|
1
|
D'Angelo A, Lixi F, Vitiello L, Gagliardi V, Pellegrino A, Giannaccare G. The Role of Diet and Oral Supplementation for the Management of Diabetic Retinopathy and Diabetic Macular Edema: A Narrative Review. BIOMED RESEARCH INTERNATIONAL 2025; 2025:6654976. [PMID: 40041571 PMCID: PMC11876532 DOI: 10.1155/bmri/6654976] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/29/2024] [Accepted: 02/08/2025] [Indexed: 03/06/2025]
Abstract
Globally, diabetic retinopathy (DR) and diabetic macular edema (DME) are the leading causes of visual loss in working people. Current treatment approaches mostly target proliferative DR and DME, such as intravitreal injections of antivascular endothelial growth factor agents and laser photocoagulation. Before DR progresses into the more severe, sight-threatening proliferative stage, patients with early stages of the disease must get early and appropriate care. It has been suggested that nutraceuticals, which are natural functional foods with minimal adverse effects, may help diabetic patients with DR and DME. Several in vitro and in vivo studies were carried out over the last years, showing the potential benefits of several nutraceuticals in DR due to their neuroprotective, vasoprotective, anti-inflammatory, and antioxidant properties. Although most of the research is restricted to animal models and many nutraceuticals have low bioavailability, these compounds may adjuvate and implement conventional DR therapies. The purpose of this review is (i) to summarize the complex pathophysiology underlying DR and DME and (ii) to examine the main natural-derived molecules and dietary habits that can assist conventional therapies for the clinical management of DR and DME.
Collapse
Affiliation(s)
- Angela D'Angelo
- Department of Clinical Sciences and Community Health–Department of Excellence 2023–2027, University of Milan, Milan, Italy
| | - Filippo Lixi
- Department of Surgical Sciences, Eye Clinic, University of Cagliari, Cagliari, Italy
| | - Livio Vitiello
- Department of Head and Neck, Eye Unit, “Luigi Curto” Hospital-Azienda Sanitaria Locale Salerno, Polla, Italy
| | - Vincenzo Gagliardi
- Department of Head and Neck, Eye Unit, “Luigi Curto” Hospital-Azienda Sanitaria Locale Salerno, Polla, Italy
| | - Alfonso Pellegrino
- Department of Head and Neck, Eye Unit, “Luigi Curto” Hospital-Azienda Sanitaria Locale Salerno, Polla, Italy
| | - Giuseppe Giannaccare
- Department of Surgical Sciences, Eye Clinic, University of Cagliari, Cagliari, Italy
| |
Collapse
|
|
2
|
Singh R, Walia A, Kaur J, Kumar P, Verma I, Rani N. Diabetic Retinopathy - Pathophysiology to Treatment: A Review. Curr Diabetes Rev 2025; 21:58-67. [PMID: 38315658 DOI: 10.2174/0115733998259940231105200251] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/10/2023] [Revised: 08/14/2023] [Accepted: 09/28/2023] [Indexed: 02/07/2024]
Abstract
Diabetic retinopathy (DR) is a microvascular disease affecting the eyes of diabetic patients, and is the most prevalent complication of diabetes mellitus. Vision improvement is not possible in the majority of DR patients. Several studies have indicated that microvascular changes, inflammation, oxidative stress, and retinal neurodegeneration are involved in the pathogenesis of DR. Therefore, there is an urgent need for the development of new and effective treatment for DR. Understanding the molecular mechanisms involved in the pathogenesis of disease will pave a way for better treatment and management of DR. This article has emphasized the molecular pathogenesis and treatment of DR.
