- John P. Hussman Institute for Human Genomics (M.A.P.-V), University of Miami Miller School of Medicine, Miami, Florida, USA
| | - Dwight Stambolian
- Department of Ophthalmology (D.S.), University of Pennsylvania, Perelman School of Medicine, Philadelphia, Pennsylvania, USA
| | - Srinivas R Sadda
- From the Doheny Eye Institute (S.B.V., A.R.A., M.E., M.A., A.H., M.G.N., G.S., S.R.S.), University of California-Los Angeles, Los Angeles, California, USA.
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Liu H, Wu C, Hu S, Leng B, Lou X, Liu Z, Su X, Huang D. Lutein Modulates Cellular Functionalities and Regulates NLRP3 Inflammasome in a H 2O 2-Challenged Three-Dimensional Retinal Pigment Epithelium Model. JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 2024; 72:14701-14712. [PMID: 38897610 DOI: 10.1021/acs.jafc.4c01537] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/21/2024]
Abstract
Excessive hydrogen peroxide (H2O2) generated during retinal cell metabolic activity could lead to oxidative degeneration of retinal pigment epithelium (RPE) tissue, a specific pathological process implicated in various retinal diseases resulting in blindness, which can be mitigated by taking dietary antioxidants to prevent inflammation and impaired cellular dysfunction. This study tested the hypothesis that damages induced by oxidative stresses can be mitigated by lutein in a H2O2-challenged model, which was based on an ARPE-19 cell monolayer cultured on three-dimensional (3D)-printed fibrous scaffolds. Pretreating these models with lutein (0.5 μM) for 24 h can significantly lower the oxidative stress and maintain phagocytosis and barrier function. Moreover, lutein can modulate the NLRP3 inflammasome, leading to a ∼40% decrease in the pro-inflammatory cytokine (IL-1β and IL-18) levels. Collectively, this study suggests that the 3D RPE model is an effective tool to examine the capability of lutein to modulate cellular functionalities and regulate NLRP3 inflammation.
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Affiliation(s)
- Hang Liu
- Department of Food Science and Technology, Faculty of Science, National University of Singapore, Singapore 117542, Singapore
- Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A*STAR), Singapore 138673, Singapore
- Department of Ophthalmology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 119074, Singapore
| | - Chushan Wu
- Department of Food Science and Technology, Faculty of Science, National University of Singapore, Singapore 117542, Singapore
| | - Shiyin Hu
- Department of Food Science and Technology, Faculty of Science, National University of Singapore, Singapore 117542, Singapore
| | - Bin Leng
- Department of Food Science and Technology, Faculty of Science, National University of Singapore, Singapore 117542, Singapore
| | - Xiaowei Lou
- Department of Food Science and Technology, Faculty of Science, National University of Singapore, Singapore 117542, Singapore
| | - Zengping Liu
- Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A*STAR), Singapore 138673, Singapore
- Department of Ophthalmology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 119074, Singapore
| | - Xinyi Su
- Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A*STAR), Singapore 138673, Singapore
- Department of Ophthalmology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 119074, Singapore
| | - Dejian Huang
- Department of Food Science and Technology, Faculty of Science, National University of Singapore, Singapore 117542, Singapore
- National University of Singapore (Suzhou) Research Institute, Suzhou, Jiangsu 215123, People's Republic of China
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Tahmasebi Sarvestani M, Chidlow G, Wood JP, Casson RJ. Effects of slit lamp-delivered retinal laser photobiomodulation in a rat model of choroidal neovascularization. Exp Eye Res 2024; 244:109909. [PMID: 38710357 DOI: 10.1016/j.exer.2024.109909] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2023] [Revised: 04/06/2024] [Accepted: 04/22/2024] [Indexed: 05/08/2024]
Abstract
Neovascular age-related macular degeneration, also known as exudative or wet age-related macular degeneration, is the leading cause of blindness in the developed world. Photobiomodulation has the potential to target the up-stream hypoxic and pro-inflammatory drivers of choroidal neovascularization. This study investigated whether photobiomodulation attenuates characteristic pathological features of choroidal neovascularization in a rodent model. Experimental choroidal neovascularization was induced in Brown Norway rats with laser photocoagulation. A custom-designed, slit-lamp-mounted, 670 nm laser was used to administer retinal photobiomodulation every 3 days, beginning 6 days prior to choroidal neovascularization induction and continuing until the animals were killed 14 days later. The effect of photobiomodulation on the size of choroidal neovascular membranes was determined using isolectin-B4 immunohistochemistry and spectral domain-optical coherence tomography. Vascular leakage was determined with fluorescein angiography. The effect of treatment on levels of vascular endothelial growth factor expression was quantified with enzyme-linked immunosorbent assay. Treatment with photobiomodulation was associated with choroidal neovascular membranes that were smaller, had less fluorescein leakage, and a diminished presence of inflammatory cells as compared to sham eyes. These effects were not associated with a statistically significant difference in the level of vascular endothelial growth factor when compared to sham eyes. The data shown herein indicate that photobiomodulation attenuates pathological features of choroidal neovascularization in a rodent model by mechanisms that may be independent of vascular endothelial growth factor.
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Affiliation(s)
| | - Glyn Chidlow
- Ophthalmic Research Laboratory, University of Adelaide, Adelaide, South Australia, Australia
| | - John P Wood
- Ophthalmic Research Laboratory, University of Adelaide, Adelaide, South Australia, Australia
| | - Robert J Casson
- Ophthalmic Research Laboratory, University of Adelaide, Adelaide, South Australia, Australia.
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Brito M, Sorbier C, Mignet N, Boudy V, Borchard G, Vacher G. Understanding the Impact of Polyunsaturated Fatty Acids on Age-Related Macular Degeneration: A Review. Int J Mol Sci 2024; 25:4099. [PMID: 38612907 PMCID: PMC11012607 DOI: 10.3390/ijms25074099] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2024] [Revised: 04/01/2024] [Accepted: 04/03/2024] [Indexed: 04/14/2024] Open
Abstract
Age-related Macular Degeneration (AMD) is a multifactorial ocular pathology that destroys the photoreceptors of the macula. Two forms are distinguished, dry and wet AMD, with different pathophysiological mechanisms. Although treatments were shown to be effective in wet AMD, they remain a heavy burden for patients and caregivers, resulting in a lack of patient compliance. For dry AMD, no real effective treatment is available in Europe. It is, therefore, essential to look for new approaches. Recently, the use of long-chain and very long-chain polyunsaturated fatty acids was identified as an interesting new therapeutic alternative. Indeed, the levels of these fatty acids, core components of photoreceptors, are significantly decreased in AMD patients. To better understand this pathology and to evaluate the efficacy of various molecules, in vitro and in vivo models reproducing the mechanisms of both types of AMD were developed. This article reviews the anatomy and the physiological aging of the retina and summarizes the clinical aspects, pathophysiological mechanisms of AMD and potential treatment strategies. In vitro and in vivo models of AMD are also presented. Finally, this manuscript focuses on the application of omega-3 fatty acids for the prevention and treatment of both types of AMD.
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Affiliation(s)
- Maëlis Brito
- Unither Développement Bordeaux, Avenue Toussaint Catros, 33185 Le Haillan, France
- Université Paris Cité, CNRS, INSERM, UTCBS, Unité de Technologies Chimiques et Biologiques pour la Santé, F-75006 Paris, France
- Département de Recherche et Développement (DRDP), Agence Générale des Equipements et Produits de Santé (AGEPS), Assistance Publique Hôpitaux de Paris (AP-HP), 7 Rue du Fer-à-Moulin, 75005 Paris, France
- Institute of Pharmaceutical Sciences of Western Switzerland (ISPSO), School of Pharmaceutical Sciences, University of Geneva, Rue Michel-Servet 1, 1206 Geneva, Switzerland
| | - Capucine Sorbier
- Unither Développement Bordeaux, Avenue Toussaint Catros, 33185 Le Haillan, France
| | - Nathalie Mignet
- Université Paris Cité, CNRS, INSERM, UTCBS, Unité de Technologies Chimiques et Biologiques pour la Santé, F-75006 Paris, France
| | - Vincent Boudy
- Université Paris Cité, CNRS, INSERM, UTCBS, Unité de Technologies Chimiques et Biologiques pour la Santé, F-75006 Paris, France
- Département de Recherche et Développement (DRDP), Agence Générale des Equipements et Produits de Santé (AGEPS), Assistance Publique Hôpitaux de Paris (AP-HP), 7 Rue du Fer-à-Moulin, 75005 Paris, France
| | - Gerrit Borchard
- Institute of Pharmaceutical Sciences of Western Switzerland (ISPSO), School of Pharmaceutical Sciences, University of Geneva, Rue Michel-Servet 1, 1206 Geneva, Switzerland
| | - Gaëlle Vacher
- Institute of Pharmaceutical Sciences of Western Switzerland (ISPSO), School of Pharmaceutical Sciences, University of Geneva, Rue Michel-Servet 1, 1206 Geneva, Switzerland
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Velmurugan S, Pauline R, Chandrashekar G, Kulanthaivel L, Subbaraj GK. Understanding the Impact of the Sirtuin 1 (SIRT1) Gene on Age-related Macular Degeneration: A Comprehensive Study. Niger Postgrad Med J 2024; 31:93-101. [PMID: 38826012 DOI: 10.4103/npmj.npmj_9_24] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2024] [Accepted: 04/02/2024] [Indexed: 06/04/2024]
Abstract
Age-related macular degeneration (AMD) is a prevalent and incurable condition affecting the central retina and posing a significant risk to vision, particularly in individuals over the age of 60. As the global population ages, the prevalence of AMD is expected to rise, leading to substantial socioeconomic impacts and increased healthcare costs. The disease manifests primarily in two forms, neovascular and non-neovascular, with genetic, environmental and lifestyle factors playing a pivotal role in disease susceptibility and progression. This review article involved conducting an extensive search across various databases, including Google Scholar, PubMed, Web of Science, ScienceDirect, Scopus and EMBASE, to compile relevant case-control studies and literature reviews from online published articles extracted using search terms related to the work. SIRT1, a key member of the sirtuin family, influences cellular processes such as ageing, metabolism, DNA repair and stress response. Its dysregulation is linked to retinal ageing and ocular conditions like AMD. This review discusses the role of SIRT1 in AMD pathology, its association with genetic variants and its potential as a biomarker, paving the way for targeted interventions and personalised treatment strategies. In addition, it highlights the findings of case-control studies investigating the relationship between SIRT1 gene polymorphisms and AMD risk. These studies collectively revealed a significant association between certain SIRT1 gene variants and AMD risk. Further studies with larger sample sizes are required to validate these findings. As the prevalence of AMD grows, understanding the role of SIRT1 and other biomarkers becomes increasingly vital for improving diagnosis, treatment and, ultimately, patient outcomes.
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Affiliation(s)
- Saranya Velmurugan
- Medical Genetics Division, Faculty of Allied Health Sciences, Chettinad Hospital and Research Institute, Chettinad Academy of Research and Education, Kelambakkam, Tamil Nadu, India
| | - Rashmi Pauline
- Medical Genetics Division, Faculty of Allied Health Sciences, Chettinad Hospital and Research Institute, Chettinad Academy of Research and Education, Kelambakkam, Tamil Nadu, India
| | | | - Langeswaran Kulanthaivel
- Department of Biomedical Sciences, Alagappa University, Science Campus, Karaikudi, Tamil Nadu, India
| | - Gowtham Kumar Subbaraj
- Medical Genetics Division, Faculty of Allied Health Sciences, Chettinad Hospital and Research Institute, Chettinad Academy of Research and Education, Kelambakkam, Tamil Nadu, India
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11
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Song Y, Lv P, Yu J. Platycodin D inhibits diabetic retinopathy via suppressing TLR4/MyD88/NF-κB signaling pathway and activating Nrf2/HO-1 signaling pathway. Chem Biol Drug Des 2024; 103:e14419. [PMID: 38230792 DOI: 10.1111/cbdd.14419] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2023] [Revised: 11/12/2023] [Accepted: 11/29/2023] [Indexed: 01/18/2024]
Abstract
Diabetic retinopathy (DR) is one of the most frequently occurring diabetic complications associated with inflammation and oxidative stress. Platycodin D (PLD) is a bio-active saponin that has been reported to exhibit anti-inflammation, anti-oxidative, and antidiabetic activities. Therefore, we speculated the protective effects of PLD on DR in the present study. Our results demonstrated that PLD attenuated high glucose (HG)-induced inflammation, as evidenced by decreased production of TNF-α, IL-1β, IL-6. The HG-induced oxidative stress was prevented by PLD with decreased ROS production and malondialdehyde (MDA) level, as well as increased activities of superoxide dismutase and glutathione (GSH). In addition, treatment of PLD significantly decreased the apoptotic rate in HG-induced ARPE-19 cells. The HG-caused increases in expression of bax and cleaved capsase-3, as well a decrease in bcl-2 expression were attenuated by PLD. Furthermore, PLD suppressed the activation of TLR4/MyD88/NF-κB and enhanced the activation of Nrf2/HO-1 pathway in HG-induced ARPE-19 cells. Additionally, overexpression of TLR4 attenuated the anti-inflammatory, while knockdown of Nrf2 reversed the anti-oxidative and anti-apoptotic activities of PLD in HG-stimulated ARPE-19 cells. Furthermore, PLD attenuates retinal damage in DR rats. Finally, we demonstrated that PLD weakened the TLR4/MyD88/NF-κB p65 pathway and promoted the Nrf2/HO-1 pathway in vivo. Taken together, these findings indicated that PLD exerted protective effects against DR, which were attributed to the regulation of TLR4/MyD88/NF-κB and Nrf2/HO-1 signaling pathways.
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Affiliation(s)
- Yanmin Song
- Department of Ophthalmology, Xi'an Hospital of Traditional Chinese Medicine, Xi'an, Shaanxi Province, P.R. China
- Shaanxi University of Traditional Chinese Medicine, Xianyang, Shaanxi Province, P.R. China
| | - Peilin Lv
- Shaanxi University of Traditional Chinese Medicine, Xianyang, Shaanxi Province, P.R. China
- Department of Ophthalmology, Affiliated Hospital of Shaanxi University of Traditional Chinese Medicine, Xianyang, Shaanxi Province, P.R. China
| | - Jingni Yu
- Department of Ophthalmology, Shaanxi Eye Hospital, Xi'an People's Hospital (Xi'an Fourth Hospital), Affiliated People's Hospital of Northwest University, Xi'an, Shaanxi Province, P.R. China
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12
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Marquina S, Ozgul M, Robertson-Brown K, Kenney MC. A review on PLGA particles as a sustained drug-delivery system and its effect on the retina. Exp Eye Res 2023; 235:109626. [PMID: 37652091 DOI: 10.1016/j.exer.2023.109626] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2023] [Revised: 07/01/2023] [Accepted: 08/21/2023] [Indexed: 09/02/2023]
Abstract
In this review, the designs and recent developments of polymer-based drug delivery of Poly(lactic-co-glycolic acid) (PLGA) will be discussed for the possible treatment of age-related macular degeneration (AMD). PLGA is a versatile co-polymer that consists of synthetic lactic acid and glycolic acid monomers that are constructed to produce nanoparticles, microparticles, and scaffolds for the intraocular delivery of various drugs. As an FDA-approved polymer, PLGA has historically been well-suited for systemic slow-sustained release therapies due to its performance in biodegradability and biocompatibility. This review will examine recent in vitro and in vivo studies that provide evidence for PLGA-based particles as a therapeutic drug carrier for the treatment of AMD. Anti-angiogenic and antiproliferative effects of small peptides, small molecules, RNA molecules, and proteins within PLGA particles are briefly discussed. AMD is a leading cause of central vision loss in people over 55 years and the number of those afflicted will rise as the aging population increases. AMD has two forms that are often sequential. Dry AMD and wet AMD account for 85-90% and 10-15% of cases, respectively. The distinct categories of PLGA-based drug delivery vehicles are important for dispensing novel small molecules, RNA molecules, peptides, and proteins as a long-term effective treatment of AMD.
