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Liu Y, Li S, Wang K, Wang Y, Wang Y, Zhang C, Wu H, Wang G, Qin F, Song Z, Tao Y. Unveiling the HSP90 inhibitor mediated effects on endoplasmic reticulum stress and redox signaling:from a cancer inhibitor to retinal degeneration catalyst. Free Radic Biol Med 2025:S0891-5849(25)00697-5. [PMID: 40414464 DOI: 10.1016/j.freeradbiomed.2025.05.414] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/16/2025] [Revised: 05/20/2025] [Accepted: 05/22/2025] [Indexed: 05/27/2025]
Abstract
Retinal degeneration (RD) is a class of polygenic blind eye disease characterized by photoreceptors loss and dysfunction of retinal pigment epithelium. Thus far, there is no effective treatment to save the declining vision in RD patients. Animal models are highly precious tools for studying the pathological mechanisms of RD, and for screening potential therapeutics. AUY922 is a heat shock protein 90 inhibitor that exhibits potent anti-cancer effects. However, it causes adverse ocular reactions such as reduced visual acuity and night blindness. This study intends to explore the pathological mechanism underlying the AUY922 induced RD. In vitro study, AUY922 induced cytotoxic effects on the 661W cells, which are ascribed to endoplasmic reticulum (ER) stress and oxidative damages. ER stress inhibitor 4-PBA alleviated 661W cells apoptosis and oxidative stress. Subsequently, AUY922 was delivered into the vitreous cavity of mouse and induced selective photoreceptor death and visual impairments. Overactivation of neuroglial and retinal remodeling occurred during the degenerative process. Moreover, enhanced CHOP expression was tied to profound disturbances in redox homeostasis, which readied photoreceptors for apoptosis. The underlying mechanism should be attributed to the activation of the PERK-eIF2α-ATF4-CHOP pathway. AUY922 can compensate for the high toxicity and instability of traditional inducers in RD modeling. These results not only enrich our understanding of the toxicology of AUY922 but also provide clues for establishing reliable RD models.
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Affiliation(s)
- Yashuang Liu
- Department of Ophthalmology, People's Hospital of Zhengzhou University, Henan Provincial People's Hospital, Henan Eye Institute, Henan Eye Hospital, Zhengzhou 450003, China
| | - Siyu Li
- Department of Ophthalmology, People's Hospital of Zhengzhou University, Henan Provincial People's Hospital, Henan Eye Institute, Henan Eye Hospital, Zhengzhou 450003, China
| | - Kexin Wang
- Department of Ophthalmology, People's Hospital of Zhengzhou University, Henan Provincial People's Hospital, Henan Eye Institute, Henan Eye Hospital, Zhengzhou 450003, China
| | - Yiwen Wang
- Department of Ophthalmology, People's Hospital of Zhengzhou University, Henan Provincial People's Hospital, Henan Eye Institute, Henan Eye Hospital, Zhengzhou 450003, China
| | - Yange Wang
- Department of Ophthalmology, People's Hospital of Zhengzhou University, Henan Provincial People's Hospital, Henan Eye Institute, Henan Eye Hospital, Zhengzhou 450003, China
| | - Chenxu Zhang
- Department of Ophthalmology, People's Hospital of Zhengzhou University, Henan Provincial People's Hospital, Henan Eye Institute, Henan Eye Hospital, Zhengzhou 450003, China
| | - Hao Wu
- Department of Ophthalmology, People's Hospital of Zhengzhou University, Henan Provincial People's Hospital, Henan Eye Institute, Henan Eye Hospital, Zhengzhou 450003, China
| | - Gang Wang
- Department of Ophthalmology, People's Hospital of Zhengzhou University, Henan Provincial People's Hospital, Henan Eye Institute, Henan Eye Hospital, Zhengzhou 450003, China
| | - Fangyuan Qin
- Department of Ophthalmology, People's Hospital of Zhengzhou University, Henan Provincial People's Hospital, Henan Eye Institute, Henan Eye Hospital, Zhengzhou 450003, China
| | - Zongming Song
- Department of Ophthalmology, People's Hospital of Zhengzhou University, Henan Provincial People's Hospital, Henan Eye Institute, Henan Eye Hospital, Zhengzhou 450003, China.
| | - Ye Tao
- Department of Ophthalmology, People's Hospital of Zhengzhou University, Henan Provincial People's Hospital, Henan Eye Institute, Henan Eye Hospital, Zhengzhou 450003, China.