Collapse
Affiliation(s)
- Randhir Singh
- Department of Pharmacology, Central University of Punjab, Bathinda, Punjab, India
- Department of Pharmacy, Graphic Era Hill University, Dehradun, India
| | - Aditya Walia
- Chitkara College of Pharmacy, Chitkara University, Punjab, India
| | - Jasleen Kaur
- Chitkara College of Pharmacy, Chitkara University, Punjab, India
| | - Praveen Kumar
- SunPharma, Hill Top Area, Vill. Bhatolikalan, P.O. Barotiwala, Distt.Solan, Himachal Pradesh, 174103, India
| | - Inderjeet Verma
- MM College of Pharmacy, Maharishi Markandeshwar (deemed to be) University, Mullana, Ambala, Haryana, India
| | - Nidhi Rani
- Chitkara College of Pharmacy, Chitkara University, Punjab, India
| |
Collapse
|
|
3
|
Koushki M, Farahani M, Yekta RF, Frazizadeh N, Bahari P, Parsamanesh N, Chiti H, Chahkandi S, Fridoni M, Amiri-Dashatan N. Potential role of resveratrol in prevention and therapy of diabetic complications: a critical review. Food Nutr Res 2024; 68:9731. [PMID: 38716357 PMCID: PMC11075469 DOI: 10.29219/fnr.v68.9731] [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: 05/23/2023] [Revised: 08/10/2023] [Accepted: 10/09/2023] [Indexed: 01/03/2025] Open
Abstract
BACKGROUND Diabetes mellitus (DM) is a category of metabolic conditions affecting about 5% of people worldwide. High mortality associated with DM is mostly due to its severe clinical complications, including diabetic nephropathy, retinopathy, neuropathy, and cardiomyopathy. Resveratrol (RSV) is a natural, biologically active polyphenol known to have various health-promoting effects in animal models and humans. OBJECTIVE In this review, we have reviewed the preventive and therapeutic role of RSV on diabetes complications with emphasis on its molecular mechanisms of action. METHODS To prepare this review, all the basic and clinical available literatures regarding this topic were gathered through electronic databases, including PubMed, Web of Science, Scopus, and Google Scholar. Therefore, we summarized previous studies that have evaluated the effects of RSV on diabetic complications and their mechanisms. Only English language studies published up to January 2023 were included in this review. RESULTS RSV improves glucose homeostasis, decreases insulin resistance, induces autophagy, regulates lipid metabolism, protects pancreatic β-cells, ameliorates metabolic disorders, and increases the GLUT4 expression. These effects induced by RSV are strongly associated with ability of this polyphenol agent to elevation expression/activity of AMP-activated protein kinase and Sirtuin 1 in various organs of diabetic subjects, which leads to prevention and therapy of diabetic complications. In addition, antioxidant and anti-inflammatory properties of RSV were reported to be involved in its action in diabetic complications, such as retinopathy and nephropathy. CONCLUSION RSV is a promising compound for improving diabetic complications. However, the exact antidiabetic mechanisms of RSV need to be further investigated.
Collapse
Affiliation(s)
- Mehdi Koushki
- Department of Clinical Biochemistry, School of Medicine, Zanjan University of Medical Sciences, Zanjan, Iran
| | - Masoumeh Farahani
- Skin Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
- Proteomics Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | | | - Naghmeh Frazizadeh
- Department of Clinical Biochemistry, School of Medicine, Zanjan University of Medical Sciences, Zanjan, Iran
| | - Parisa Bahari
- Department of Clinical Biochemistry, School of Medicine, Zanjan University of Medical Sciences, Zanjan, Iran
| | - Negin Parsamanesh
- Zanjan Metabolic Diseases Research Center, Zanjan University of Medical Sciences, Zanjan, Iran
| | - Hossein Chiti
- Zanjan Metabolic Diseases Research Center, Zanjan University of Medical Sciences, Zanjan, Iran
| | - Somayeh Chahkandi
- Zanjan Metabolic Diseases Research Center, Zanjan University of Medical Sciences, Zanjan, Iran
| | - Mohammadjavad Fridoni
- Department of Anatomy, School of Medicine, Zanjan University of Medical Sciences, Zanjan, Iran