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Affiliation(s)
- Sylvana Marquina
- School of Medicine, University of California Irvine, 843 Health Sciences Road, Irvine, CA, 92697, USA.
| | - Mustafa Ozgul
- Gavin Herbert Eye Institute, Department of Ophthalmology, University of California Irvine, 843 Health Sciences Road, Irvine, CA, 92697, USA.
| | - Kenneth Robertson-Brown
- School of Medicine, University of California Irvine, 843 Health Sciences Road, Irvine, CA, 92697, USA
| | - M Cristina Kenney
- Department of Pathology and Laboratory Medicine, University of California Irvine, 843 Health Sciences Road, Irvine, CA, 92697, USA
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13
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Venkatesh R, Handa A, Prabhu V, Chitturi SP, Joshi A, Acharya I, Mangla R, Yadav NK, Chhablani J. Central posterior hyaloid fibrosis: evolution and outcomes. Int J Retina Vitreous 2023; 9:54. [PMID: 37679852 PMCID: PMC10486079 DOI: 10.1186/s40942-023-00494-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2023] [Accepted: 08/24/2023] [Indexed: 09/09/2023] Open
Abstract
PURPOSE To report contributory factors and clinical outcomes of central posterior hyaloid fibrosis (CPHF) associated with neovascular age-related macular degeneration (nAMD). METHODS In this retrospective, single-center study, patients with CPHF and nAMD were included. Demographic and imaging characteristics, as well as the anatomical and functional outcomes, of these patients were analysed. RESULTS We identified 530 eyes in 273 patients with chronic predominantly scarred macular neovascularisation (MNV), and 32 eyes in 29 patients revealed CPHF, representing a prevalence of 6%. Patients had a mean age of 72.76 years. Before and during the development of CPHF, Type 2 MNV was observed in all eyes. At the time of MNV diagnosis, mean logMAR visual acuity was 1.308 ± 0.559 (20/407). The average time to develop CPHF was 27.3 months since the diagnosis of MNV. At the time of CPHF identification, the mean logMAR visual acuity was 1.498 ± 0.374 (20/630). RPE tear was observed in 6% (n = 2) of CPHF eyes. The average number of intravitreal anti-VEGF injections administered prior to the diagnosis of CPHF was 2.4 and after the onset of CPHF was 0.9. The final visual acuity was not significantly different at the final follow-up visit [1.304 ± 0.42 (20/402); p = 0.646]. CONCLUSION Rarely observed in eyes with predominantly scarred subfoveal type 2 MNVs and extensive subretinal fibrosis, CPHF is associated with poor visual outcomes. Its presence could possibly suggest a profibrotic effect of MNV on the posterior hyaloid. TRIAL REGISTRATION NUMBER Not applicable.
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Affiliation(s)
- Ramesh Venkatesh
- Dept. of Retina and Vitreous, Narayana Nethralaya, #121/C, 1st R Block, Chord Road, Rajaji Nagar, 560010, Bengaluru, Karnataka, India.
- Medical Retina and Vitreoretinal Surgery, University of Pittsburgh School of Medicine, 203 Lothrop Street, Suite 800, Pittsburg, PA, 15213, USA.
| | - Ashit Handa
- Dept. of Retina and Vitreous, Narayana Nethralaya, #121/C, 1st R Block, Chord Road, Rajaji Nagar, 560010, Bengaluru, Karnataka, India
| | - Vishma Prabhu
- Dept. of Retina and Vitreous, Narayana Nethralaya, #121/C, 1st R Block, Chord Road, Rajaji Nagar, 560010, Bengaluru, Karnataka, India
| | - Sai Prashanti Chitturi
- Dept. of Retina and Vitreous, Narayana Nethralaya, #121/C, 1st R Block, Chord Road, Rajaji Nagar, 560010, Bengaluru, Karnataka, India
| | - Aishwarya Joshi
- Dept. of Retina and Vitreous, Narayana Nethralaya, #121/C, 1st R Block, Chord Road, Rajaji Nagar, 560010, Bengaluru, Karnataka, India
| | - Isha Acharya
- Dept. of Retina and Vitreous, Narayana Nethralaya, #121/C, 1st R Block, Chord Road, Rajaji Nagar, 560010, Bengaluru, Karnataka, India
| | - Rubble Mangla
- Dept. of Retina and Vitreous, Narayana Nethralaya, #121/C, 1st R Block, Chord Road, Rajaji Nagar, 560010, Bengaluru, Karnataka, India
| | - Naresh Kumar Yadav
- Dept. of Retina and Vitreous, Narayana Nethralaya, #121/C, 1st R Block, Chord Road, Rajaji Nagar, 560010, Bengaluru, Karnataka, India
| | - Jay Chhablani
- Medical Retina and Vitreoretinal Surgery, University of Pittsburgh School of Medicine, 203 Lothrop Street, Suite 800, Pittsburg, PA, 15213, USA
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Twarog M, Schustak J, Xu Y, Coble M, Dolan K, Esterberg R, Huang Q, Saint-Geniez M, Bao Y. TNFα induced by DNA-sensing in macrophage compromises retinal pigment epithelial (RPE) barrier function. Sci Rep 2023; 13:14451. [PMID: 37660150 PMCID: PMC10475136 DOI: 10.1038/s41598-023-41610-7] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2023] [Accepted: 08/29/2023] [Indexed: 09/04/2023] Open
Abstract
Increasing evidence suggests that chronic inflammation plays an important role in the pathogenesis of age-related macular degeneration (AMD); however, the precise pathogenic stressors and sensors, and their impact on disease progression remain unclear. Several studies have demonstrated that type I interferon (IFN) response is activated in the retinal pigment epithelium (RPE) of AMD patients. Previously, we demonstrated that human RPE cells can initiate RNA-mediated type I IFN responses through RIG-I, yet are unable to directly sense and respond to DNA. In this study, we utilized a co-culture system combining primary human macrophage and iPS-derived RPE to study how each cell type responds to nucleic acids challenges and their effect on RPE barrier function in a homotypic and heterotypic manner. We find that DNA-induced macrophage activation induces an IFN response in the RPE, and compromises RPE barrier function via tight-junction remodeling. Investigation of the secreted cytokines responsible for RPE dysfunction following DNA-induced macrophages activation indicates that neutralization of macrophage-secreted TNFα, but not IFNβ, is sufficient to rescue RPE morphology and barrier function. Our data reveals a novel mechanism of intercellular communication by which DNA induces RPE dysfunction via macrophage-secreted TNFa, highlighting the complexity and potential pathological relevance of RPE and macrophage interactions.
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Affiliation(s)
- Michael Twarog
- Department of Ophthalmology, Novartis Institutes for BioMedical Research, 22 Windsor Street, Cambridge, MA, USA
| | - Joshua Schustak
- Department of Ophthalmology, Novartis Institutes for BioMedical Research, 22 Windsor Street, Cambridge, MA, USA
| | - YongYao Xu
- Department of Ophthalmology, Novartis Institutes for BioMedical Research, 22 Windsor Street, Cambridge, MA, USA
| | - Matthew Coble
- Department of Ophthalmology, Novartis Institutes for BioMedical Research, 22 Windsor Street, Cambridge, MA, USA
| | - Katie Dolan
- Department of Ophthalmology, Novartis Institutes for BioMedical Research, 22 Windsor Street, Cambridge, MA, USA
| | - Robert Esterberg
- Department of Ophthalmology, Novartis Institutes for BioMedical Research, 22 Windsor Street, Cambridge, MA, USA
| | - Qian Huang
- Department of Ophthalmology, Novartis Institutes for BioMedical Research, 22 Windsor Street, Cambridge, MA, USA
| | - Magali Saint-Geniez
- Department of Ophthalmology, Novartis Institutes for BioMedical Research, 22 Windsor Street, Cambridge, MA, USA
| | - Yi Bao
- Department of Ophthalmology, Novartis Institutes for BioMedical Research, 22 Windsor Street, Cambridge, MA, USA.
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15
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Espitia-Arias MD, de la Villa P, Paleo-García V, Germain F, Milla-Navarro S. Oxidative Model of Retinal Neurodegeneration Induced by Sodium Iodate: Morphofunctional Assessment of the Visual Pathway. Antioxidants (Basel) 2023; 12:1594. [PMID: 37627589 PMCID: PMC10451746 DOI: 10.3390/antiox12081594] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2023] [Revised: 08/05/2023] [Accepted: 08/07/2023] [Indexed: 08/27/2023] Open
Abstract
Sodium iodate (NaIO3) has been shown to cause severe oxidative stress damage to retinal pigment epithelium cells. This results in the indirect death of photoreceptors, leading to a loss of visual capabilities. The aim of this work is the morphological and functional characterization of the retina and the visual pathway of an animal model of retinal neurodegeneration induced by oxidative stress. Following a single intraperitoneal dose of NaIO3 (65 mg/kg) to C57BL/6J mice with a mutation in the Opn4 gene (Opn4-/-), behavioral and electroretinographic tests were performed up to 42 days after administration, as well as retinal immunohistochemistry at day 57. A near total loss of the pupillary reflex was observed at 3 days, as well as an early deterioration of visual acuity. Behavioral tests showed a late loss of light sensitivity. Full-field electroretinogram recordings displayed a progressive and marked decrease in wave amplitude, disappearing completely at 14 days. A reduction in the amplitude of the visual evoked potentials was observed, but not their total disappearance. Immunohistochemistry showed structural alterations in the outer retinal layers. Our results show that NaIO3 causes severe structural and functional damage to the retina. Therefore, the current model can be presented as a powerful tool for the study of new therapies for the prevention or treatment of retinal pathologies mediated by oxidative stress.
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Affiliation(s)
- Michael D. Espitia-Arias
- Department of Systems Biology, University of Alcalá, 28805 Madrid, Spain; (M.D.E.-A.); (P.d.l.V.); (V.P.-G.)
| | - Pedro de la Villa
- Department of Systems Biology, University of Alcalá, 28805 Madrid, Spain; (M.D.E.-A.); (P.d.l.V.); (V.P.-G.)
- Visual Neurophysiology Group-Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), 28034 Madrid, Spain
| | - Victor Paleo-García
- Department of Systems Biology, University of Alcalá, 28805 Madrid, Spain; (M.D.E.-A.); (P.d.l.V.); (V.P.-G.)
| | - Francisco Germain
- Department of Systems Biology, University of Alcalá, 28805 Madrid, Spain; (M.D.E.-A.); (P.d.l.V.); (V.P.-G.)
- Visual Neurophysiology Group-Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), 28034 Madrid, Spain
| | - Santiago Milla-Navarro
- Department of Systems Biology, University of Alcalá, 28805 Madrid, Spain; (M.D.E.-A.); (P.d.l.V.); (V.P.-G.)
- Visual Neurophysiology Group-Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), 28034 Madrid, Spain
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16
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Benlahbib M, Cohen SY, Torrell N, Colantuono D, Crincoli E, Amoroso F, Semoun O, Jung C, Souied EH. PHOTOBIOMODULATION THERAPY FOR LARGE SOFT DRUSEN AND DRUSENOID PIGMENT EPITHELIAL DETACHMENT IN AGE-RELATED MACULAR DEGENERATION: A Single-Center Prospective Pilot Study. Retina 2023; 43:1246-1254. [PMID: 37027819 DOI: 10.1097/iae.0000000000003805] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/09/2023]
Abstract
PURPOSE To evaluate visual acuity and morphologic changes after photobiomodulation (PBM) for patients affected with large soft drusen and/or drusenoid pigment epithelial detachment associated with dry age-related macular degeneration. METHOD Twenty eyes with large soft drusen and/or drusenoid pigment epithelial detachment age-related macular degeneration were included and treated using the LumiThera Valeda Light Delivery System. All patients underwent two treatments per week for 5 weeks. Outcome measures included best-corrected visual acuity, microperimetry-scotopic testing, drusen volume, central drusen thickness, and quality of life score at baseline and month 6 (M6) follow-up. Data of best-corrected visual acuity, drusen volume, and central drusen thickness were also recorded at week 5 (W5). RESULTS Best-corrected visual acuity significantly improved at M6 with a mean score gain of 5.5 letters ( P = 0.007). Retinal sensitivity decreased by 0.1 dB ( P = 0.17). The mean fixation stability increased by 0.45% ( P = 0.72). Drusen volume decreased by 0.11 mm 3 ( P = 0.03). Central drusen thickness was reduced by a mean of 17.05 µ m ( P = 0.01). Geographic atrophy area increased by 0.06 mm 2 ( P = 0.01) over a 6-month follow-up, and quality of life score increased by 3,07 points on average ( P = 0.05). One patient presented a drusenoid pigment epithelial detachment rupture at M6 after PBM treatment. CONCLUSION The visual and anatomical improvements in our patients support previous reports on PBM. PBM may provide a valid therapeutic option for large soft drusen and drusenoid pigment epithelial detachment age-related macular degeneration and may potentially slow the natural course of the disease.