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Colombo L, Baldesi J, Martella S, Quisisana C, Antico A, Mapelli L, Montagner S, Primon A, Rossetti L. Managing Retinitis Pigmentosa: A Literature Review of Current Non-Surgical Approaches. J Clin Med 2025; 14:330. [PMID: 39860336 PMCID: PMC11765533 DOI: 10.3390/jcm14020330] [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: 12/04/2024] [Revised: 12/30/2024] [Accepted: 01/02/2025] [Indexed: 01/27/2025] Open
Abstract
Retinitis pigmentosa (RP) is a heterogeneous group of inherited retinal diseases characterized by the progressive loss of photoreceptor function, visual impairment, and, ultimately, blindness. While gene therapy has emerged as a promising therapy, it is currently available only for the RPE65 gene mutation, leaving many patients without targeted genetic treatments. Non-surgical interventions may help in managing the progression of RP and improving patients' quality of life. Visual training and rehabilitation, maximizing residual vision, have shown potential in improving mobility and patients' ability to perform daily activities. Visual aids enhance visual function. Moreover, photo-protection demonstrated effectiveness in mitigating light-induced damage and improving visual comfort. Alternative therapies (i.e., electrostimulation, acupuncture, and ozone therapy) are being explored to preserve retinal function and reduce disease progression. Pharmacological interventions supported by nutritional and psychological counseling play a role in slowing retinal degeneration while managing the emotional burden of progressive vision loss. Although for these interventions, further validation is required, their potential benefits make them valuable additions to care for RP patients. The integration of these interventions into a multidisciplinary care approach-including ophthalmologists, orthoptist, dietitians, and psychologists-is essential for providing comprehensive, personalized care to RP patients while awaiting more widespread gene therapy solutions.
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Affiliation(s)
- Leonardo Colombo
- Eye Clinic, ASST Santi Paolo e Carlo Hospital, University of Milan, 20142 Milan, Italy; (J.B.); (S.M.); (C.Q.); (A.A.); (L.M.); (L.R.)
| | - Jacopo Baldesi
- Eye Clinic, ASST Santi Paolo e Carlo Hospital, University of Milan, 20142 Milan, Italy; (J.B.); (S.M.); (C.Q.); (A.A.); (L.M.); (L.R.)
| | - Salvatore Martella
- Eye Clinic, ASST Santi Paolo e Carlo Hospital, University of Milan, 20142 Milan, Italy; (J.B.); (S.M.); (C.Q.); (A.A.); (L.M.); (L.R.)
| | - Chiara Quisisana
- Eye Clinic, ASST Santi Paolo e Carlo Hospital, University of Milan, 20142 Milan, Italy; (J.B.); (S.M.); (C.Q.); (A.A.); (L.M.); (L.R.)
| | - Aleksei Antico
- Eye Clinic, ASST Santi Paolo e Carlo Hospital, University of Milan, 20142 Milan, Italy; (J.B.); (S.M.); (C.Q.); (A.A.); (L.M.); (L.R.)
| | - Luca Mapelli
- Eye Clinic, ASST Santi Paolo e Carlo Hospital, University of Milan, 20142 Milan, Italy; (J.B.); (S.M.); (C.Q.); (A.A.); (L.M.); (L.R.)
| | - Stefania Montagner
- Eye & Vision—Visual Rehabilitation Center, 20128 Milan, Italy; (S.M.); (A.P.)
| | - Alberto Primon
- Eye & Vision—Visual Rehabilitation Center, 20128 Milan, Italy; (S.M.); (A.P.)
| | - Luca Rossetti
- Eye Clinic, ASST Santi Paolo e Carlo Hospital, University of Milan, 20142 Milan, Italy; (J.B.); (S.M.); (C.Q.); (A.A.); (L.M.); (L.R.)
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Yang H, Zhang H, Li X. Navigating the future of retinitis pigmentosa treatments: A comprehensive analysis of therapeutic approaches in rd10 mice. Neurobiol Dis 2024; 193:106436. [PMID: 38341159 DOI: 10.1016/j.nbd.2024.106436] [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: 12/27/2023] [Revised: 02/06/2024] [Accepted: 02/07/2024] [Indexed: 02/12/2024] Open
Abstract
Retinitis pigmentosa (RP) is a degenerative disease, caused by genetic mutations that lead to a loss in photoreceptors. For research on RP, rd10 mice, which carry mutations in the phosphodiesterase (PDE) gene, exhibit degenerative patterns comparable to those of patients with RP, making them an ideal model for investigating potential treatments. Although numerous studies have reported the potential of biochemical drugs, gene correction, and stem cell transplantation in decelerating rd10 retinal degeneration, a comprehensive review of these studies has yet to be conducted. Therefore, here, a comparative analysis of rd10 mouse treatment research over the past decade was performed. Our findings suggest that biochemical drugs capable of inhibiting the inflammatory response may be promising therapeutics. Additionally, significant progress has been made in the field of gene therapy; nevertheless, challenges such as strict delivery requirements, bystander editing, and off-target effects still need to be resolved. Nevertheless, secretory function is the only unequivocal protective effect of stem cell transplantation. In summary, this review presents a comprehensive analysis and synthesis of the treatment approaches employing rd10 mice as experimental subjects, describing a clear pathway for future RP treatment research and identifies potential clinical interventions.