| | - Nasrin Amiri-Dashatan
- Zanjan Metabolic Diseases Research Center, Zanjan University of Medical Sciences, Zanjan, Iran
| |
Collapse
|
|
4
|
Rodella U, Honisch C, Gatto C, Ruzza P, D'Amato Tóthová J. Antioxidant Nutraceutical Strategies in the Prevention of Oxidative Stress Related Eye Diseases. Nutrients 2023; 15:nu15102283. [PMID: 37242167 DOI: 10.3390/nu15102283] [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: 04/14/2023] [Revised: 05/04/2023] [Accepted: 05/09/2023] [Indexed: 05/28/2023] Open
Abstract
This review aims to discuss the delicate balance between the physiological production of reactive oxygen species and the role of antioxidant nutraceutical molecules in managing radicals in the complex anatomical structure of the eye. Many molecules and enzymes with reducing and antioxidant potential are present in different parts of the eye. Some of these, such as glutathione, N-acetylcysteine, α-lipoic acid, coenzyme Q10, and enzymatic antioxidants, are endogenously produced by the body. Others, such as plant-derived polyphenols and carotenoids, vitamins B2, C, and E, zinc and selenium, and omega-3 polyunsaturated fatty acids, must be obtained through the diet and are considered essential nutrients. When the equilibrium between the production of reactive oxygen species and their scavenging is disrupted, radical generation overwhelms the endogenous antioxidant arsenal, leading to oxidative stress-related eye disorders and aging. Therefore, the roles of antioxidants contained in dietary supplements in preventing oxidative stress-based ocular dysfunctions are also discussed. However, the results of studies investigating the efficacy of antioxidant supplementation have been mixed or inconclusive, indicating a need for future research to highlight the potential of antioxidant molecules and to develop new preventive nutritional strategies.
Collapse
Affiliation(s)
- Umberto Rodella
- Fondazione Banca degli Occhi del Veneto Onlus (FBOV), 30174 Zelarino, Italy
- Research and Development, AL.CHI.MI.A. S.R.L., Viale Austria 14, 35020 Ponte San Nicoló, Italy
| | - Claudia Honisch
- Institute of Biomolecular Chemistry of CNR (ICB-CNR), Via F. Marzolo, 1, 35131 Padova, Italy
| | - Claudio Gatto
- Research and Development, AL.CHI.MI.A. S.R.L., Viale Austria 14, 35020 Ponte San Nicoló, Italy
| | - Paolo Ruzza
- Institute of Biomolecular Chemistry of CNR (ICB-CNR), Via F. Marzolo, 1, 35131 Padova, Italy
| | - Jana D'Amato Tóthová
- Research and Development, AL.CHI.MI.A. S.R.L., Viale Austria 14, 35020 Ponte San Nicoló, Italy
| |
Collapse
|
|
5
|
Resveratrol: Its Path from Isolation to Therapeutic Action in Eye Diseases. Antioxidants (Basel) 2022; 11:antiox11122447. [PMID: 36552655 PMCID: PMC9774148 DOI: 10.3390/antiox11122447] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2022] [Revised: 12/05/2022] [Accepted: 12/07/2022] [Indexed: 12/14/2022] Open
Abstract
Due to the confirmed therapeutic potential of resveratrol (Rv) for eye diseases, namely its powerful anti-angiogenic and antioxidant effects, this molecule must be studied more deeply. Nowadays, the pharmaceutic and pharmacokinetic available studies offer a troubling picture because of its low stability and bioavailability. To overcome this problem, researchers started to design and create different delivery systems that could improve the delivery amount of Rv. Therefore, this review aims to shed light on the proper and efficient techniques to isolate, purify and quantify the Rv molecule, and how this therapeutic molecule can be a part of a delivery system. The Rv great impact on aspects regarding its stability, bioavailability and absorption are also debated here, based on the existent literature on in vitro and in vivo human and animal studies. Moreover, after its absorption the Rv influence at the molecular level in ocular pathologies is described. In addition, the present review summarizes the available literature about Rv, hoping that Rv will gain more attention to investigate its unexplored side.