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Affiliation(s)
- Manal Benlahbib
- Department of Ophthalmology, Department of Ophthalmology, Centre Hospitaliser Intercommunal de Creteil, University of Paris Est-Creteil, Creteil, France
| | - Salomon Yves Cohen
- Department of Ophthalmology, Department of Ophthalmology, Centre Hospitaliser Intercommunal de Creteil, University of Paris Est-Creteil, Creteil, France
- Ophthalmology Center for Imaging and Laser, Paris, France; and
| | - Nuria Torrell
- Department of Ophthalmology, Department of Ophthalmology, Centre Hospitaliser Intercommunal de Creteil, University of Paris Est-Creteil, Creteil, France
| | - Donato Colantuono
- Department of Ophthalmology, Department of Ophthalmology, Centre Hospitaliser Intercommunal de Creteil, University of Paris Est-Creteil, Creteil, France
| | - Emanuele Crincoli
- Department of Ophthalmology, Department of Ophthalmology, Centre Hospitaliser Intercommunal de Creteil, University of Paris Est-Creteil, Creteil, France
| | - Francesca Amoroso
- Department of Ophthalmology, Department of Ophthalmology, Centre Hospitaliser Intercommunal de Creteil, University of Paris Est-Creteil, Creteil, France
| | - Oudy Semoun
- Department of Ophthalmology, Department of Ophthalmology, Centre Hospitaliser Intercommunal de Creteil, University of Paris Est-Creteil, Creteil, France
| | - Camille Jung
- Clinical Research Center, Centre Hospitaliser Intercommunal de Creteil, Creteil, France
| | - Eric H Souied
- Department of Ophthalmology, Department of Ophthalmology, Centre Hospitaliser Intercommunal de Creteil, University of Paris Est-Creteil, Creteil, France
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Lenin RR, Koh YH, Zhang Z, Yeo YZ, Parikh BH, Seah I, Wong W, Su X. Dysfunctional Autophagy, Proteostasis, and Mitochondria as a Prelude to Age-Related Macular Degeneration. Int J Mol Sci 2023; 24:ijms24108763. [PMID: 37240109 DOI: 10.3390/ijms24108763] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2022] [Revised: 05/05/2023] [Accepted: 05/06/2023] [Indexed: 05/28/2023] Open
Abstract
Retinal pigment epithelial (RPE) cell dysfunction is a key driving force of AMD. RPE cells form a metabolic interface between photoreceptors and choriocapillaris, performing essential functions for retinal homeostasis. Through their multiple functions, RPE cells are constantly exposed to oxidative stress, which leads to the accumulation of damaged proteins, lipids, nucleic acids, and cellular organelles, including mitochondria. As miniature chemical engines of the cell, self-replicating mitochondria are heavily implicated in the aging process through a variety of mechanisms. In the eye, mitochondrial dysfunction is strongly associated with several diseases, including age-related macular degeneration (AMD), which is a leading cause of irreversible vision loss in millions of people globally. Aged mitochondria exhibit decreased rates of oxidative phosphorylation, increased reactive oxygen species (ROS) generation, and increased numbers of mitochondrial DNA mutations. Mitochondrial bioenergetics and autophagy decline during aging because of insufficient free radical scavenger systems, the impairment of DNA repair mechanisms, and reductions in mitochondrial turnover. Recent research has uncovered a much more complex role of mitochondrial function and cytosolic protein translation and proteostasis in AMD pathogenesis. The coupling of autophagy and mitochondrial apoptosis modulates the proteostasis and aging processes. This review aims to summarise and provide a perspective on (i) the current evidence of autophagy, proteostasis, and mitochondrial dysfunction in dry AMD; (ii) current in vitro and in vivo disease models relevant to assessing mitochondrial dysfunction in AMD, and their utility in drug screening; and (iii) ongoing clinical trials targeting mitochondrial dysfunction for AMD therapeutics.
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Affiliation(s)
- Raji Rajesh Lenin
- Department of Ophthalmology, Yong Loo Lin School of Medicine, National University of Singapore (NUS), 1E Kent Ridge Road, NUHS Tower Block Level 7, Singapore 119228, Singapore
- Department of Medical Research, SRM Institute of Science and Technology, Kattankulathur 603203, Tamil Nadu, India
| | - Yi Hui Koh
- Department of Ophthalmology, Yong Loo Lin School of Medicine, National University of Singapore (NUS), 1E Kent Ridge Road, NUHS Tower Block Level 7, Singapore 119228, Singapore
| | - Zheting Zhang
- Department of Ophthalmology, Yong Loo Lin School of Medicine, National University of Singapore (NUS), 1E Kent Ridge Road, NUHS Tower Block Level 7, Singapore 119228, Singapore
- Lee Kong Chian School of Medicine, Nanyang Technological University (NTU), 11 Mandalay Road, Experimental Medicine Building, Singapore 308232, Singapore
| | - Yan Zhuang Yeo
- Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology, and Research (A*STAR), 61 Biopolis Drive, Proteos, Singapore 138673, Singapore
| | - Bhav Harshad Parikh
- Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology, and Research (A*STAR), 61 Biopolis Drive, Proteos, Singapore 138673, Singapore
| | - Ivan Seah
- Department of Ophthalmology, Yong Loo Lin School of Medicine, National University of Singapore (NUS), 1E Kent Ridge Road, NUHS Tower Block Level 7, Singapore 119228, Singapore
| | - Wendy Wong
- Department of Ophthalmology, National University Hospital (NUH), 1E Kent Ridge Road, NUHS Tower Block Level 7, Singapore 119228, Singapore
| | - Xinyi Su
- Department of Ophthalmology, Yong Loo Lin School of Medicine, National University of Singapore (NUS), 1E Kent Ridge Road, NUHS Tower Block Level 7, Singapore 119228, Singapore
- Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology, and Research (A*STAR), 61 Biopolis Drive, Proteos, Singapore 138673, Singapore
- Department of Ophthalmology, National University Hospital (NUH), 1E Kent Ridge Road, NUHS Tower Block Level 7, Singapore 119228, Singapore
- Singapore Eye Research Institute (SERI), The Academia, 20 College Road, Level 6 Discovery Tower, Singapore 169856, Singapore
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18
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Jia X, Sun Y, Wang T, Zhong L, Deng J, Zhu X. Mechanism of circular RNA-mediated regulation of L-DOPA to improve wet age-related macular degeneration. Gene 2023; 861:147247. [PMID: 36736867 DOI: 10.1016/j.gene.2023.147247] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2022] [Revised: 01/14/2023] [Accepted: 01/27/2023] [Indexed: 02/04/2023]
Abstract
This study aimed to investigate the effect and mechanism of levodopa (L-DOPA) in the treatment of age-related macular degeneration (AMD). A wet AMD cell model was created via CoCl2 treatment of ARPE-19 cells. The cytoprotective effects of L-DOPA in the model were determined using CCK-8, flow cytometry, TUNEL, qPCR, and ELISA assays. Subsequently, circRNA sequencing and bioinformatics analysis were used to screen differentially expressed circRNAs, which were overexpressed in ARPE-19 cells, to explore their role in wet AMD. The findings revealed that 200 μM CoCl2 treatment inhibited the cell viability and the production of tyrosinase, melanin, and pigment epithelium-derived growth factor but promoted apoptosis and the expression of vascular endothelial growth factor in ARPE-19 cells. Moreover, 20 μM L-DOPA exerted the best therapeutic effect on the model. qPCR showed that Hsa_circ_0018401 (circ-SGMS1) was significantly differentially expressed in each experimental group, which was consistent with the sequencing results. The overexpression of circ-SGMS1 in ARPE-19 cells reversed the effects of CoCl2. Fluorescence in situ hybridization showed that circ-SGMS1 was expressed more in the nucleus than in the cytoplasm. qPCR assays indicated that circ-SGMS1 overexpression did not have a significant effect on the expressions of VEGFA and KDR but significantly reduced the expressions of HIF-1a and THBS1. Circ-SGMS1 is of immense significance in the AMD treatment mechanism of L-DOPA. Overexpression of circ-SGMS1 may alleviate wet AMD by inhibiting HIF-1a and THBS1 expression.
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Affiliation(s)
- Xiuhua Jia
- Department of Ophthalmology, Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Yi Sun
- Department of Ophthalmology, Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Tao Wang
- Department of Ophthalmology, Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Lei Zhong
- Department of Ophthalmology, Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Juan Deng
- Department of Ophthalmology, Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China.
| | - Xiang Zhu
- Department of Infectious Diseases, Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China.
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Nrf2-mediated activation of HO-1 is required in the blocking effect of compound K, a ginseng saponin metabolite, against oxidative stress damage in ARPE-19 human retinal pigment epithelial cells. J Ginseng Res 2023; 47:311-318. [PMID: 36926611 PMCID: PMC10014180 DOI: 10.1016/j.jgr.2022.09.007] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2022] [Revised: 07/04/2022] [Accepted: 09/27/2022] [Indexed: 11/06/2022] Open
Abstract
Background The beneficial effects of compound K (CK) on different chronic diseases have been shown to be at least related to antioxidant action. Nevertheless, since its antioxidant activity in human retinal pigment epithelial (RPE) cells is still unknown, here we investigated whether CK alleviates oxidative stress-stimulated damage in RPE ARPE-19 cells. Methods The cytoprotective consequence of CK in hydrogen peroxide (H2O2)-treated cells was evaluated by cell viability, DNA damage, and apoptosis assays. Fluorescence analysis and immunoblotting were performed to investigate the inhibitory action of CK on reactive oxygen species (ROS) production and mitochondrial dysfunction. Results H2O2-promoted cytotoxicity, oxidative stress, DNA damage, mitochondrial impairment, and apoptosis were significantly attenuated by CK in ARPE-19 cells. Furthermore, nuclear factor erythroid 2-related factor 2 (Nrf2) phosphorylation level and its shuttling to the nucleus were increased, which was correlated with upregulated activation of heme oxygenase-1 (HO-1). However, zinc protoporphyrin, a blocker of HO-1, significantly abrogated the preventive action of CK in H2O2-treated ARPE-19 cells. Conclusion This study indicates that activation of Nrf2/HO-1 signaling by CK plays an important role in rescuing ARPE-19 cells from oxidative cellular damage.
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20
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Activation of Nrf2/HO-1 antioxidant signaling correlates with the preventive effect of loganin on oxidative injury in ARPE-19 human retinal pigment epithelial cells. Genes Genomics 2023; 45:271-284. [PMID: 36018494 DOI: 10.1007/s13258-022-01302-4] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2022] [Accepted: 08/03/2022] [Indexed: 11/04/2022]
Abstract
BACKGROUND Loganin, a type of iridoid glycoside derived from Corni Fructus, is known to have beneficial effects various chronic diseases. However, studies on mechanisms related to antioxidant efficacy in human retinal pigment epithelial (RPE) cells have not yet been conducted. OBJECTIVES This study was to investigate whether loganin could inhibit oxidative stress-mediated cellular damage caused by hydrogen peroxide (H2O2) in human RPE ARPE-19 cells. METHODS The preventive effect of loganin on H2O2-induced cytotoxicity, reactive oxygen species (ROS) generation, DNA damage and apoptosis was investigated. In addition, immunofluorescence staining and immunoblotting analysis were applied to evaluate the related mechanisms. RESULTS The loss of cell viability and increased ROS accumulation in H2O2-treated ARPE-19 cells were significantly abrogated by loganin pretreatment, which was associated with activation of nuclear factor erythroid 2-related factor 2 (Nrf2) and increased expression of heme oxygenase-1 (HO-1). Loganin also markedly attenuated H2O2-induced DNA damage, ultimately ameliorating apoptosis. In addition, H2O2-induced mitochondrial dysfunction was reversed in the presence of loganin as indicated by preservation of mitochondrial integrity, decrease of Bax/Bcl-2 expression ratio, reduction of caspase-3 activity and suppression of cytochrome c release into the cytoplasm. However, zinc protoporphyrin, a selective inhibitor of HO-1, remarkably alleviated the preventive effect offered by loganin against H2O2-mediated ARPE-19 cell injury, suggesting a critical role of Nrf2-mediated activation of HO-1 in the antioxidant activity of loganin. CONCLUSION The results of this study suggest that loganin-induced activation of the Nrf2/HO-1 axis is at least involved in protecting at least ARPE-19 cells from oxidative injury.
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21
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Morgan CE, Zhang Z, Miyagi M, Golczak M, Yu EW. Toward structural-omics of the bovine retinal pigment epithelium. Cell Rep 2022; 41:111876. [PMID: 36577381 PMCID: PMC9875382 DOI: 10.1016/j.celrep.2022.111876] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2022] [Revised: 10/12/2022] [Accepted: 12/02/2022] [Indexed: 12/28/2022] Open
Abstract
The use of an integrated systems biology approach to investigate tissues and organs has been thought to be impracticable in the field of structural biology, where the techniques mainly focus on determining the structure of a particular biomacromolecule of interest. Here, we report the use of cryoelectron microscopy (cryo-EM) to define the composition of a raw bovine retinal pigment epithelium (RPE) lysate. From this sample, we simultaneously identify and solve cryo-EM structures of seven different RPE enzymes whose functions affect neurotransmitter recycling, iron metabolism, gluconeogenesis, glycolysis, axonal development, and energy homeostasis. Interestingly, dysfunction of these important proteins has been directly linked to several neurodegenerative disorders, including Huntington's disease, amyotrophic lateral sclerosis (ALS), Parkinson's disease, Alzheimer's disease, and schizophrenia. Our work underscores the importance of cryo-EM in facilitating tissue and organ proteomics at the atomic level.
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Affiliation(s)
- Christopher E. Morgan
- Department of Pharmacology, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA,Department of Chemistry, Thiel College, Greenville, PA 16125, USA,These authors contributed equally
| | - Zhemin Zhang
- Department of Pharmacology, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA,These authors contributed equally
| | - Masaru Miyagi
- Department of Pharmacology, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA
| | - Marcin Golczak
- Department of Pharmacology, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA,Cleveland Center for Membrane and Structural Biology, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA
| | - Edward W. Yu
- Department of Pharmacology, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA,Cleveland Center for Membrane and Structural Biology, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA,Lead contact,Correspondence:
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22
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Noncoding RNAs Are Promising Therapeutic Targets for Diabetic Retinopathy: An Updated Review (2017-2022). Biomolecules 2022; 12:biom12121774. [PMID: 36551201 PMCID: PMC9775338 DOI: 10.3390/biom12121774] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2022] [Revised: 11/10/2022] [Accepted: 11/26/2022] [Indexed: 12/03/2022] Open
Abstract
Diabetic retinopathy (DR) is the most common complication of diabetes. It is also the main cause of blindness caused by multicellular damage involving retinal endothelial cells, ganglial cells, and pigment epithelial cells in adults worldwide. Currently available drugs for DR do not meet the clinical needs; thus, new therapeutic targets are warranted. Noncoding RNAs (ncRNAs), a new type of biomarkers, have attracted increased attention in recent years owing to their crucial role in the occurrence and development of DR. NcRNAs mainly include microRNAs, long noncoding RNAs, and circular RNAs, all of which regulate gene and protein expression, as well as multiple biological processes in DR. NcRNAs, can regulate the damage caused by various retinal cells; abnormal changes in the aqueous humor, exosomes, blood, tears, and the formation of new blood vessels. This study reviews the different sources of the three ncRNAs-microRNAs, long noncoding RNAs, and circular RNAs-involved in the pathogenesis of DR and the related drug development progress. Overall, this review improves our understanding of the role of ncRNAs in various retinal cells and offers therapeutic directions and targets for DR treatment.
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23
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Le HM, Mehanna CJ, De Rosa I, Miere A, Souied E. Effects of Photobiomodulation in Patients Presenting with Reticular Pseudodrusen: A Retrospective Observational Case Series Study. MEDICINA (KAUNAS, LITHUANIA) 2022; 58:1662. [PMID: 36422201 PMCID: PMC9694204 DOI: 10.3390/medicina58111662] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/30/2022] [Revised: 09/27/2022] [Accepted: 11/16/2022] [Indexed: 08/15/2024]
Abstract
Background and Objectives: The purpose of this study is to describe the effects of photobiomodulation on drusen regression with patients presenting with reticular pseudodrusen (RPD). Materials and Methods: This study is a retrospective observational case series study including patients presenting with RPD who underwent treatment by photobiomodulation. All patients underwent a complete ophthalmic examination and multimodal imaging prior to treatment, including spectral-domain optical coherence tomography (SD-OCT). Eyes were treated two times per week for six consecutive weeks. Best corrected-visual acuity (BVCA) was measured prior and after treatment for all patients. The number of RPD on the SD-OCT scans centered on the macula and stages of RPD was noted at baseline and 6 months after the first treatment session. Results: Five eyes of five patients were included in the study. Mean BCVA did not change 6 months after treatment compared to baseline. Mean number of RPD per eye was 112.60 +/- 48.33 RPD at baseline and 111.6 +/- 49.29 in the same area 6 months after treatment. Changes in RPD distribution according to RPD classification were observed before and after treatment with photobiomodulation. Changes in distribution mostly concerned stages 1 and 3 RPD: Total number of stage 1 RPD was 289 and increased to 324 after treatment. Total number of stage 3 RPD was 97 at baseline and decreased to 67 6 months after treatment. Percentage of stage 1 RPD increased from 46% to 56% after treatment. Percentage of stage 3 RPD decreased from 20% to 13% after treatment. Conclusions: Changes in RPD distribution were observed before and after treatment with photobiomodulation. The number of stage 3 reticular pseudodrusen decreased while number of stage 1 reticular pseudodrusen increased after treatment.