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Affiliation(s)
- Hongli Yang
- Tianjin Key Laboratory of Retinal Functions and Diseases, Tianjin Branch of National Clinical Research Center for Ocular Disease, Eye Institute and School of Optometry, Tianjin Medical University Eye Hospital, No. 251, Fukang Road, Tianjin 300384, China.
| | - Hui Zhang
- Tianjin Key Laboratory of Retinal Functions and Diseases, Tianjin Branch of National Clinical Research Center for Ocular Disease, Eye Institute and School of Optometry, Tianjin Medical University Eye Hospital, No. 251, Fukang Road, Tianjin 300384, China
| | - Xiaorong Li
- Tianjin Key Laboratory of Retinal Functions and Diseases, Tianjin Branch of National Clinical Research Center for Ocular Disease, Eye Institute and School of Optometry, Tianjin Medical University Eye Hospital, No. 251, Fukang Road, Tianjin 300384, China.
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Vingolo EM, Mascolo S, Miccichè F, Manco G. Retinitis Pigmentosa: From Pathomolecular Mechanisms to Therapeutic Strategies. MEDICINA (KAUNAS, LITHUANIA) 2024; 60:189. [PMID: 38276069 PMCID: PMC10819364 DOI: 10.3390/medicina60010189] [Citation(s) in RCA: 8] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/04/2023] [Revised: 01/13/2024] [Accepted: 01/15/2024] [Indexed: 01/27/2024]
Abstract
Retinitis pigmentosa is an inherited disease, in which mutations in different types of genes lead to the death of photoreceptors and the loss of visual function. Although retinitis pigmentosa is the most common type of inherited retinal dystrophy, a clear line of therapy has not yet been defined. In this review, we will focus on the therapeutic aspect and attempt to define the advantages and disadvantages of the protocols of different therapies. The role of some therapies, such as antioxidant agents or gene therapy, has been established for years now. Many clinical trials on different genes and mutations causing RP have been conducted, and the approval of voretigene nepavorec by the FDA has been an important step forward. Nonetheless, even if gene therapy is the most promising type of treatment for these patients, other innovative strategies, such as stem cell transplantation or hyperbaric oxygen therapy, have been shown to be safe and improve visual quality during clinical trials. The treatment of this disease remains a challenge, to which we hope to find a solution as soon as possible.
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Affiliation(s)
| | - Simona Mascolo
- Sense Organs Department, UOSD of Ophtalmology, University la Sapienza of Rome, Polo Pontino-Ospedale A. Fiorini, 4019 Terracina, Italy; (E.M.V.); (F.M.); (G.M.)
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Pinilla I, Maneu V, Campello L, Fernández-Sánchez L, Martínez-Gil N, Kutsyr O, Sánchez-Sáez X, Sánchez-Castillo C, Lax P, Cuenca N. Inherited Retinal Dystrophies: Role of Oxidative Stress and Inflammation in Their Physiopathology and Therapeutic Implications. Antioxidants (Basel) 2022; 11:antiox11061086. [PMID: 35739983 PMCID: PMC9219848 DOI: 10.3390/antiox11061086] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2022] [Revised: 05/24/2022] [Accepted: 05/26/2022] [Indexed: 12/13/2022] Open
Abstract
Inherited retinal dystrophies (IRDs) are a large group of genetically and clinically heterogeneous diseases characterized by the progressive degeneration of the retina, ultimately leading to loss of visual function. Oxidative stress and inflammation play fundamental roles in the physiopathology of these diseases. Photoreceptor cell death induces an inflammatory state in the retina. The activation of several molecular pathways triggers different cellular responses to injury, including the activation of microglia to eliminate debris and recruit inflammatory cells from circulation. Therapeutical options for IRDs are currently limited, although a small number of patients have been successfully treated by gene therapy. Many other therapeutic strategies are being pursued to mitigate the deleterious effects of IRDs associated with oxidative metabolism and/or inflammation, including inhibiting reactive oxygen species’ accumulation and inflammatory responses, and blocking autophagy. Several compounds are being tested in clinical trials, generating great expectations for their implementation. The present review discusses the main death mechanisms that occur in IRDs and the latest therapies that are under investigation.
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Affiliation(s)
- Isabel Pinilla
- Aragón Health Research Institute (IIS Aragón), 50009 Zaragoza, Spain
- Department of Ophthalmology, Lozano Blesa, University Hospital, 50009 Zaragoza, Spain
- Department of Surgery, University of Zaragoza, 50009 Zaragoza, Spain
- Correspondence: (I.P.); (V.M.)
| | - Victoria Maneu
- Department of Optics, Pharmacology and Anatomy, University of Alicante, 03690 Alicante, Spain;
- Alicante Institute for Health and Biomedical Research (ISABIAL), 03010 Alicante, Spain; (P.L.); (N.C.)