Collapse
|
|
6
|
Hu HC, Lei YH, Zhang WH, Luo XQ. Antioxidant and Anti-inflammatory Properties of Resveratrol in Diabetic Nephropathy: A Systematic Review and Meta-analysis of Animal Studies. Front Pharmacol 2022; 13:841818. [PMID: 35355720 PMCID: PMC8959544 DOI: 10.3389/fphar.2022.841818] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2021] [Accepted: 02/18/2022] [Indexed: 12/25/2022] Open
Abstract
Background: Accumulated experimental evidence suggests that resveratrol may have an effect on diabetic nephropathy by inhibiting inflammation and decreasing oxidative stress. However, the credibility of the evidence for this practice is unclear. Thus, we aimed to perform a systematic review and meta-analysis of animal studies to evaluate the antioxidant and anti-inflammatory properties of resveratrol when used in the treatment of diabetic nephropathy. Methods: Electronic bibliographic databases including PubMed, EMBASE, and Web of Science were searched for relevant studies. The methodological quality of animal studies was assessed based on the SYstematic Review Center for Laboratory animal Experimentation Risk of Bias (SYRCLE’s RoB) tool. A meta-analysis was performed based on the Cochrane Handbook for Systematic Reviews of Interventions by using RevMan 5.4 software. This study was registered within International Prospective Register of Systematic Reviews (PROSPERO) as number CRD42021293784. Results: Thirty-six qualified studies involving 726 animals were included. There was a significant association of resveratrol with the levels of blood glucose (BG), serum creatinine (Scr), blood urea nitrogen (BUN), catalase (CAT), superoxide dismutase (SOD), malondialdehyde (MDA), glutathione (GSH), glutathione peroxidase (GPx), and interleukin-1β (IL-1β). Nevertheless, resveratrol treatment did not effectively decrease the levels of tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6). In addition, more remarkable antioxidant and hypoglycemic effects were observed in type 2 diabetic nephropathy rather than in type 1 diabetic nephropathy based on subgroup analysis. Conclusion: In this meta-analysis, resveratrol can exert its antioxidant activities by reducing the levels of MDA and recovering the activities of SOD, CAT, GSH, and GPx. With regard to pro-inflammatory cytokines, resveratrol had a positive effect on the reduction of IL-1β. However, the analysis indicated that resveratrol had no effect on IL-6 and TNF-α levels, probably because of the methodological quality of the studies and their heterogeneity. Current evidence supports the antioxidant and anti-inflammatory properties of resveratrol, but its relationship with the levels of some inflammatory cytokines such as IL-6 and TNF-α in animals with diabetic nephropathy needs further elucidation.
Collapse
Affiliation(s)
- Heng-Chang Hu
- College of Basic Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Yuan-Hong Lei
- College of Basic Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Wei-Hua Zhang
- College of Basic Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Xiao-Qiong Luo
- Department of Neurology, Chongqing Traditional Chinese Medicine Hospital, Chongqing, China
| |
Collapse
|
|
7
|
Caban M, Lewandowska U. Polyphenols and Posterior Segment Eye Diseases: Effects on Angiogenesis, Invasion, Migration and Epithelial-Mesenchymal Transition. FOOD REVIEWS INTERNATIONAL 2021. [DOI: 10.1080/87559129.2021.2012792] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Affiliation(s)
- Miłosz Caban
- Department of Biochemistry, Faculty of Medicine, Medical University of Lodz, Lodz, Poland
| | - Urszula Lewandowska
- Department of Biochemistry, Faculty of Medicine, Medical University of Lodz, Lodz, Poland
| |
Collapse
|
|
8
|
Diabetic retinal neurodegeneration as a form of diabetic retinopathy. Int Ophthalmol 2021; 41:3223-3248. [PMID: 33954860 DOI: 10.1007/s10792-021-01864-4] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2020] [Accepted: 04/08/2021] [Indexed: 12/11/2022]
Abstract
PURPOSE To review the evidence supporting diabetic retinal neurodegeneration (DRN) as a form of diabetic retinopathy. METHOD Review of literature. RESULTS DRN is recognized to be a part of retinopathy in patients with diabetes mellitus (DM), in addition to the well-established diabetic retinal vasculopathy (DRV). DRN has been noted in the early stages of DM, before the onset of clinically evident diabetic retinopathy. The occurrence of DRN has been confirmed in animal models of DM, histopathological examination of donor's eyes from diabetic individuals and assessment of neural structure and function in humans. DRN involves alterations in retinal ganglion cells, photoreceptors, amacrine cells and bipolar cells, and is thought to be driven by glutamate, oxidative stress and dysregulation of neuroprotective factors in the retina. Potential therapeutic options for DRN are under evaluation. CONCLUSIONS Literature is divided on the temporal relation between DRN and DRV, with evidence of both precedence and simultaneous occurrence. The relationship between DRN and multi-system neuropathy in DM is yet to be evaluated critically.