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Affiliation(s)
- Hoang Mai Le
- Centre Hospitalier Intercommunal de Créteil, 94 000 Créteil, France
- Faculty of Medicine, University Paris-Est Créteil (UPEC), 94 000 Créteil, France
| | - Carl-Joe Mehanna
- Centre Hospitalier Intercommunal de Créteil, 94 000 Créteil, France
| | - Irene De Rosa
- Centre Hospitalier Intercommunal de Créteil, 94 000 Créteil, France
| | - Alexandra Miere
- Centre Hospitalier Intercommunal de Créteil, 94 000 Créteil, France
- Faculty of Medicine, University Paris-Est Créteil (UPEC), 94 000 Créteil, France
| | - Eric Souied
- Centre Hospitalier Intercommunal de Créteil, 94 000 Créteil, France
- Faculty of Medicine, University Paris-Est Créteil (UPEC), 94 000 Créteil, France
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24
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Harju N. Regulation of oxidative stress and inflammatory responses in human retinal pigment epithelial cells. Acta Ophthalmol 2022; 100 Suppl 273:3-59. [DOI: 10.1111/aos.15275] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Affiliation(s)
- Niina Harju
- School of Pharmacy University of Eastern Finland Kuopio Finland
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25
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Li JK, Rao YQ, Koh SK, Zhao P, Zhou L, Li J. Proteomic analysis of s-acylated proteins in human retinal pigment epithelial cells and the role of palmitoylation of Niemann-Pick type C1 protein in cholesterol transport. Front Aging Neurosci 2022; 14:965943. [PMID: 36262888 PMCID: PMC9576141 DOI: 10.3389/fnagi.2022.965943] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2022] [Accepted: 08/26/2022] [Indexed: 11/13/2022] Open
Abstract
Palmitoylation is a dynamic process that regulates the activity of the modified proteins. Retinal pigment epithelial (RPE) cells play pivotal roles in the visual cycle and maintaining healthy photoreceptor cells. Dysfunctional RPE cells are often associated with degenerative retinal diseases. The aim of the study was to identify potentially palmitoylated proteins in human RPE cells. By using the detergent-resistant membrane, we found 312 potentially palmitoylated peptides which corresponded to 192 proteins in RPE cells, including 55 new candidate proteins which were not reported before. Gene enrichment analysis highlighted significant enrichment of palmitoylated proteins in cell-matrix adhesion, cell-cell recognition, protein cellular localization, and translation, among others. We further studied the effect of 3 potential palmitoylation sites (Cys 799, 900, and 816) of Niemann-Pick type C1 protein (NPC1) on cholesterol accumulation. We found that mutation of any single Cys alone had no significant effect on intracellular cholesterol accumulation while simultaneous mutation of Cys799 and 800 caused significant cholesterol accumulation in the late endosome. No further cholesterol accumulation was observed by adding another mutation at Cys 816. However, the mutation did not alter the cellular localization of the protein. Conclusion: PRE cells have an abundant number of palmitoylated proteins which are involved in cellular processes critical to visual function. The palmitoylation at Cys799 and 800 was needed for cholesterol export, but not the intracellular localization of NPC1.
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Affiliation(s)
- Jia Kai Li
- Department of Ophthalmology, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Yu Qing Rao
- Department of Ophthalmology, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Siew Kwan Koh
- Singapore Eye Research Institute, Singapore, Singapore
| | - Peiquan Zhao
- Department of Ophthalmology, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Lei Zhou
- Singapore Eye Research Institute, Singapore, Singapore
- Department of Ophthalmology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
- Ophthalmology and Visual Sciences Academic Clinical Research Program, Duke-NUS Medical School, National University of Singapore, Singapore, Singapore
- *Correspondence: Lei Zhou,
| | - Jing Li
- Department of Ophthalmology, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Jing Li,
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26
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Liang Y, Tan F, Sun X, Cui Z, Gu J, Mao S, Chan HF, Tang S, Chen J. Aberrant Retinal Pigment Epithelial Cells Derived from Induced Pluripotent Stem Cells of a Retinitis Pigmentosa Patient with the PRPF6 Mutation. Int J Mol Sci 2022; 23:ijms23169049. [PMID: 36012314 PMCID: PMC9409096 DOI: 10.3390/ijms23169049] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2022] [Revised: 08/08/2022] [Accepted: 08/11/2022] [Indexed: 11/16/2022] Open
Abstract
Pre-mRNA processing factors (PRPFs) are vital components of the spliceosome and are involved in the physiological process necessary for pre-mRNA splicing to mature mRNA. As an important member, PRPF6 mutation resulting in autosomal dominant retinitis pigmentosa (adRP) is not common. Recently, we reported the establishment of an induced pluripotent stem cells (iPSCs; CSUASOi004-A) model by reprogramming the peripheral blood mononuclear cells of a PRPF6-related adRP patient, which could recapitulate a consistent disease-specific genotype. In this study, a disease model of retinal pigment epithelial (RPE) cells was generated from the iPSCs of this patient to further investigate the underlying molecular and pathological mechanisms. The results showed the irregular morphology, disorganized apical microvilli and reduced expressions of RPE-specific genes in the patient’s iPSC-derived RPE cells. In addition, RPE cells carrying the PRPF6 mutation displayed a decrease in the phagocytosis of fluorescein isothiocyanate-labeled photoreceptor outer segments and exhibited impaired cell polarity and barrier function. This study will benefit the understanding of PRPF6-related RPE cells and future cell therapy.
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Affiliation(s)
- Yuqin Liang
- Aier School of Ophthalmology, Central South University, Changsha 410015, China
- Aier Eye Institute, Changsha 410015, China
| | - Feng Tan
- Aier School of Ophthalmology, Central South University, Changsha 410015, China
- Aier Eye Institute, Changsha 410015, China
| | - Xihao Sun
- Aier School of Ophthalmology, Central South University, Changsha 410015, China
- Aier Eye Institute, Changsha 410015, China
| | - Zekai Cui
- Aier School of Ophthalmology, Central South University, Changsha 410015, China
- Aier Eye Institute, Changsha 410015, China
| | - Jianing Gu
- Aier Eye Institute, Changsha 410015, China
| | | | - Hon Fai Chan
- Institute for Tissue Engineering and Regenerative Medicine, The Chinese University of Hong Kong, Hong Kong 999077, China
- School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong 999077, China
| | - Shibo Tang
- Aier School of Ophthalmology, Central South University, Changsha 410015, China
- Aier Eye Institute, Changsha 410015, China
- Correspondence: (S.T.); (J.C.); Tel.: +86-139-2510-0123 (S.T.); +86-186-7583-9029 (J.C.)
| | - Jiansu Chen
- Aier School of Ophthalmology, Central South University, Changsha 410015, China
- Aier Eye Institute, Changsha 410015, China
- Key Laboratory for Regenerative Medicine, Ministry of Education, Jinan University, Guangzhou 510632, China
- Correspondence: (S.T.); (J.C.); Tel.: +86-139-2510-0123 (S.T.); +86-186-7583-9029 (J.C.)
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27
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Jin X, Liu J, Wang W, Li J, Liu G, Qiu R, Yang M, Liu M, Yang L, Du X, Lei B. Identification of Age-associated Proteins and Functional Alterations in Human Retinal Pigment Epithelium. GENOMICS, PROTEOMICS & BIOINFORMATICS 2022; 20:633-647. [PMID: 35752290 PMCID: PMC9880895 DOI: 10.1016/j.gpb.2022.06.001] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 01/28/2021] [Revised: 05/15/2022] [Accepted: 06/13/2022] [Indexed: 01/31/2023]
Abstract
Retinal pigment epithelium (RPE) has essential functions, such as nourishing and supporting the neural retina, and is of vital importance in the pathogenesis of age-related retinal degeneration. However, the exact molecular changes of RPE during aging remain poorly understood. Here, we isolated human primary RPE (hRPE) cells from 18 eye donors distributed over a wide age range (10-67 years old). A quantitative proteomic analysis was performed to analyze changes in their intracellular and secreted proteins. Age-group related subtypes and age-associated proteins were revealed and potential age-associated mechanisms were validated in ARPE-19 and hRPE cells. The results of proteomic data analysis and verifications suggest that RNF123- and RNF149-related protein ubiquitination plays an important role in protecting hRPE cells from oxidative damage during aging. In older hRPE cells, apoptotic signaling-related pathways were up-regulated, and endoplasmic reticulum organization was down-regulated both in the intracellular and secreted proteomes. Our work paints a detailed molecular picture of hRPE cells during the aging process and provides new insights into the molecular characteristics of RPE during aging and under other related clinical retinal conditions.
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Affiliation(s)
- Xiuxiu Jin
- Henan Eye Institute, Henan Eye Hospital, People’s Hospital of Zhengzhou University, Henan Provincial People’s Hospital, Zhengzhou 450003, China,Branch of National Clinical Research Center for Ocular Disease, Henan Provincial People’s Hospital, Zhengzhou 450003, China,School of Medicine, Henan Provincial People’s Hospital, Henan University, Zhengzhou 450003, China
| | - Jingyang Liu
- Henan Eye Institute, Henan Eye Hospital, People’s Hospital of Zhengzhou University, Henan Provincial People’s Hospital, Zhengzhou 450003, China,Branch of National Clinical Research Center for Ocular Disease, Henan Provincial People’s Hospital, Zhengzhou 450003, China
| | - Weiping Wang
- Henan Eye Institute, Henan Eye Hospital, People’s Hospital of Zhengzhou University, Henan Provincial People’s Hospital, Zhengzhou 450003, China,Branch of National Clinical Research Center for Ocular Disease, Henan Provincial People’s Hospital, Zhengzhou 450003, China
| | - Jiangfeng Li
- School of Basic Medical Sciences, Zhengzhou University, Zhengzhou 450001, China
| | - Guangming Liu
- Henan Eye Institute, Henan Eye Hospital, People’s Hospital of Zhengzhou University, Henan Provincial People’s Hospital, Zhengzhou 450003, China,Branch of National Clinical Research Center for Ocular Disease, Henan Provincial People’s Hospital, Zhengzhou 450003, China
| | - Ruiqi Qiu
- Henan Eye Institute, Henan Eye Hospital, People’s Hospital of Zhengzhou University, Henan Provincial People’s Hospital, Zhengzhou 450003, China,Branch of National Clinical Research Center for Ocular Disease, Henan Provincial People’s Hospital, Zhengzhou 450003, China
| | - Mingzhu Yang
- Henan Eye Institute, Henan Eye Hospital, People’s Hospital of Zhengzhou University, Henan Provincial People’s Hospital, Zhengzhou 450003, China,Branch of National Clinical Research Center for Ocular Disease, Henan Provincial People’s Hospital, Zhengzhou 450003, China
| | - Meng Liu
- Henan Eye Institute, Henan Eye Hospital, People’s Hospital of Zhengzhou University, Henan Provincial People’s Hospital, Zhengzhou 450003, China,Academy of Medical Sciences, Zhengzhou University, Zhengzhou 450001, China
| | - Lin Yang
- Henan Eye Institute, Henan Eye Hospital, People’s Hospital of Zhengzhou University, Henan Provincial People’s Hospital, Zhengzhou 450003, China,Academy of Medical Sciences, Zhengzhou University, Zhengzhou 450001, China
| | - Xiaofeng Du
- Henan Eye Institute, Henan Eye Hospital, People’s Hospital of Zhengzhou University, Henan Provincial People’s Hospital, Zhengzhou 450003, China,Branch of National Clinical Research Center for Ocular Disease, Henan Provincial People’s Hospital, Zhengzhou 450003, China
| | - Bo Lei
- Henan Eye Institute, Henan Eye Hospital, People’s Hospital of Zhengzhou University, Henan Provincial People’s Hospital, Zhengzhou 450003, China,Branch of National Clinical Research Center for Ocular Disease, Henan Provincial People’s Hospital, Zhengzhou 450003, China,Academy of Medical Sciences, Zhengzhou University, Zhengzhou 450001, China,Corresponding author.
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28
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Shu DY, Frank SI, Fitch TC, Karg MM, Butcher ER, Nnuji-John E, Kim LA, Saint-Geniez M. Dimethyl Fumarate Blocks Tumor Necrosis Factor-Alpha-Driven Inflammation and Metabolic Rewiring in the Retinal Pigment Epithelium. Front Mol Neurosci 2022; 15:896786. [PMID: 35813071 PMCID: PMC9259930 DOI: 10.3389/fnmol.2022.896786] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2022] [Accepted: 05/25/2022] [Indexed: 11/13/2022] Open
Abstract
The retinal pigment epithelium (RPE) acts as a metabolic gatekeeper between photoreceptors and the choroidal vasculature to maintain retinal function. RPE dysfunction is a key feature of age-related macular degeneration (AMD), the leading cause of blindness in developed countries. Inflammation is a key pathogenic mechanism in AMD and tumor necrosis factor-alpha (TNFα) has been implicated as a pro-inflammatory cytokine involved in AMD. While mitochondrial dysfunction has been implicated in AMD pathogenesis, the interplay between inflammation and cellular metabolism remains elusive. The present study explores how the pro-inflammatory cytokine, TNFα, impacts mitochondrial morphology and metabolic function in RPE. Matured human primary RPE (H-RPE) were treated with TNFα (10 ng/ml) for up to 5 days. TNFα-induced upregulation of IL-6 secretion and inflammatory genes (IL-6, IL-8, MCP-1) was accompanied by increased oxidative phosphorylation (OXPHOS) and reduced glycolysis, leading to an increase in cellular adenosine triphosphate (ATP) content. Transmission electron microscopy (TEM) revealed defects in mitochondrial morphology with engorged mitochondria and loss of cristae integrity following TNFα treatment. Pre-treatment with the anti-inflammatory drug, 80 μM dimethyl fumarate (DMFu), blocked TNFα-induced inflammatory activation of RPE (IL-6, IL-8, MCP-1, CFH, CFB, C3) and normalized their bioenergetic profile to control levels by regulating PFKFB3 and PKM2 gene expression. Furthermore, DMFu prevented TNFα-induced mitochondrial dysfunction and morphological anomalies. Thus, our results indicate that DMFu serves as a novel therapeutic avenue for combating inflammatory activation and metabolic dysfunction of RPE in AMD.