- Correspondence: (I.P.); (V.M.)
| | - Laura Campello
- Department of Physiology, Genetics and Microbiology, University of Alicante, 03690 Alicante, Spain; (L.C.); (N.M.-G.); (O.K.); (X.S.-S.); (C.S.-C.)
| | - Laura Fernández-Sánchez
- Department of Optics, Pharmacology and Anatomy, University of Alicante, 03690 Alicante, Spain;
| | - Natalia Martínez-Gil
- Department of Physiology, Genetics and Microbiology, University of Alicante, 03690 Alicante, Spain; (L.C.); (N.M.-G.); (O.K.); (X.S.-S.); (C.S.-C.)
| | - Oksana Kutsyr
- Department of Physiology, Genetics and Microbiology, University of Alicante, 03690 Alicante, Spain; (L.C.); (N.M.-G.); (O.K.); (X.S.-S.); (C.S.-C.)
| | - Xavier Sánchez-Sáez
- Department of Physiology, Genetics and Microbiology, University of Alicante, 03690 Alicante, Spain; (L.C.); (N.M.-G.); (O.K.); (X.S.-S.); (C.S.-C.)
| | - Carla Sánchez-Castillo
- Department of Physiology, Genetics and Microbiology, University of Alicante, 03690 Alicante, Spain; (L.C.); (N.M.-G.); (O.K.); (X.S.-S.); (C.S.-C.)
| | - Pedro Lax
- Alicante Institute for Health and Biomedical Research (ISABIAL), 03010 Alicante, Spain; (P.L.); (N.C.)
- Department of Physiology, Genetics and Microbiology, University of Alicante, 03690 Alicante, Spain; (L.C.); (N.M.-G.); (O.K.); (X.S.-S.); (C.S.-C.)
| | - Nicolás Cuenca
- Alicante Institute for Health and Biomedical Research (ISABIAL), 03010 Alicante, Spain; (P.L.); (N.C.)
- Department of Physiology, Genetics and Microbiology, University of Alicante, 03690 Alicante, Spain; (L.C.); (N.M.-G.); (O.K.); (X.S.-S.); (C.S.-C.)
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Olivares-González L, Salom D, González-García E, Hervás D, Mejía-Chiqui N, Melero M, Velasco S, Muresan BT, Campillo I, Vila-Clérigues N, López-Briz E, Merino-Torres JF, Millán JM, Soriano Del Castillo JM, Rodrigo R. NUTRARET: Effect of 2-Year Nutraceutical Supplementation on Redox Status and Visual Function of Patients With Retinitis Pigmentosa: A Randomized, Double-Blind, Placebo-Controlled Trial. Front Nutr 2022; 9:847910. [PMID: 35387197 PMCID: PMC8979249 DOI: 10.3389/fnut.2022.847910] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2022] [Accepted: 02/22/2022] [Indexed: 11/25/2022] Open
Abstract
Oxidative stress plays a major role in the pathogenesis of retinitis pigmentosa (RP). The main goal of this study was to evaluate the effect of 2-year nutritional intervention with antioxidant nutraceuticals on the visual function of RP patients. Secondly, we assessed how nutritional intervention affected ocular and systemic redox status. We carried out a randomized, double-blind, placebo-controlled study. Thirty-one patients with RP participated in the study. RP patients randomly received either a mixture of nutraceuticals (NUT) containing folic acid, vitamin B6, vitamin A, zinc, copper, selenium, lutein, and zeaxanthin or placebo daily for 2 years. At baseline and after 2-year of the nutritional supplementation, visual function, dietetic-nutritional evaluations, serum concentration of nutraceuticals, plasma and aqueous humor concentration of several markers of redox status and inflammation were assessed. Retinal function and structure were assessed by multifocal electroretinogram (mfERG), spectral domain-optical coherence tomography (SD-OCT) and automated visual field (VF) tests. Nutritional status was estimated with validated questionnaires. Total antioxidant capacity, extracellular superoxide dismutase (SOD3), catalase (CAT), and glutathione peroxidase (GPx) activities, protein carbonyl adducts (CAR) content, thiobarbituric acid reactive substances (TBARS) formation (as indicator of lipid peroxidation), metabolites of the nitric oxide (NOX) and cytokine (interleukin 6 and tumor necrosis factor alpha) concentrations were assessed by biochemical and immunological techniques in aqueous humor or/and blood. Bayesian approach was performed to determine the probability of an effect. Region of practical equivalence (ROPE) was used. At baseline, Bayesian analysis revealed a high probability of an altered ocular redox status and to a lesser extent systemic redox status in RP patients compared to controls. Twenty-five patients (10 in the treated arm and 15 in the placebo arm) completed the nutritional intervention. After 2 years of supplementation, patients who received NUT presented better retinal responses (mfERG responses) compared to patients who received placebo. Besides, patients who received NUT showed better ocular antioxidant response (SOD3 activity) and lower oxidative damage (CAR) than those who received placebo. This study suggested that long-term NUT supplementation could slow down visual impairment and ameliorate ocular oxidative stress.