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Affiliation(s)
- Daisy Y. Shu
- Schepens Eye Research Institute of Massachusetts Eye and Ear, Boston, MA, United States
- Department of Ophthalmology, Harvard Medical School, Boston, MA, United States
| | - Scott I. Frank
- Schepens Eye Research Institute of Massachusetts Eye and Ear, Boston, MA, United States
| | - Tessa C. Fitch
- Schepens Eye Research Institute of Massachusetts Eye and Ear, Boston, MA, United States
| | - Margarete M. Karg
- Schepens Eye Research Institute of Massachusetts Eye and Ear, Boston, MA, United States
- Department of Ophthalmology, Harvard Medical School, Boston, MA, United States
| | - Erik R. Butcher
- Schepens Eye Research Institute of Massachusetts Eye and Ear, Boston, MA, United States
| | - Emmanuella Nnuji-John
- Schepens Eye Research Institute of Massachusetts Eye and Ear, Boston, MA, United States
- Cold Spring Harbor Laboratory, School of Biological Sciences, Cold Spring Harbor, NY, United States
| | - Leo A. Kim
- Schepens Eye Research Institute of Massachusetts Eye and Ear, Boston, MA, United States
- Department of Ophthalmology, Harvard Medical School, Boston, MA, United States
| | - Magali Saint-Geniez
- Schepens Eye Research Institute of Massachusetts Eye and Ear, Boston, MA, United States
- Department of Ophthalmology, Harvard Medical School, Boston, MA, United States
- *Correspondence: Magali Saint-Geniez,
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29
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Kim J, Won JY. Effect of Photobiomodulation in Suppression of Oxidative Stress on Retinal Pigment Epithelium. Int J Mol Sci 2022; 23:ijms23126413. [PMID: 35742861 PMCID: PMC9224180 DOI: 10.3390/ijms23126413] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2022] [Revised: 06/04/2022] [Accepted: 06/07/2022] [Indexed: 11/16/2022] Open
Abstract
As the world undergoes aging, the number of age-related diseases has increased. One of them is disease related to retinal pigment epithelium (RPE) degeneration, such as age-related macular degeneration, causing vision loss without physical damage in the ocular system. It is the leading cause of blindness, with no cure. Although the exact pathogenesis is still unknown, the research shows that oxidative stress is one of the risk factors. Various molecules have been reported as anti-oxidative materials; however, the disease has not yet been conquered. Here, we would like to introduce photobiomodulation (PBM). PBM is a non-invasive treatment based on red and near-infrared light and has been used to cure various diseases by regulating cellular functions. Furthermore, recent studies showed its antioxidant effect, and due to this reason, PBM is arising as a new treatment for ocular disease. In this study, we confirm the antioxidant effect of PBM in retinal pigment epithelium via an RPE model with hypoxia. The function of RPE is protected by PBM against damage from hypoxia. Furthermore, we observed the protective mechanism of PBM by its suppression effect on reactive oxygen species generation. These results indicate that PBM shows great potential to cure RPE degeneration to help patients with blindness.
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Affiliation(s)
- Jongmin Kim
- Department of Mechanical Engineering, Pohang University of Science and Technology (POSTECH), Pohang 37673, Korea;
| | - Jae Yon Won
- Department of Ophthalmology and Visual Science, Eunpyeong St. Mary’s Hospital, The Catholic University of Korea, Seoul 03312, Korea
- Catholic Institute for Visual Science, College of Medicine, The Catholic University of Korea, Seoul 14662, Korea
- Correspondence:
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30
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Luo S, Xu H, Gong X, Shen J, Chen X, Wu Z. The complement C3a‑C3aR and C5a‑C5aR pathways promote viability and inflammation of human retinal pigment epithelium cells by targeting NF‑κB signaling. Exp Ther Med 2022; 24:493. [PMID: 35837068 PMCID: PMC9257899 DOI: 10.3892/etm.2022.11420] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2022] [Accepted: 04/08/2022] [Indexed: 11/05/2022] Open
Abstract
Retinal detachment (RD) and its special form of rhegmatogenous RD associated with choroidal detachment (RRDCD) feature similar pathological alterations, including enhanced retinal cell inflammation. Although the importance of the complement components C3a and C5a and their corresponding receptors in retinal maintenance has been demonstrated, the relevance of these molecules to the pathogenesis of RD or RRDCD remains to be investigated. The contents of C3a, C5a and inflammatory factors, such as TNF-α, IL-1β, IL-6 and prostaglandin (PG)E2, in related clinical samples were examined by ELISA. Subsequently, human retinal pigment epithelial (HRPE) cells were subjected to challenge with the C3a and C5a recombinant proteins with or without C3a and C5a antagonists and NF-κB inhibitor, and the cell viability and inflammatory cytokines were then determined by a Cell Counting Kit-8 assay and ELISA, respectively. In addition, reverse transcription-quantitative PCR and western blot analyses were utilized to examine the mRNA or/and protein levels of C3a and its receptor C3aR, as well as C5a and its receptor C5aR, and NF-κB. In addition, the correlation of C3a and C5a with the aforementioned inflammatory factors was analyzed. The inflammatory factor levels of C3a and C5a were considerably elevated in patients with RRDCD compared to those in the controls. Consistently, C3a and C5a treatment led to increased cell viability and aggravated inflammation in HRPE cells. Accordingly, C3a and C5a induced upregulation of their corresponding receptors C3aR and C5aR, which was in turn observed to be linked to the activation of the NF-κB signaling pathway. Furthermore, there was a positive correlation of the complements C3a and C5a with individual TNF-α, IL-1β, IL-6 and PGE2. Taken together, the C3a-C3aR and C5a-C5aR pathways were indicated to promote cell viability and inflammation of HRPE cells by targeting the NF-κB signaling pathway.
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Affiliation(s)
- Shasha Luo
- Department of Ophthalmology, Nanjing Medical University Affiliated Wuxi Second Hospital, Wuxi, Jiangsu 214002, P.R. China
| | - Huiyan Xu
- Department of Ophthalmology, Nanjing Medical University Affiliated Wuxi Second Hospital, Wuxi, Jiangsu 214002, P.R. China
| | - Xuechun Gong
- Department of Ophthalmology, Nanjing Medical University Affiliated Wuxi Second Hospital, Wuxi, Jiangsu 214002, P.R. China
| | - Jinyan Shen
- Department of Ophthalmology, Nanjing Medical University Affiliated Wuxi Second Hospital, Wuxi, Jiangsu 214002, P.R. China
| | - Xuan Chen
- Department of Ophthalmology, Nanjing Medical University Affiliated Wuxi Second Hospital, Wuxi, Jiangsu 214002, P.R. China
| | - Zhifeng Wu
- Department of Ophthalmology, Nanjing Medical University Affiliated Wuxi Second Hospital, Wuxi, Jiangsu 214002, P.R. China
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Hung LT, Poon SHL, Yan WH, Lace R, Zhou L, Wong JKW, Williams RL, Shih KC, Shum HC, Chan YK. Scaffold-Free Strategy Using a PEG-Dextran Aqueous Two-Phase-System for Corneal Tissue Repair. ACS Biomater Sci Eng 2022; 8:1987-1999. [PMID: 35362956 DOI: 10.1021/acsbiomaterials.1c01500] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Abstract
Forming thin tissue constructs with minimal extracellular matrix surrounding them is important for tissue engineering applications. Here, we explore and optimize a strategy that enables rapid fabrication of scaffold-free corneal tissue constructs using the liquid-liquid interface of an aqueous two-phase system (ATPS) that is based on biocompatible polymers, dextran and polyethylene glycol. Intact tissue-like constructs, made of corneal epithelial or endothelial cells, can be formed on the interface between the two liquid phases of ATPS within hours and subsequently collected simply by removing the liquid phases. The formed corneal cell constructs express essential physiological markers and have preserved viability and proliferative ability in vitro. The corneal epithelial cell constructs are also able to re-epithelialize the corneal epithelial wound in vitro. The results suggest the promise of our reported strategy in corneal repair.
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Affiliation(s)
- Lap Tak Hung
- Department of Mechanical Engineering, Faculty of Engineering, University of Hong Kong, Rm 7-25, Haking Wong Building, Pokfulam Road, Hong Kong SAR 999077, China
| | - Stephanie Hiu Ling Poon
- Department of Ophthalmology, Li Ka Shing Faculty of Medicine, University of Hong Kong, 301B Cyberport 4, 100 Cyberport Road, Pokfulam, Hong Kong SAR 999077, China
| | - Wing Huen Yan
- Department of Ophthalmology, Li Ka Shing Faculty of Medicine, University of Hong Kong, 301B Cyberport 4, 100 Cyberport Road, Pokfulam, Hong Kong SAR 999077, China
| | - Rebecca Lace
- Department of Eye and Vision Sciences, Institute of Life Course and Medical Sciences, University of Liverpool, William Henry Duncan Building, 6 West Derby Street, Liverpool L7 8TX, U.K
| | - Liangyu Zhou
- Department of Ophthalmology, Li Ka Shing Faculty of Medicine, University of Hong Kong, 301B Cyberport 4, 100 Cyberport Road, Pokfulam, Hong Kong SAR 999077, China
| | - Jasper Ka Wai Wong
- Department of Ophthalmology, Li Ka Shing Faculty of Medicine, University of Hong Kong, 301B Cyberport 4, 100 Cyberport Road, Pokfulam, Hong Kong SAR 999077, China
| | - Rachel L Williams
- Department of Eye and Vision Sciences, Institute of Life Course and Medical Sciences, University of Liverpool, William Henry Duncan Building, 6 West Derby Street, Liverpool L7 8TX, U.K
| | - Kendrick Co Shih
- Department of Ophthalmology, Li Ka Shing Faculty of Medicine, University of Hong Kong, 301B Cyberport 4, 100 Cyberport Road, Pokfulam, Hong Kong SAR 999077, China
| | - Ho Cheung Shum
- Department of Mechanical Engineering, Faculty of Engineering, University of Hong Kong, Rm 7-25, Haking Wong Building, Pokfulam Road, Hong Kong SAR 999077, China
| | - Yau Kei Chan
- Department of Ophthalmology, Li Ka Shing Faculty of Medicine, University of Hong Kong, 301B Cyberport 4, 100 Cyberport Road, Pokfulam, Hong Kong SAR 999077, China
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32
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Kim KL, Joo K, Park SJ, Park KH, Woo SJ. Progression from intermediate to neovascular age-related macular degeneration according to drusen subtypes: Bundang AMD cohort study report 3. Acta Ophthalmol 2022; 100:e710-e718. [PMID: 34390191 DOI: 10.1111/aos.14960] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2020] [Revised: 06/01/2021] [Accepted: 06/17/2021] [Indexed: 01/07/2023]
Abstract
PURPOSE To investigate the ophthalmic risk factors related to neovascular change and the subtype-wise incidence of progression from intermediate to neovascular age-related macular degeneration (AMD). METHODS In this retrospective cohort study, 632 eyes with intermediate AMD from 418 patients (older than 50 years) were enrolled. The systemic factors and ophthalmic factors were statistically analysed with respect to neovascular change. RESULTS The 5-year cumulative incidence of progression to neovascular AMD (nAMD) from intermediate AMD was 17.8% and 17.0% in eyes with soft drusen and pachydrusen (p = 0.316). Older age (p = 0.025), preexisting nAMD in the fellow eye (p < 0.001), and reticular pseudodrusen (RPD; p = 0.007) were associated with the risk of progression to nAMD. In reference to soft drusen, pachydrusen was associated with progression to polypoidal choroidal vasculopathy (PCV; p < 0.001) and not to typical nAMD (p = 0.064). CONCLUSIONS The ophthalmic risk factors related to the progression of nAMD from intermediate AMD were found to be preexisting nAMD in the fellow eye and RPD. Pachydrusen showed a similar incidence of neovascular change with soft drusen, and was associated with the progression to PCV but not to typical nAMD.
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Affiliation(s)
- Kyoung Lae Kim
- Department of Ophthalmology Seoul National University College of Medicine Seoul National University Bundang Hospital Seongnam Korea
- Department of Ophthalmology Gangwon National University College of Medicine Gangwon National University Hospital Chuncheon Korea
| | - Kwangsic Joo
- Department of Ophthalmology Seoul National University College of Medicine Seoul National University Bundang Hospital Seongnam Korea
| | - Sang Jun Park
- Department of Ophthalmology Seoul National University College of Medicine Seoul National University Bundang Hospital Seongnam Korea
| | - Kyu Hyung Park
- Department of Ophthalmology Seoul National University College of Medicine Seoul National University Bundang Hospital Seongnam Korea
| | - Se Joon Woo
- Department of Ophthalmology Seoul National University College of Medicine Seoul National University Bundang Hospital Seongnam Korea
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Aloperine: A Potent Modulator of Crucial Biological Mechanisms in Multiple Diseases. Biomedicines 2022; 10:biomedicines10040905. [PMID: 35453655 PMCID: PMC9028564 DOI: 10.3390/biomedicines10040905] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2022] [Revised: 03/30/2022] [Accepted: 03/31/2022] [Indexed: 01/18/2023] Open
Abstract
Aloperine is an alkaloid found in the seeds and leaves of the medicinal plant Sophora alopecuroides L. It has been used as herbal medicine in China for centuries due to its potent anti-inflammatory, antioxidant, antibacterial, and antiviral properties. Recently, aloperine has been widely investigated for its therapeutic activities. Aloperine is proven to be an effective therapeutic agent against many human pathological conditions, including cancer, viral diseases, and cardiovascular and inflammatory disorders. Aloperine is reported to exert therapeutic effects through triggering various biological processes, including cell cycle arrest, apoptosis, autophagy, suppressing cell migration, and invasion. It has also been found to be associated with the modulation of various signaling pathways in different diseases. In this review, we summarize the most recent knowledge on the modulatory effects of aloperine on various critical biological processes and signaling mechanisms, including the PI3K, Akt, NF-κB, Ras, and Nrf2 pathways. These data demonstrate that aloperine is a promising therapeutic candidate. Being a potent modulator of signaling mechanisms, aloperine can be employed in clinical settings to treat various human disorders in the future.
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Badiei A, Beltran WA, Aguirre GD. Altered transsulfuration pathway enzymes and redox homeostasis in inherited retinal degenerative diseases. Exp Eye Res 2022; 215:108902. [PMID: 34954206 PMCID: PMC8923955 DOI: 10.1016/j.exer.2021.108902] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2021] [Revised: 12/04/2021] [Accepted: 12/15/2021] [Indexed: 02/03/2023]
Abstract
Retinal degenerative diseases result from apoptotic photoreceptor cell death. As endogenously produced gaseous molecules such as hydrogen sulfide (H2S) and nitric oxide (NO) play a key role in apoptosis, we compared the expression levels of genes and proteins involved in the production of these molecules in the retina of normal dogs and three canine models (rcd1, crd2, and xlpra2) of human inherited retinal degeneration (IRD). Using qRT-PCR, Western blot, and immunohistochemistry (IHC), we showed that mRNA and protein levels of cystathionine β-synthase (CBS), an enzyme that produces H2S in neurons, are increased in retinal degeneration, but those of cystathionine γ-lyase (CSE), an enzyme involved in the production of glutathione (GSH), an antioxidant, are not. Such findings suggest that increased levels of H2S that are not counterbalanced by increased antioxidant potential may contribute to disease in affected retinas. We also studied the expression of neuronal and inducible nitric oxide synthase (nNOS and iNOS), the enzymes responsible for NO production. Western blot and IHC results revealed increased levels of nNOS and iNOS, resulting in increased NO levels in mutant retinas. Finally, photoreceptors are rich in polyunsaturated fatty acids (PUFAs) that can make these cells vulnerable to oxidative damage through reactive oxygen species (ROS). Our results showed increased levels of acrolein and hydroxynonenal (4HNE), two main toxic products of PUFAs, surrounding the membranes of photoreceptors in affected canines. Increased levels of these toxic products, together with increased NO and ROS, likely render these cells susceptible to an intrinsic apoptotic pathway involving mitochondrial membranes. To assess this possibility, we measured the levels of BCL2, an anti-apoptotic protein in the mitochondrial membrane. Western blot results showed decreased levels of BCL2 protein in affected retinas. Overall, the results of this study identify alterations in the expression of enzymes directly involved in maintaining the normal redox status of the retina during retinal degeneration, thereby supporting future studies to investigate the role of H2S and NO in retinal degeneration and apoptosis.
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Affiliation(s)
- Alireza Badiei
- Department of Veterinary Medicine, College of Natural Science and Mathematics, University of Alaska Fairbanks, AK, USA; Division of Experimental Retinal Therapies, Department of Clinical Sciences and Advanced Medicine, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA, USA.
| | - William A Beltran
- Division of Experimental Retinal Therapies, Department of Clinical Sciences and Advanced Medicine, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Gustavo D Aguirre
- Division of Experimental Retinal Therapies, Department of Clinical Sciences and Advanced Medicine, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA, USA.
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35
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Raimondi R, Zollet P, De Rosa FP, Tsoutsanis P, Stravalaci M, Paulis M, Inforzato A, Romano MR. Where Are We with RPE Replacement Therapy? A Translational Review from the Ophthalmologist Perspective. Int J Mol Sci 2022; 23:ijms23020682. [PMID: 35054869 PMCID: PMC8775975 DOI: 10.3390/ijms23020682] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2021] [Revised: 12/28/2021] [Accepted: 12/30/2021] [Indexed: 02/06/2023] Open
Abstract
The retinal pigmented epithelium (RPE) plays a pivotal role in retinal homeostasis. It is therefore an interesting target to fill the unmet medical need of different retinal diseases, including age-related macular degeneration and Stargardt disease. RPE replacement therapy may use different cellular sources: induced pluripotent stem cells or embryonic stem cells. Cells can be transferred as suspension on a patch with different surgical approaches. Results are promising although based on very limited samples. In this review, we summarize the current progress of RPE replacement and provide a comparative assessment of different published approaches which may become standard of care in the future.
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Affiliation(s)
- Raffaele Raimondi
- IRCCS Humanitas Research Hospital, Via Manzoni 56, 20089 Rozzano–Milan, Italy; (P.Z.); (M.S.); (M.P.); (A.I.)
- Department of Biomedical Sciences, Humanitas University, Via Rita Levi Montalcini 4, 20072 Pieve Emanuele–Milan, Italy; (F.P.D.R.); (P.T.); (M.R.R.)
- Correspondence:
| | - Piero Zollet
- IRCCS Humanitas Research Hospital, Via Manzoni 56, 20089 Rozzano–Milan, Italy; (P.Z.); (M.S.); (M.P.); (A.I.)
- Department of Biomedical Sciences, Humanitas University, Via Rita Levi Montalcini 4, 20072 Pieve Emanuele–Milan, Italy; (F.P.D.R.); (P.T.); (M.R.R.)
| | - Francesco Paolo De Rosa
- Department of Biomedical Sciences, Humanitas University, Via Rita Levi Montalcini 4, 20072 Pieve Emanuele–Milan, Italy; (F.P.D.R.); (P.T.); (M.R.R.)
| | - Panagiotis Tsoutsanis
- Department of Biomedical Sciences, Humanitas University, Via Rita Levi Montalcini 4, 20072 Pieve Emanuele–Milan, Italy; (F.P.D.R.); (P.T.); (M.R.R.)
| | - Matteo Stravalaci
- IRCCS Humanitas Research Hospital, Via Manzoni 56, 20089 Rozzano–Milan, Italy; (P.Z.); (M.S.); (M.P.); (A.I.)
- Department of Biomedical Sciences, Humanitas University, Via Rita Levi Montalcini 4, 20072 Pieve Emanuele–Milan, Italy; (F.P.D.R.); (P.T.); (M.R.R.)
| | - Marianna Paulis
- IRCCS Humanitas Research Hospital, Via Manzoni 56, 20089 Rozzano–Milan, Italy; (P.Z.); (M.S.); (M.P.); (A.I.)
- Institute of Genetic and Biomedical Research (IRGB), UOS of Milan, National Research Council of Italy, 20138 Milan, Italy
| | - Antonio Inforzato
- IRCCS Humanitas Research Hospital, Via Manzoni 56, 20089 Rozzano–Milan, Italy; (P.Z.); (M.S.); (M.P.); (A.I.)
- Department of Biomedical Sciences, Humanitas University, Via Rita Levi Montalcini 4, 20072 Pieve Emanuele–Milan, Italy; (F.P.D.R.); (P.T.); (M.R.R.)
| | - Mario R. Romano
- Department of Biomedical Sciences, Humanitas University, Via Rita Levi Montalcini 4, 20072 Pieve Emanuele–Milan, Italy; (F.P.D.R.); (P.T.); (M.R.R.)
- Eye Center, Humanitas Gavazzeni-Castelli, 24128 Bergamo, Italy
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36
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Chang YH, Kumar VB, Wen YT, Huang CY, Tsai RK, Ding DC. Induction of Human Umbilical Mesenchymal Stem Cell Differentiation Into Retinal Pigment Epithelial Cells Using a Transwell-Based Co-culture System. Cell Transplant 2022; 31:9636897221085901. [PMID: 35321565 PMCID: PMC8961389 DOI: 10.1177/09636897221085901] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/02/2022] Open
Abstract
There is an increasing interest in generating retinal pigment epithelial (RPE)
cells from stem cells for treating degenerative eye diseases. However, whether
human umbilical cord mesenchymal stem cells (HUCMSCs) can differentiate into
RPE-like cells in a co-culture system has not been fully understood. In this
study, induction of HUCMSC differentiation into RPE-like cells was performed by
co-culturing HUCMSCs and a human RPE-like cell line (ARPE19) in a transwell
system and then analyzed for biomarkers using quantitative reverse transcription
polymerase chain reaction (RT-PCR) and immunofluorescence staining technique.
Moreover, the functional characterization of induced cells was carried out by
examining their phagocytic and neurotrophic factor–secreting activities. Our
results showed that mRNA expressions of RPE-specific markers—MITF, OTX2, RPE65,
PEDF, PME17, and CRALBP—and protein markers—RPE65, CRALBP, and ZO-1—were
significantly increased in HUCMSC-derived RPE-like cells. Functional
characteristic studies showed that these induced cells were capable of engulfing
photoreceptor outer segments and secreting brain-derived neurotrophic factor
(BDNF) and glial-derived neurotrophic factor (GDNF), which are typical functions
of RPE-like cells. Overall, the study findings indicate that the morphology and
proliferation of HUCMSCs can be maintained in a serum-free medium, and
differentiation into RPE-like cells can be induced by simply co-culturing
HUCMSCs with ARPE19 cells. Thus, the study provides fundamental information
regarding the clinical-scale generation of RPE-like cells from HUCMSCs.
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Affiliation(s)
- Yu-Hsun Chang
- Department of Pediatrics, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Foundation and Tzu Chi University, Hualien
| | - V Bharath Kumar
- Department of Medical Laboratory Science and Biotechnology, Asia University, Taichung
| | - Yao-Tseng Wen
- Department of Ophthalmology, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Foundation and Tzu Chi University, Hualien
| | - Chih-Yang Huang
- Department of Medical Laboratory Science and Biotechnology, Asia University, Taichung.,Department of Chinese Medicine, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Hualien.,Graduate Institute of Biomedical Sciences, China Medical University, Taichung.,Center of General Education, Buddhist Tzu Chi Medical Foundation, Tzu Chi University of Science and Technology, Hualien.,Department of Medical Research, China Medical University Hospital, China Medical University, Taichung
| | - Rong-Kung Tsai
- Department of Ophthalmology, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Foundation and Tzu Chi University, Hualien
| | - Dah-Ching Ding
- Department of Obstetrics and Gynecology, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Foundation and Tzu Chi University, Hualien.,Institute of Medical Sciences, Tzu Chi University, Hualien
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German OL, Vallese-Maurizi H, Soto TB, Rotstein NP, Politi LE. Retina stem cells, hopes and obstacles. World J Stem Cells 2021; 13:1446-1479. [PMID: 34786153 PMCID: PMC8567457 DOI: 10.4252/wjsc.v13.i10.1446] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/28/2021] [Revised: 07/14/2021] [Accepted: 09/17/2021] [Indexed: 02/07/2023] Open
Abstract
Retinal degeneration is a major contributor to visual dysfunction worldwide. Although it comprises several eye diseases, loss of retinal pigment epithelial (RPE) and photoreceptor cells are the major contributors to their pathogenesis. Early therapies included diverse treatments, such as provision of anti-vascular endothelial growth factor and many survival and trophic factors that, in some cases, slow down the progression of the degeneration, but do not effectively prevent it. The finding of stem cells (SC) in the eye has led to the proposal of cell replacement strategies for retina degeneration. Therapies using different types of SC, such as retinal progenitor cells (RPCs), embryonic SC, pluripotent SCs (PSCs), induced PSCs (iPSCs), and mesenchymal stromal cells, capable of self-renewal and of differentiating into multiple cell types, have gained ample support. Numerous preclinical studies have assessed transplantation of SC in animal models, with encouraging results. The aim of this work is to revise the different preclinical and clinical approaches, analyzing the SC type used, their efficacy, safety, cell attachment and integration, absence of tumor formation and immunorejection, in order to establish which were the most relevant and successful. In addition, we examine the questions and concerns still open in the field. The data demonstrate the existence of two main approaches, aimed at replacing either RPE cells or photoreceptors. Emerging evidence suggests that RPCs and iPSC are the best candidates, presenting no ethical concerns and a low risk of immunorejection. Clinical trials have already supported the safety and efficacy of SC treatments. Serious concerns are pending, such as the risk of tumor formation, lack of attachment or integration of transplanted cells into host retinas, immunorejection, cell death, and also ethical. However, the amazing progress in the field in the last few years makes it possible to envisage safe and effective treatments to restore vision loss in a near future.
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Affiliation(s)
- Olga L German
- Department of Biology, Biochemistry and Pharmacy, Universidad Nacional del Sur, Bahia blanca 8000, Buenos Aires, Argentina
- Department of Biology, Biochemistry and Pharmacy, Universidad Nacional del Sur, and Neurobiology Department, Instituto de Investigaciones Bioquímicas de Bahía Blanca (INIBIBB) Conicet, Bahía Blanca 8000, Buenos Aires, Argentina
| | - Harmonie Vallese-Maurizi
- Department of Biology, Biochemistry and Pharmacy, Universidad Nacional del Sur, Bahia blanca 8000, Buenos Aires, Argentina
- Department of Biology, Biochemistry and Pharmacy, Universidad Nacional del Sur, and Neurobiology Department, Instituto de Investigaciones Bioquímicas de Bahía Blanca (INIBIBB) Conicet, Bahía Blanca 8000, Buenos Aires, Argentina
| | - Tamara B Soto
- Department of Biology, Biochemistry and Pharmacy, Universidad Nacional del Sur, and Neurobiology Department, Instituto de Investigaciones Bioquímicas de Bahía Blanca (INIBIBB) Conicet, Bahía Blanca 8000, Buenos Aires, Argentina
| | - Nora P Rotstein
- Department of Biology, Biochemistry and Pharmacy, Universidad Nacional del Sur, Bahia blanca 8000, Buenos Aires, Argentina
- Department of Biology, Biochemistry and Pharmacy, Universidad Nacional del Sur, and Neurobiology Department, Instituto de Investigaciones Bioquímicas de Bahía Blanca (INIBIBB) Conicet, Bahía Blanca 8000, Buenos Aires, Argentina
| | - Luis Enrique Politi
- Department of Biology, Biochemistry and Pharmacy, Universidad Nacional del Sur, and Neurobiology Department, Instituto de Investigaciones Bioquímicas de Bahía Blanca (INIBIBB) Conicet, Bahía Blanca 8000, Buenos Aires, Argentina
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38
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Xu J, Liu X, Zhang X, Marshall B, Dong Z, Smith SB, Espinosa-Heidmann DG, Zhang M. Retinal and Choroidal Pathologies in Aged BALB/c Mice Following Systemic Neonatal Murine Cytomegalovirus Infection. THE AMERICAN JOURNAL OF PATHOLOGY 2021; 191:1787-1804. [PMID: 34197777 PMCID: PMC8485058 DOI: 10.1016/j.ajpath.2021.06.008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/16/2021] [Revised: 06/04/2021] [Accepted: 06/14/2021] [Indexed: 11/30/2022]
Abstract
Although pathologies associated with acute virus infections have been extensively studied, the effects of long-term latent virus infections are less well understood. Human cytomegalovirus, which infects 50% to 80% of humans, is usually acquired during early life and persists in a latent state for the lifetime. The purpose of this study was to determine whether systemic murine cytomegalovirus (MCMV) infection acquired early in life disseminates to and becomes latent in the eye and if ocular MCMV can trigger in situ inflammation and occurrence of ocular pathology. This study found that neonatal infection of BALB/c mice with MCMV resulted in dissemination of virus to the eye, where it localized principally to choroidal endothelia and pericytes and less frequently to the retinal pigment epithelium (RPE) cells. MCMV underwent ocular latency, which was associated with expression of multiple virus genes and from which MCMV could be reactivated by immunosuppression. Latent ocular infection was associated with significant up-regulation of several inflammatory/angiogenic factors. Retinal and choroidal pathologies developed in a progressive manner, with deposits appearing at both basal and apical aspects of the RPE, RPE/choroidal atrophy, photoreceptor degeneration, and neovascularization. The pathologies induced by long-term ocular MCMV latency share features of previously described human ocular diseases, such as age-related macular degeneration.
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Affiliation(s)
- Jinxian Xu
- Department of Cellular Biology and Anatomy, Medical College of Georgia, Augusta University, Augusta, Georgia; James and Jean Vision Discovery Institute, Medical College of Georgia, Augusta University, Augusta, Georgia
| | - Xinglou Liu
- Department of Cellular Biology and Anatomy, Medical College of Georgia, Augusta University, Augusta, Georgia; James and Jean Vision Discovery Institute, Medical College of Georgia, Augusta University, Augusta, Georgia
| | - Xinyan Zhang
- Department of Cellular Biology and Anatomy, Medical College of Georgia, Augusta University, Augusta, Georgia; James and Jean Vision Discovery Institute, Medical College of Georgia, Augusta University, Augusta, Georgia
| | - Brendan Marshall
- Department of Cellular Biology and Anatomy, Medical College of Georgia, Augusta University, Augusta, Georgia
| | - Zheng Dong
- Department of Cellular Biology and Anatomy, Medical College of Georgia, Augusta University, Augusta, Georgia; Charlie Norwood Veterans Affairs Medical Center, Augusta, Georgia
| | - Sylvia B Smith
- Department of Cellular Biology and Anatomy, Medical College of Georgia, Augusta University, Augusta, Georgia; James and Jean Vision Discovery Institute, Medical College of Georgia, Augusta University, Augusta, Georgia; Department of Ophthamology, Medical College of Georgia, Augusta University, Augusta, Georgia
| | - Diego G Espinosa-Heidmann
- James and Jean Vision Discovery Institute, Medical College of Georgia, Augusta University, Augusta, Georgia; Department of Ophthamology, Medical College of Georgia, Augusta University, Augusta, Georgia
| | - Ming Zhang
- Department of Cellular Biology and Anatomy, Medical College of Georgia, Augusta University, Augusta, Georgia; James and Jean Vision Discovery Institute, Medical College of Georgia, Augusta University, Augusta, Georgia.