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Affiliation(s)
- Lorena Olivares-González
- Pathophysiology and Therapies for Vision Disorders, Principe Felipe Research Center (CIPF), Valencia, Spain
- Joint Research Unit on Rare Diseases CIPF-Health Research Institute Hospital La Fe (IIS-La Fe), Valencia, Spain
| | - David Salom
- Department of Ophthalmology, Manises Hospital, Manises, Spain
- Center for Biomedical Network Research on Rare Diseases (CIBERER), Madrid, Spain
| | | | - David Hervás
- Department of Applied Statistics, Operations Research and Quality, Universitat Politècnica de València, Valencia, Spain
| | - Natalia Mejía-Chiqui
- Pathophysiology and Therapies for Vision Disorders, Principe Felipe Research Center (CIPF), Valencia, Spain
| | - Mar Melero
- Service of Pharmacy, La Fe University and Polytechnic Hospital, Valencia, Spain
| | - Sheyla Velasco
- Pathophysiology and Therapies for Vision Disorders, Principe Felipe Research Center (CIPF), Valencia, Spain
| | - Bianca Tabita Muresan
- Service of Endocrinology and Nutrition, University General Hospital, Valencia, Spain
| | - Isabel Campillo
- Pathophysiology and Therapies for Vision Disorders, Principe Felipe Research Center (CIPF), Valencia, Spain
| | | | - Eduardo López-Briz
- Service of Pharmacy, La Fe University and Polytechnic Hospital, Valencia, Spain
| | - Juan Francisco Merino-Torres
- Service of Endocrinology and Nutrition, La Fe University and Polytechnic Hospital, Valencia, Spain
- Joint Research Unit on Endocrinology, Nutrition and Clinical Dietetics UV-IIS La Fe, Valencia, Spain
| | - José María Millán
- Joint Research Unit on Rare Diseases CIPF-Health Research Institute Hospital La Fe (IIS-La Fe), Valencia, Spain
- Center for Biomedical Network Research on Rare Diseases (CIBERER), Madrid, Spain
- Molecular, Cellular and Genomic Biomedicine, IIS-La Fe, Valencia, Spain
| | - José Miguel Soriano Del Castillo
- Joint Research Unit on Endocrinology, Nutrition and Clinical Dietetics UV-IIS La Fe, Valencia, Spain
- Food & Health Laboratory, Institute of Materials Science, University of Valencia (UV), Valencia, Spain
| | - Regina Rodrigo
- Pathophysiology and Therapies for Vision Disorders, Principe Felipe Research Center (CIPF), Valencia, Spain
- Joint Research Unit on Rare Diseases CIPF-Health Research Institute Hospital La Fe (IIS-La Fe), Valencia, Spain
- Center for Biomedical Network Research on Rare Diseases (CIBERER), Madrid, Spain
- Joint Research Unit on Endocrinology, Nutrition and Clinical Dietetics UV-IIS La Fe, Valencia, Spain
- Department of Physiology, University of Valencia (UV), Valencia, Spain
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Zhang HJ, Liu XB, Chen XM, Kong QH, Liu YS, So KF, Chen JS, Xu Y, Mi XS, Tang SB. Lutein delays photoreceptor degeneration in a mouse model of retinitis pigmentosa. Neural Regen Res 2021; 17:1596-1603. [PMID: 34916446 PMCID: PMC8771084 DOI: 10.4103/1673-5374.330622] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
Abstract
Retinitis pigmentosa is a retinal disease characterized by photoreceptor degeneration. There is currently no effective treatment for retinitis pigmentosa. Although a mixture of lutein and other antioxidant agents has shown promising effects in protecting the retina from degeneration, the role of lutein alone remains unclear. In this study, we administered intragastric lutein to Pde6brd10 model mice, which display degeneration of retinal photoreceptors, on postnatal days 17 (P17) to P25, when rod apoptosis reaches peak. Lutein at the optimal protective dose of 200 mg/kg promoted the survival of photoreceptors compared with vehicle control. Lutein increased rhodopsin expression in rod cells and opsin expression in cone cells, in line with an increased survival rate of photoreceptors. Functionally, lutein improved visual behavior, visual acuity, and retinal electroretinogram responses in Pde6brd10 mice. Mechanistically, lutein reduced the expression of glial fibrillary acidic protein in Müller glial cells. The results of this study confirm the ability of lutein to postpone photoreceptor degeneration by reducing reactive gliosis of Müller cells in the retina and exerting anti-inflammatory effects. This study was approved by the Laboratory Animal Ethics Committee of Jinan University (approval No. LACUC-20181217-02) on December 17, 2018.