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Muste JC, Russell MW, Singh RP. Photobiomodulation Therapy for Age-Related Macular Degeneration and Diabetic Retinopathy: A Review. Clin Ophthalmol 2021; 15:3709-3720. [PMID: 34511875 PMCID: PMC8421781 DOI: 10.2147/opth.s272327] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2021] [Accepted: 08/24/2021] [Indexed: 01/11/2023] Open
Abstract
Purpose Photobiomodulation therapy (PBT) has emerged as a possible treatment for age-related macular degeneration (AMD) and diabetic retinopathy (DR). This review seeks to summarize the application of PBT in AMD and DR. Methods The National Clinical Trial (NCT) database and PubMed were queried using a literature search strategy and reviewed by the authors. Results Fourteen studies examining the application of PBT for AMD and nine studies examining the application of PBT for diabetic macular edema (DME) were extracted from 60 candidate publications. Discussion Despite notable methodological differences between studies, PBT has been reported to treat certain DR and AMD patients. DR patients with center involving DME and VA ≥ 20/25 have demonstrated response to treatment. AMD patients at Age-Related Eye Disease Study Stages 2–4 with VA ≥20/200 have also shown response to treatment. Results of major clinical trials are pending. Conclusion PBT remains an emergent therapy with possible applications in DR and AMD. Further, high powered studies monitored by a neutral party with standard devices, treatment delivery and treatment timing are needed.
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Affiliation(s)
- Justin C Muste
- Center for Ophthalmic Bioinformatics, Cole Eye Institute, Cleveland Clinic, Cleveland, Ohio, USA
| | - Matthew W Russell
- Center for Ophthalmic Bioinformatics, Cole Eye Institute, Cleveland Clinic, Cleveland, Ohio, USA
| | - Rishi P Singh
- Center for Ophthalmic Bioinformatics, Cole Eye Institute, Cleveland Clinic, Cleveland, Ohio, USA
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40
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Caras IW, Collins LR, Creasey AA. A stem cell JOURNEY IN OPHTHALMOLOGY: From the bench to the clinic. Stem Cells Transl Med 2021; 10:1581-1587. [PMID: 34515419 PMCID: PMC8641078 DOI: 10.1002/sctm.21-0239] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2021] [Revised: 08/05/2021] [Accepted: 08/21/2021] [Indexed: 01/10/2023] Open
Abstract
Debilitating diseases of the eye represent a large unmet medical need potentially addressable with stem cell-based approaches. Over the past decade, the California Institute for Regenerative Medicine (CIRM) has funded and supported the translation, from early research concepts to human trials, of therapeutic stem cell approaches for dry age-related macular degeneration, retinitis pigmentosa, and limbal stem cell deficiency. This article chronicles CIRM's journey in the ophthalmology field and discusses some key challenges and questions that were addressed along the way as well as questions that remain.
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Affiliation(s)
- Ingrid W Caras
- The California Institute for Regenerative Medicine, Oakland, California, USA
| | - Lila R Collins
- The California Institute for Regenerative Medicine, Oakland, California, USA
| | - Abla A Creasey
- The California Institute for Regenerative Medicine, Oakland, California, USA
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41
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Wang Y, Zhang Q, Yang G, Wei Y, Li M, Du E, Li H, Song Z, Tao Y. RPE-derived exosomes rescue the photoreceptors during retina degeneration: an intraocular approach to deliver exosomes into the subretinal space. Drug Deliv 2021; 28:218-228. [PMID: 33501868 PMCID: PMC7850421 DOI: 10.1080/10717544.2020.1870584] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/03/2022] Open
Abstract
Retinal degeneration (RD) refers to a group of blinding retinopathies leading to the progressive photoreceptor demise and vision loss. Treatments against this debilitating disease are urgently needed. Intraocular delivery of exosomes represents an innovative therapeutic strategy against RD. In this study, we aimed to determine whether the subretinal delivery of RPE-derived exosomes (RPE-Exos) can prevent the photoreceptor death in RD. RD was induced in C57BL6 mice by MNU administration. These MNU administered mice received a single subretinal injection of RPE-Exos. Two weeks later, the RPE-Exos induced effects were evaluated via functional, morphological, and behavior examinations. Subretinal delivery of RPE-Exos efficiently ameliorates the visual function impairments, and alleviated the structural damages in the retina of MNU administered mice. Moreover, RPE-Exos exert beneficial effects on the electrical response of the inner retinal circuits. Treatment with RPE-Exos suppressed the expression levels of inflammatory factors, and mitigated the oxidative damage, indicating that subretinal delivery of RPE-Exos constructed a cytoprotective microenvironment in the retina of MNU administered mice. Our data suggest that RPE-Exos have therapeutic effects against the visual impairments and photoreceptor death. These findings will enrich our knowledge of RPE-Exos, and highlight the discovery of a promising medication for RD.
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Affiliation(s)
- Yange Wang
- Department of Ophthalmology, People's Hospital of Zhengzhou University; Department of Physiology, Basic College of Medicine, Zhengzhou University, Zhengzhou, China
| | - Qian Zhang
- Department of Clinical Aerospace Medicine, Fourth Military Medical University, Xi'an, China
| | - Guoqing Yang
- Department of Clinical Aerospace Medicine, Fourth Military Medical University, Xi'an, China
| | - Yuanmeng Wei
- Department of Ophthalmology, People's Hospital of Zhengzhou University; Department of Physiology, Basic College of Medicine, Zhengzhou University, Zhengzhou, China
| | - Miao Li
- Department of Ophthalmology, People's Hospital of Zhengzhou University; Department of Physiology, Basic College of Medicine, Zhengzhou University, Zhengzhou, China
| | - Enming Du
- Department of Ophthalmology, People's Hospital of Zhengzhou University; Department of Physiology, Basic College of Medicine, Zhengzhou University, Zhengzhou, China
| | - Haijun Li
- Department of Ophthalmology, People's Hospital of Zhengzhou University; Department of Physiology, Basic College of Medicine, Zhengzhou University, Zhengzhou, China
| | - Zongming Song
- Department of Ophthalmology, People's Hospital of Zhengzhou University; Department of Physiology, Basic College of Medicine, Zhengzhou University, Zhengzhou, China
| | - Ye Tao
- Department of Ophthalmology, People's Hospital of Zhengzhou University; Department of Physiology, Basic College of Medicine, Zhengzhou University, Zhengzhou, China
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Xu HJ, Li QY, Zou T, Yin ZQ. Development-related mitochondrial properties of retinal pigment epithelium cells derived from hEROs. Int J Ophthalmol 2021; 14:1138-1150. [PMID: 34414076 DOI: 10.18240/ijo.2021.08.02] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2021] [Accepted: 06/21/2021] [Indexed: 11/23/2022] Open
Abstract
AIM To explore the temporal mitochondrial characteristics of retinal pigment epithelium (RPE) cells obtained from human embryonic stem cells (hESC)-derived retinal organoids (hEROs-RPE), to verify the optimal period for using hEROs-RPE as donor cells from the aspect of mitochondria and to optimize RPE cell-based therapeutic strategies for age-related macular degeneration (AMD). METHODS RPE cells were obtained from hEROs and from spontaneous differentiation (SD-RPE). The mitochondrial characteristics were analyzed every 20d from day 60 to 160. Mitochondrial quantity was measured by MitoTracker Green staining. Transmission electron microscopy (TEM) was adopted to assess the morphological features of the mitochondria, including their distribution, length, and cristae. Mitochondrial membrane potentials (MMPs) were determined by JC-1 staining and evaluated by flow cytometry, reactive oxygen species (ROS) levels were evaluated by flow cytometry, and adenosine triphosphate (ATP) levels were measured by a luminometer. Differences between two groups were analyzed by the independent-samples t-test, and comparisons among multiple groups were made using one-way ANOVA or Kruskal-Wallis H test when equal variance was not assumed. RESULTS hEROs-RPE and SD-RPE cells from day 60 to 160 were successfully differentiated from hESCs and expressed RPE markers (Pax6, MITF, Bestrophin-1, RPE65, Cralbp). RPE features, including a cobblestone-like morphology with tight junctions (ZO-1), pigments and microvilli, were also observed in both hEROs-RPE and SD-RPE cells. The mitochondrial quantities of hEROs-RPE and SD-RPE cells both peaked at day 80. However, the cristae of hEROs-RPE mitochondria were less mature and abundant than those of SD-RPE mitochondria at day 80, with hEROs-RPE mitochondria becoming mature at day 100. Both hEROs-RPE and SD-RPE cells showed low ROS levels from day 100 to 140 and maintained a normal MMP during this period. However, hEROs-RPE mitochondria maintained a longer time to produce high levels of ATP (from day 120 to 140) than SD-RPE cells (only day 120). CONCLUSION hEROs-RPE mitochondria develop more slowly and maintain a longer time to supply high-level energy than SD-RPE mitochondria. From the mitochondrial perspective, hEROs-RPE cells from day 100 to 140 are an optimal cell source for treating AMD.
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Affiliation(s)
- Hao-Jue Xu
- Southwest Hospital/Southwest Eye Hospital, Third Military Medical University (Army Medical University), Chongqing 400038, China.,Key Lab of Visual Damage and Regeneration & Restoration of Chongqing, Chongqing 400038, China
| | - Qi-You Li
- Southwest Hospital/Southwest Eye Hospital, Third Military Medical University (Army Medical University), Chongqing 400038, China.,Key Lab of Visual Damage and Regeneration & Restoration of Chongqing, Chongqing 400038, China
| | - Ting Zou
- Southwest Hospital/Southwest Eye Hospital, Third Military Medical University (Army Medical University), Chongqing 400038, China.,Key Lab of Visual Damage and Regeneration & Restoration of Chongqing, Chongqing 400038, China
| | - Zheng-Qin Yin
- Southwest Hospital/Southwest Eye Hospital, Third Military Medical University (Army Medical University), Chongqing 400038, China.,Key Lab of Visual Damage and Regeneration & Restoration of Chongqing, Chongqing 400038, China
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ElShelmani H, Wride MA, Saad T, Rani S, Kelly DJ, Keegan D. The Role of Deregulated MicroRNAs in Age-Related Macular Degeneration Pathology. Transl Vis Sci Technol 2021; 10:12. [PMID: 34003896 PMCID: PMC7881277 DOI: 10.1167/tvst.10.2.12] [Citation(s) in RCA: 31] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022] Open
Abstract
Purpose We previously identified three microRNAs (miRNAs) with significantly increased expression in the serum of patients with age-related macular degeneration (AMD) compared with healthy controls. Our objective was to identify potential functional roles of these upregulated miRNAs (miR-19a, miR-126, and miR-410) in AMD, using computational tools for miRNAs prediction and identification, and to demonstrate the miRNAs target genes and signaling pathways. We also aim to demonstrate the pathologic role of isolated sera-derived exosomes from patients with AMD and controls using in vitro models. Methods miR-19a, miR-126, and miR-410 were investigated using bioinformatic approaches, including DIANA-mirPath and miR TarBase. Data on the resulting target genes and signaling pathways were incorporated with the differentially expressed miRNAs in AMD. Apoptosis markers, human apoptosis miRNAs polymerase chain reaction arrays and angiogenesis/vasculogenesis assays were performed by adding serum-isolated AMD patient or control patient derived exosomes into an in vitro human angiogenesis model and ARPE-19 cell lines. Results A number of pathways known to be involved in AMD development and progression were predicted, including the vascular endothelial growth factor signaling, apoptosis, and neurodegenerative pathways. The study also provides supporting evidence for the involvement of serum-isolated AMD-derived exosomes in the pathology of AMD, via apoptosis and/or angiogenesis. Conclusions miR-19a, miR-126, miR-410 and their target genes had a significant correlation with AMD pathogenesis. As such, they could be potential new targets as predictive biomarkers or therapies for patients with AMD. Translational Relevance The functional analysis and the pathologic role of altered miRNA expression in AMD may be applicable in developing new therapies for AMD through the disruption of individual or multiple pathophysiologic pathways.
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Affiliation(s)
- Hanan ElShelmani
- Ocular Development and Neurobiology Research Group, Zoology Department, School of Natural Sciences, University of Dublin, Trinity College Dublin, Dublin 2, Ireland.,Mater Retina Research Group, Mater Misericordiae University Hospital, Eccles St., Dublin 7, Ireland
| | - Michael A Wride
- Ocular Development and Neurobiology Research Group, Zoology Department, School of Natural Sciences, University of Dublin, Trinity College Dublin, Dublin 2, Ireland
| | - Tahira Saad
- Mater Retina Research Group, Mater Misericordiae University Hospital, Eccles St., Dublin 7, Ireland
| | - Sweta Rani
- Department of Science, Waterford Institute of Technology, Waterford, Ireland
| | - David J Kelly
- Zoology Department, School of Natural Sciences, University of Dublin, Trinity College Dublin, Ireland
| | - David Keegan
- Mater Retina Research Group, Mater Misericordiae University Hospital, Eccles St., Dublin 7, Ireland
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Abstract
In diabetic patients, diabetic retinopathy (DR) is the leading cause of blindness and seriously affects the quality of life. However, current treatment methods of DR are not satisfactory. Advances have been made in understanding abnormal protein interactions and signaling pathways in DR pathology, but little is known about epigenetic regulation. Non-coding RNAs, such as circular RNAs (circRNAs), have been shown to be associated with DR. In this review, we summarized the function of circRNAs and indicated their roles in the pathogenesis of DR, which may provide new therapeutic targets for clinical treatment.
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Affiliation(s)
- Huan-Ran Zhou
- Department of Endocrinology, the First Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Hong-Yu Kuang
- Department of Endocrinology, the First Affiliated Hospital of Harbin Medical University, Harbin, China.
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Broustas CG, Duval AJ, Amundson SA. Impact of aging on gene expression response to x-ray irradiation using mouse blood. Sci Rep 2021; 11:10177. [PMID: 33986387 PMCID: PMC8119453 DOI: 10.1038/s41598-021-89682-7] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2021] [Accepted: 04/27/2021] [Indexed: 02/07/2023] Open
Abstract
As a radiation biodosimetry tool, gene expression profiling is being developed using mouse and human peripheral blood models. The impact of dose, dose-rate, and radiation quality has been studied with the goal of predicting radiological tissue injury. In this study, we determined the impact of aging on the gene expression profile of blood from mice exposed to radiation. Young (2 mo) and old (21 mo) male mice were irradiated with 4 Gy x-rays, total RNA was isolated from whole blood 24 h later, and subjected to whole genome microarray analysis. Pathway analysis of differentially expressed genes revealed young mice responded to x-ray exposure by significantly upregulating pathways involved in apoptosis and phagocytosis, a process that eliminates apoptotic cells and preserves tissue homeostasis. In contrast, the functional annotation of senescence was overrepresented among differentially expressed genes from irradiated old mice without enrichment of phagocytosis pathways. Pathways associated with hematologic malignancies were enriched in irradiated old mice compared with irradiated young mice. The fibroblast growth factor signaling pathway was underrepresented in older mice under basal conditions. Similarly, brain-related functions were underrepresented in unirradiated old mice. Thus, age-dependent gene expression differences should be considered when developing gene signatures for use in radiation biodosimetry.
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Affiliation(s)
- Constantinos G Broustas
- Center for Radiological Research, Columbia University Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, 630 W. 168th St., New York, NY, 10032, USA.
| | - Axel J Duval
- Center for Radiological Research, Columbia University Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, 630 W. 168th St., New York, NY, 10032, USA
| | - Sally A Amundson
- Center for Radiological Research, Columbia University Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, 630 W. 168th St., New York, NY, 10032, USA
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Muste JC, Kalur A, Iyer A, Valentim CCS, Singh RP. Photobiomodulation therapy in age-related macular degeneration. Curr Opin Ophthalmol 2021; 32:225-232. [PMID: 33606405 DOI: 10.1097/icu.0000000000000742] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
PURPOSE OF REVIEW To review the available data supporting the use of photobiomodulation therapy (PBT) in the treatment of age-related macular degeneration (AMD). RECENT FINDINGS PBT might be used in treating nonexudative AMD. Limited evidence suggests that exudative AMD may also benefit from PBT. SUMMARY The optimal device would deliver doses of 60 J/cm2 or more with a multiwavelength composition through the pupil over short treatment intervals. Safe upper limits have not been established. More studies are needed to evaluate the efficacy of PBT in treating exudative and nonexudative AMD.
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Affiliation(s)
- Justin C Muste
- Center for Ophthalmic Bioinformatics, Cole Eye Institute, Cleveland Clinic
| | - Aneesha Kalur
- Center for Ophthalmic Bioinformatics, Cole Eye Institute, Cleveland Clinic
| | - Amogh Iyer
- Center for Ophthalmic Bioinformatics, Cole Eye Institute, Cleveland Clinic
| | | | - Rishi P Singh
- Center for Ophthalmic Bioinformatics, Cole Eye Institute, Cleveland Clinic
- Cole Eye Institute - Retina Service, Cleveland Clinic Foundation, Cleveland, Ohio, USA
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47
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Ferrara M, Lugano G, Sandinha MT, Kearns VR, Geraghty B, Steel DHW. Biomechanical properties of retina and choroid: a comprehensive review of techniques and translational relevance. Eye (Lond) 2021; 35:1818-1832. [PMID: 33649576 PMCID: PMC8225810 DOI: 10.1038/s41433-021-01437-w] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2020] [Revised: 12/06/2020] [Accepted: 01/26/2021] [Indexed: 02/06/2023] Open
Abstract
Studying the biomechanical properties of biological tissue is crucial to improve our understanding of disease pathogenesis. The biomechanical characteristics of the cornea, sclera and the optic nerve head have been well addressed with an extensive literature and an in-depth understanding of their significance whilst, in comparison, knowledge of the retina and choroid is relatively limited. Knowledge of these tissues is important not only to clarify the underlying pathogenesis of a wide variety of retinal and vitreoretinal diseases, including age-related macular degeneration, hereditary retinal dystrophies and vitreoretinal interface diseases but also to optimise the surgical handling of retinal tissues and, potentially, the design and properties of implantable retinal prostheses and subretinal therapies. Our aim with this article is to comprehensively review existing knowledge of the biomechanical properties of retina, internal limiting membrane (ILM) and the Bruch’s membrane–choroidal complex (BMCC), highlighting the potential implications for clinical and surgical practice. Prior to this we review the testing methodologies that have been used both in vitro, and those starting to be used in vivo to aid understanding of their results and significance.
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Affiliation(s)
| | - Gaia Lugano
- Department of Eye and Vision Science, Institute of Life Course and Medical Sciences, University of Liverpool, Liverpool, UK
| | | | - Victoria R Kearns
- Department of Eye and Vision Science, Institute of Life Course and Medical Sciences, University of Liverpool, Liverpool, UK
| | - Brendan Geraghty
- Musculoskeletal and Ageing Science, Institute of Life Course and Medical Sciences, University of Liverpool, Liverpool, UK.
| | - David H W Steel
- Sunderland Eye Infirmary, Sunderland, UK. .,Bioscience Institute, Newcastle University, Newcastle Upon Tyne, UK.
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48
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Potilinski MC, Tate PS, Lorenc VE, Gallo JE. New insights into oxidative stress and immune mechanisms involved in age-related macular degeneration tackled by novel therapies. Neuropharmacology 2021; 188:108513. [PMID: 33662390 DOI: 10.1016/j.neuropharm.2021.108513] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2020] [Revised: 02/14/2021] [Accepted: 02/22/2021] [Indexed: 12/20/2022]
Abstract
The prevalence of age-related macular degeneration (AMD) has increased in the last years. Although anti-VEGF agents have improved the prognosis of exudative AMD, dry AMD has still devastating effects on elderly people vision. Oxidative stress and inflammation are mechanisms involved in AMD pathogenesis and its progression. Molecular pathways involving epidermal growth factor receptor (EGFR), bone morphogenetic protein (BMP4) and the nuclear erythroid related factor 2 (Nrf2) are behind oxidative stress in AMD due to their participation in antioxidant cellular pathways. As a consequence of the disbalance produced in the antioxidant mechanisms, there is an activation of innate and adaptative immune response with cell recruitment, changes in complement factors expression, and modification of cellular milieu. Different therapies are being studied to treat dry AMD based on the possible effects on antioxidant molecular pathways or their action on the immune response. There is a wide range of treatments presented in this review, from natural antioxidant compounds to cell and gene therapy, based on their mechanisms. Finally, we hypothesize that alpha-1-antitrypsin (AAT), an anti-inflammatory and immunomodulatory molecule that can also modulate antioxidant cellular defenses, could be a good candidate for testing in AMD. This article is part of the special ssue on 'The Quest for Disease-Modifying Therapies for Neurodegenerative Disorders'.
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Affiliation(s)
- María Constanza Potilinski
- Nanomedicine & Vision Lab, Instituto de Investigaciones en Medicina Translacional, Universidad Austral, CONICET, Pilar, Buenos Aires, Argentina
| | - Pablo S Tate
- Laboratorio de Enfermedades Neurodegenerativas, Instituto de Investigaciones en Medicina Translacional, Universidad Austral, CONICET, Pilar, Buenos Aires, Argentina
| | - Valeria E Lorenc
- Nanomedicine & Vision Lab, Instituto de Investigaciones en Medicina Translacional, Universidad Austral, CONICET, Pilar, Buenos Aires, Argentina
| | - Juan E Gallo
- Nanomedicine & Vision Lab, Instituto de Investigaciones en Medicina Translacional, Universidad Austral, CONICET, Pilar, Buenos Aires, Argentina; Departamento de Oftalmología, Hospital Universitario Austral, Pilar, Buenos Aires, Argentina.
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Ruiz-Alonso S, Villate-Beitia I, Gallego I, Lafuente-Merchan M, Puras G, Saenz-del-Burgo L, Pedraz JL. Current Insights Into 3D Bioprinting: An Advanced Approach for Eye Tissue Regeneration. Pharmaceutics 2021; 13:pharmaceutics13030308. [PMID: 33653003 PMCID: PMC7996883 DOI: 10.3390/pharmaceutics13030308] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2021] [Revised: 02/17/2021] [Accepted: 02/19/2021] [Indexed: 12/19/2022] Open
Abstract
Three-dimensional (3D) printing is a game changer technology that holds great promise for a wide variety of biomedical applications, including ophthalmology. Through this emerging technique, specific eye tissues can be custom-fabricated in a flexible and automated way, incorporating different cell types and biomaterials in precise anatomical 3D geometries. However, and despite the great progress and possibilities generated in recent years, there are still challenges to overcome that jeopardize its clinical application in regular practice. The main goal of this review is to provide an in-depth understanding of the current status and implementation of 3D bioprinting technology in the ophthalmology field in order to manufacture relevant tissues such as cornea, retina and conjunctiva. Special attention is paid to the description of the most commonly employed bioprinting methods, and the most relevant eye tissue engineering studies performed by 3D bioprinting technology at preclinical level. In addition, other relevant issues related to use of 3D bioprinting for ocular drug delivery, as well as both ethical and regulatory aspects, are analyzed. Through this review, we aim to raise awareness among the research community and report recent advances and future directions in order to apply this advanced therapy in the eye tissue regeneration field.
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Affiliation(s)
- Sandra Ruiz-Alonso
- NanoBioCel Research Group, Laboratory of Pharmacy and Pharmaceutical Technology, Department of Pharmacy and Food Science, Faculty of Pharmacy, University of the Basque Country (UPV/EHU), Paseo de la Universidad 7, 01006 Vitoria-Gasteiz, Spain; (S.R.-A.); (I.V.-B.); (I.G.); (M.L.-M.); (G.P.)
- Networking Research Centre of Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), Institute of Health Carlos III, 28029 Madrid, Spain
- Bioaraba, NanoBioCel Research Group, 01009 Vitoria-Gasteiz, Spain
| | - Ilia Villate-Beitia
- NanoBioCel Research Group, Laboratory of Pharmacy and Pharmaceutical Technology, Department of Pharmacy and Food Science, Faculty of Pharmacy, University of the Basque Country (UPV/EHU), Paseo de la Universidad 7, 01006 Vitoria-Gasteiz, Spain; (S.R.-A.); (I.V.-B.); (I.G.); (M.L.-M.); (G.P.)
- Networking Research Centre of Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), Institute of Health Carlos III, 28029 Madrid, Spain
- Bioaraba, NanoBioCel Research Group, 01009 Vitoria-Gasteiz, Spain
| | - Idoia Gallego
- NanoBioCel Research Group, Laboratory of Pharmacy and Pharmaceutical Technology, Department of Pharmacy and Food Science, Faculty of Pharmacy, University of the Basque Country (UPV/EHU), Paseo de la Universidad 7, 01006 Vitoria-Gasteiz, Spain; (S.R.-A.); (I.V.-B.); (I.G.); (M.L.-M.); (G.P.)
- Networking Research Centre of Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), Institute of Health Carlos III, 28029 Madrid, Spain
- Bioaraba, NanoBioCel Research Group, 01009 Vitoria-Gasteiz, Spain
| | - Markel Lafuente-Merchan
- NanoBioCel Research Group, Laboratory of Pharmacy and Pharmaceutical Technology, Department of Pharmacy and Food Science, Faculty of Pharmacy, University of the Basque Country (UPV/EHU), Paseo de la Universidad 7, 01006 Vitoria-Gasteiz, Spain; (S.R.-A.); (I.V.-B.); (I.G.); (M.L.-M.); (G.P.)
- Networking Research Centre of Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), Institute of Health Carlos III, 28029 Madrid, Spain
- Bioaraba, NanoBioCel Research Group, 01009 Vitoria-Gasteiz, Spain
| | - Gustavo Puras
- NanoBioCel Research Group, Laboratory of Pharmacy and Pharmaceutical Technology, Department of Pharmacy and Food Science, Faculty of Pharmacy, University of the Basque Country (UPV/EHU), Paseo de la Universidad 7, 01006 Vitoria-Gasteiz, Spain; (S.R.-A.); (I.V.-B.); (I.G.); (M.L.-M.); (G.P.)
- Networking Research Centre of Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), Institute of Health Carlos III, 28029 Madrid, Spain
- Bioaraba, NanoBioCel Research Group, 01009 Vitoria-Gasteiz, Spain
| | - Laura Saenz-del-Burgo
- NanoBioCel Research Group, Laboratory of Pharmacy and Pharmaceutical Technology, Department of Pharmacy and Food Science, Faculty of Pharmacy, University of the Basque Country (UPV/EHU), Paseo de la Universidad 7, 01006 Vitoria-Gasteiz, Spain; (S.R.-A.); (I.V.-B.); (I.G.); (M.L.-M.); (G.P.)
- Networking Research Centre of Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), Institute of Health Carlos III, 28029 Madrid, Spain
- Bioaraba, NanoBioCel Research Group, 01009 Vitoria-Gasteiz, Spain
- Correspondence: (L.S.-d.-B.); (J.L.P.); Tel.: +(34)-945014542 (L.S.-d.-B.); +(34)-945013091 (J.L.P.)
| | - José Luis Pedraz
- NanoBioCel Research Group, Laboratory of Pharmacy and Pharmaceutical Technology, Department of Pharmacy and Food Science, Faculty of Pharmacy, University of the Basque Country (UPV/EHU), Paseo de la Universidad 7, 01006 Vitoria-Gasteiz, Spain; (S.R.-A.); (I.V.-B.); (I.G.); (M.L.-M.); (G.P.)
- Networking Research Centre of Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), Institute of Health Carlos III, 28029 Madrid, Spain
- Bioaraba, NanoBioCel Research Group, 01009 Vitoria-Gasteiz, Spain
- Correspondence: (L.S.-d.-B.); (J.L.P.); Tel.: +(34)-945014542 (L.S.-d.-B.); +(34)-945013091 (J.L.P.)
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Wang J, Wang Y, Yu D, Liu Q, Lin S, Tian R, Li J, Luo Y. Protective Effect of a Bispecific Fc-Fusion Protein on the Barrier of Human Retinal Pigment Epithelial Cells. Ophthalmic Res 2021; 64:656-663. [PMID: 33550303 DOI: 10.1159/000515053] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2020] [Accepted: 01/28/2021] [Indexed: 02/05/2023]
Abstract
INTRODUCTION The aim of the study was to evaluate the protective effects of IBI302, a bispecific Fc-fusion protein that theoretically can bind vascular endothelial growth factor (VEGF), complement C3b, and C4b in the barrier of the cultured human retinal pigment epithelial (hRPE) cells. METHODS Primary hRPE cells were isolated and cultured to monolayer barrier. hRPE monolayers were divided into the PBS control group, VEGF-Trap group, complement receptor 1 (CR1) group, and IBI302 group. Identification of hRPE cells, barrier function, inflammation factors, and immune response products was tested by immunofluorescent staining, transepithelial resistance (TER), and ELISA. RESULTS IBI302 treatment significantly improved the TER of the barrier of hRPE cells after complement-activated oxidative stress compared with the PBS control group, VEGF-Trap group, and CR1 group. The maximum effect of IBI302 on protecting hRPE cell viability was observed at the concentration of 1 μg/mL. The elevated expression of VEGF, chemokine (C-C Motif) ligand 2, C3a, C5a, and membrane attack complex was reduced by IBI302. CONCLUSION IBI302 could protect the barrier function of hRPE cells. IBI302 might be a potentially effective drug for the RPE barrier-associated ocular diseases.
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Affiliation(s)
- Jing Wang
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, China
| | - Yishen Wang
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, China
| | - Dechao Yu
- State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China
| | - Qiuhui Liu
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, China
| | - Shaofen Lin
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, China
| | - Rong Tian
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, China
| | - Jia Li
- State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China
| | - Yan Luo
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, China
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