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Affiliation(s)
- Hui-Jun Zhang
- Department of Ophthalmology, The First Affiliated Hospital of Jinan University; Department of Ophthalmology, Guangzhou Panyu Central Hospital, Guangzhou, Guangdong Province, China
| | - Xiao-Bin Liu
- Guangdong-Hong Kong-Macau Institute of CNS Regeneration, Jinan University, Guangzhou, Guangdong Province, China
| | - Xiong-Min Chen
- Guangdong-Hong Kong-Macau Institute of CNS Regeneration, Jinan University, Guangzhou, Guangdong Province, China
| | - Qi-Hang Kong
- Department of Ophthalmology, The First Affiliated Hospital of Jinan University, Guangzhou, Guangdong Province, China
| | - Yu-Sang Liu
- Guangdong-Hong Kong-Macau Institute of CNS Regeneration, Jinan University, Guangzhou, Guangdong Province, China
| | - Kwok-Fai So
- Guangdong-Hong Kong-Macau Institute of CNS Regeneration, Jinan University, Guangzhou, Guangdong Province; Aier Academician Station, Changsha, Hunan Province; Key Laboratory of CNS Regeneration (Jinan University), Ministry of Education, Guangzhou, Guangdong Province; Co-Innovation Center of Neuroregeneration, Nantong University, Nantong, Jiangsu Province, China
| | - Jian-Su Chen
- Department of Ophthalmology, The First Affiliated Hospital of Jinan University, Guangzhou, Guangdong Province; Laboratory of Retinal Cell Biology, Aier Eye Institute; Aier Academician Station, Changsha, Hunan Province, China
| | - Ying Xu
- Guangdong-Hong Kong-Macau Institute of CNS Regeneration, Jinan University, Guangzhou, Guangdong Province; Aier Academician Station, Changsha, Hunan Province; Key Laboratory of CNS Regeneration (Jinan University), Ministry of Education, Guangzhou, Guangdong Province; Co-Innovation Center of Neuroregeneration, Nantong University, Nantong, Jiangsu Province, China
| | - Xue-Song Mi
- Department of Ophthalmology, The First Affiliated Hospital of Jinan University, Guangzhou, Guangdong Province; Aier Academician Station, Changsha, Hunan Province, China
| | - Shi-Bo Tang
- Laboratory of Retinal Cell Biology, Aier Eye Institute; Aier Academician Station, Changsha, Hunan Province, China
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Liu F, Liu X, Zhou Y, Yu Y, Wang K, Zhou Z, Gao H, So KF, Vardi N, Xu Y. Wolfberry-derived zeaxanthin dipalmitate delays retinal degeneration in a mouse model of retinitis pigmentosa through modulating STAT3, CCL2 and MAPK pathways. J Neurochem 2021; 158:1131-1150. [PMID: 34265077 DOI: 10.1111/jnc.15472] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2021] [Revised: 06/20/2021] [Accepted: 07/13/2021] [Indexed: 12/13/2022]
Abstract
Retinitis pigmentosa (RP) is a group of inherited photoreceptor degeneration diseases that causes blindness without effective treatment. The pathogenesis of retinal degeneration involves mainly oxidative stress and inflammatory responses. Zeaxanthin dipalmitate (ZD), a wolfberry-derived carotenoid, has anti-inflammatory and anti-oxidative stress effects. Here we investigated whether these properties of ZD can delay the retinal degeneration in rd10 mice, a model of RP, and explored its underlying mechanism. One shot of ZD or control vehicle was intravitreally injected into rd10 mice on postnatal day 16 (P16). Retinal function and structure of rd10 mice were assessed at P25, when rods degenerate substantially, using a visual behavior test, multi-electrode-array recordings and immunostaining. Retinal pathogenic gene expression and regulation of signaling pathways by ZD were explored using transcriptome sequencing and western blotting. Our results showed that ZD treatment improved the visual behavior of rd10 mice and delayed the degeneration of retinal photoreceptors. It also improved the light responses of photoreceptors, bipolar cells and retinal ganglion cells. The expression of genes that are involved in inflammation, apoptosis and oxidative stress were up-regulated in rd10 mice, and were reduced by ZD. ZD further reduced the activation of two key factors, signal transducer and activator of transcription 3 and chemokine (C-C motif) ligand 2, down-regulated the expression of the inflammatory factor GFAP, and inhibited extracellular signal regulated protein kinases and P38, but not the JNK pathways. In conclusion, ZD delays the degeneration of the rd10 retina both morphologically and functionally. Its anti-inflammatory function is mediated primarily through the signal transducer and activator of transcription 3, chemokine (C-C motif) ligand 2 and MAPK pathways. Thus, ZD may serve as a potential clinical candidate to treat RP.
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Affiliation(s)
- Feng Liu
- Guangdong-Hongkong-Macau Institute of CNS Regeneration, Jinan University, Guangzhou, China.,State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, China
| | - Xiaobin Liu
- Guangdong-Hongkong-Macau Institute of CNS Regeneration, Jinan University, Guangzhou, China
| | - Yamin Zhou
- The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Yankun Yu
- Guangdong-Hongkong-Macau Institute of CNS Regeneration, Jinan University, Guangzhou, China.,The First Affiliated Hospital, Shihezi University School of Medicine, Shihezi, China
| | - Ke Wang
- Guangdong-Hongkong-Macau Institute of CNS Regeneration, Jinan University, Guangzhou, China
| | - Zhengqun Zhou
- Institute of Traditional Chinese Medicine and Natural Products, College of Pharmacy, Jinan University, Guangzhou, China
| | - Hao Gao
- Institute of Traditional Chinese Medicine and Natural Products, College of Pharmacy, Jinan University, Guangzhou, China
| | - Kwok-Fai So
- Guangdong-Hongkong-Macau Institute of CNS Regeneration, Jinan University, Guangzhou, China.,Key Laboratory of CNS Regeneration (Jinan University), Ministry of Education, China.,Co-Innovation Center of Neuroregeneration, Nantong University, Jiangsu, China
| | - Noga Vardi
- Department of Neuroscience, University of Pennsylvania, Philadelphia, PA, USA
| | - Ying Xu
- Guangdong-Hongkong-Macau Institute of CNS Regeneration, Jinan University, Guangzhou, China.,Key Laboratory of CNS Regeneration (Jinan University), Ministry of Education, China.,Co-Innovation Center of Neuroregeneration, Nantong University, Jiangsu, China
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Nutraceutical Supplementation Ameliorates Visual Function, Retinal Degeneration, and Redox Status in rd10 Mice. Antioxidants (Basel) 2021; 10:antiox10071033. [PMID: 34206804 PMCID: PMC8300708 DOI: 10.3390/antiox10071033] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2021] [Revised: 06/23/2021] [Accepted: 06/24/2021] [Indexed: 12/17/2022] Open
Abstract
Retinitis pigmentosa (RP) is a group of inherited retinal dystrophies characterized by progressive degeneration of photoreceptor cells. Ocular redox status is altered in RP suggesting oxidative stress could contribute to their progression. In this study, we investigated the effect of a mixture of nutraceuticals with antioxidant properties (NUT) on retinal degeneration in rd10 mice, a model of RP. NUT was orally administered to rd10 mice from postnatal day (PD) 9 to PD18. At PD18 retinal function and morphology were examined by electroretinography (ERG) and histology including TUNEL assay, immunolabeling of microglia, Müller cells, and poly ADP ribose polymers. Retinal redox status was determined by measuring the activity of antioxidant enzymes and some oxidative stress markers. Gene expression of the cytokines IL-6, TNFα, and IL-1β was assessed by real-time PCR. NUT treatment delayed the loss of photoreceptors in rd10 mice partially preserving their electrical responses to light stimuli. Moreover, it ameliorated redox status and reduced inflammation including microglia activation, upregulation of cytokines, reactive gliosis, and PARP overactivation. NUT ameliorated retinal functionality and morphology at early stages of RP in rd10 mice. This formulation could be useful as a neuroprotective approach for patients with RP in the future.
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11
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Lutein protected the retina from light induced retinal damage by inhibiting increasing oxidative stress and inflammation. J Funct Foods 2020. [DOI: 10.1016/j.jff.2020.104107] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022] Open
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12
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Collin GB, Gogna N, Chang B, Damkham N, Pinkney J, Hyde LF, Stone L, Naggert JK, Nishina PM, Krebs MP. Mouse Models of Inherited Retinal Degeneration with Photoreceptor Cell Loss. Cells 2020; 9:E931. [PMID: 32290105 PMCID: PMC7227028 DOI: 10.3390/cells9040931] [Citation(s) in RCA: 57] [Impact Index Per Article: 11.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/29/2020] [Revised: 04/05/2020] [Accepted: 04/07/2020] [Indexed: 12/12/2022] Open
Abstract
Inherited retinal degeneration (RD) leads to the impairment or loss of vision in millions of individuals worldwide, most frequently due to the loss of photoreceptor (PR) cells. Animal models, particularly the laboratory mouse, have been used to understand the pathogenic mechanisms that underlie PR cell loss and to explore therapies that may prevent, delay, or reverse RD. Here, we reviewed entries in the Mouse Genome Informatics and PubMed databases to compile a comprehensive list of monogenic mouse models in which PR cell loss is demonstrated. The progression of PR cell loss with postnatal age was documented in mutant alleles of genes grouped by biological function. As anticipated, a wide range in the onset and rate of cell loss was observed among the reported models. The analysis underscored relationships between RD genes and ciliary function, transcription-coupled DNA damage repair, and cellular chloride homeostasis. Comparing the mouse gene list to human RD genes identified in the RetNet database revealed that mouse models are available for 40% of the known human diseases, suggesting opportunities for future research. This work may provide insight into the molecular players and pathways through which PR degenerative disease occurs and may be useful for planning translational studies.
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Affiliation(s)
- Gayle B. Collin
- The Jackson Laboratory, Bar Harbor, Maine, ME 04609, USA; (G.B.C.); (N.G.); (B.C.); (N.D.); (J.P.); (L.F.H.); (L.S.); (J.K.N.)
| | - Navdeep Gogna
- The Jackson Laboratory, Bar Harbor, Maine, ME 04609, USA; (G.B.C.); (N.G.); (B.C.); (N.D.); (J.P.); (L.F.H.); (L.S.); (J.K.N.)
| | - Bo Chang
- The Jackson Laboratory, Bar Harbor, Maine, ME 04609, USA; (G.B.C.); (N.G.); (B.C.); (N.D.); (J.P.); (L.F.H.); (L.S.); (J.K.N.)
| | - Nattaya Damkham
- The Jackson Laboratory, Bar Harbor, Maine, ME 04609, USA; (G.B.C.); (N.G.); (B.C.); (N.D.); (J.P.); (L.F.H.); (L.S.); (J.K.N.)
- Department of Immunology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok 10700, Thailand
- Siriraj Center of Excellence for Stem Cell Research, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok 10700, Thailand
| | - Jai Pinkney
- The Jackson Laboratory, Bar Harbor, Maine, ME 04609, USA; (G.B.C.); (N.G.); (B.C.); (N.D.); (J.P.); (L.F.H.); (L.S.); (J.K.N.)
| | - Lillian F. Hyde
- The Jackson Laboratory, Bar Harbor, Maine, ME 04609, USA; (G.B.C.); (N.G.); (B.C.); (N.D.); (J.P.); (L.F.H.); (L.S.); (J.K.N.)
| | - Lisa Stone
- The Jackson Laboratory, Bar Harbor, Maine, ME 04609, USA; (G.B.C.); (N.G.); (B.C.); (N.D.); (J.P.); (L.F.H.); (L.S.); (J.K.N.)
| | - Jürgen K. Naggert
- The Jackson Laboratory, Bar Harbor, Maine, ME 04609, USA; (G.B.C.); (N.G.); (B.C.); (N.D.); (J.P.); (L.F.H.); (L.S.); (J.K.N.)
| | - Patsy M. Nishina
- The Jackson Laboratory, Bar Harbor, Maine, ME 04609, USA; (G.B.C.); (N.G.); (B.C.); (N.D.); (J.P.); (L.F.H.); (L.S.); (J.K.N.)
| | - Mark P. Krebs
- The Jackson Laboratory, Bar Harbor, Maine, ME 04609, USA; (G.B.C.); (N.G.); (B.C.); (N.D.); (J.P.); (L.F.H.); (L.S.); (J.K.N.)
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Gorbatyuk MS, Starr CR, Gorbatyuk OS. Endoplasmic reticulum stress: New insights into the pathogenesis and treatment of retinal degenerative diseases. Prog Retin Eye Res 2020; 79:100860. [PMID: 32272207 DOI: 10.1016/j.preteyeres.2020.100860] [Citation(s) in RCA: 33] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2019] [Revised: 03/08/2020] [Accepted: 03/17/2020] [Indexed: 12/13/2022]
Abstract
Physiological equilibrium in the retina depends on coordinated work between rod and cone photoreceptors and can be compromised by the expression of mutant proteins leading to inherited retinal degeneration (IRD). IRD is a diverse group of retinal dystrophies with multifaceted molecular mechanisms that are not fully understood. In this review, we focus on the contribution of chronically activated unfolded protein response (UPR) to inherited retinal pathogenesis, placing special emphasis on studies employing genetically modified animal models. As constitutively active UPR in degenerating retinas may activate pro-apoptotic programs associated with oxidative stress, pro-inflammatory signaling, dysfunctional autophagy, free cytosolic Ca2+ overload, and altered protein synthesis rate in the retina, we focus on the regulatory mechanisms of translational attenuation and approaches to overcoming translational attenuation in degenerating retinas. We also discuss current research on the role of the UPR mediator PERK and its downstream targets in degenerating retinas and highlight the therapeutic benefits of reprogramming PERK signaling in preclinical animal models of IRD. Finally, we describe pharmacological approaches targeting UPR in ocular diseases and consider their potential applications to IRD.
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Affiliation(s)
- Marina S Gorbatyuk
- The University of Alabama at Birmingham, Department of Optometry and Vision Science, School of Optometry, USA.
| | - Christopher R Starr
- The University of Alabama at Birmingham, Department of Optometry and Vision Science, School of Optometry, USA
| | - Oleg S Gorbatyuk
- The University of Alabama at Birmingham, Department of Optometry and Vision Science, School of Optometry, USA
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Progesterone, Lipoic Acid, and Sulforaphane as Promising Antioxidants for Retinal Diseases: A Review. Antioxidants (Basel) 2019; 8:antiox8030053. [PMID: 30832304 PMCID: PMC6466531 DOI: 10.3390/antiox8030053] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2019] [Revised: 02/21/2019] [Accepted: 02/28/2019] [Indexed: 12/19/2022] Open
Abstract
Oxidative stress has been documented to be a key factor in the cause and progression of different retinal diseases. Oxidative cellular unbalance triggers a sequence of reactions which prompt cell degeneration and retinal dysfunction, both hallmarks of several retinal pathologies. There is no effective treatment, yet, for many retinal diseases. Antioxidant treatment have been pointed out to be an encouraging palliative treatment; the beneficial effects documented involve slowing the progression of the disease, a reduction of cell degeneration, and improvement of retinal functions. There is a vast information corpus on antioxidant candidates. In this review, we expose three of the main antioxidant treatments, selected for their promising results that has been reported to date. Recently, the sulforaphane, an isothiocyanate molecule, has been unveiled as a neuroprotective candidate, by its antioxidant properties. Progesterone, a neurosteroid has been proposed to be a solid and effective neuroprotective agent. Finally, the lipoic acid, an organosulfur compound, is a well-recognized antioxidant. All of them, have been tested and studied on different retinal disease models. In this review, we summarized the published results of these works, to offer a general view of the current antioxidant treatment advances, including the main effects and mechanisms described.
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