Collapse
|
|
9
|
Eshaq RS, Watts MN, Carter PR, Leskova W, Aw TY, Alexander JS, Harris NR. Candesartan Normalizes Changes in Retinal Blood Flow and p22phox in the Diabetic Rat Retina. PATHOPHYSIOLOGY 2021; 28:86-97. [PMID: 35366272 PMCID: PMC8830460 DOI: 10.3390/pathophysiology28010008] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2021] [Revised: 02/25/2021] [Accepted: 02/25/2021] [Indexed: 11/23/2022] Open
Abstract
Angiotensin II has been implicated in the progression of diabetic retinopathy, which is characterized by altered microvasculature, oxidative stress, and neuronal dysfunction. The signaling induced by angiotensin II can occur not only via receptor-mediated calcium release that causes vascular constriction, but also through a pathway whereby angiotensin II activates NADPH oxidase to elicit the formation of reactive oxygen species (ROS). In the current study, we administered the angiotensin II receptor antagonist candesartan (or vehicle, in untreated animals) in a rat model of type 1 diabetes in which hyperglycemia was induced by injection of streptozotocin (STZ). Eight weeks after the STZ injection, untreated diabetic rats were found to have a significant increase in tissue levels of angiotensin converting enzyme (ACE; p < 0.05) compared to non-diabetic controls, a 33% decrease in retinal blood flow rate (p < 0.001), and a dramatic increase in p22phox (a subunit of the NADPH oxidase). The decrease in retinal blood flow, and the increases in retinal ACE and p22phox in the diabetic rats, were all significantly attenuated (p < 0.05) by the administration of candesartan in drinking water within one week. Neither STZ nor candesartan induced any changes in tissue levels of superoxide dismutase (SOD-1), 4-hydroxynonenal (4-HNE), or nitrotyrosine. We conclude that one additional benefit of candesartan (and other angiotensin II antagonists) may be to normalize retinal blood flow, which may have clinical benefits in diabetic retinopathy.
Collapse
|
|
10
|
Delmas D, Cornebise C, Courtaut F, Xiao J, Aires V. New Highlights of Resveratrol: A Review of Properties against Ocular Diseases. Int J Mol Sci 2021; 22:1295. [PMID: 33525499 PMCID: PMC7865717 DOI: 10.3390/ijms22031295] [Citation(s) in RCA: 42] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2020] [Revised: 01/22/2021] [Accepted: 01/24/2021] [Indexed: 02/06/2023] Open
Abstract
Eye diseases are currently a major public health concern due to the growing number of cases resulting from both an aging of populations and exogenous factors linked to our lifestyles. Thus, many treatments including surgical pharmacological approaches have emerged, and special attention has been paid to prevention, where diet plays a preponderant role. Recently, potential antioxidants such as resveratrol have received much attention as potential tools against various ocular diseases. In this review, we focus on the mechanisms of resveratrol against ocular diseases, in particular age-related macular degeneration, glaucoma, cataract, diabetic retinopathy, and vitreoretinopathy. We analyze, in relation to the different steps of each disease, the resveratrol properties at multiple levels, such as cellular and molecular signaling as well as physiological effects. We show and discuss the relationship to reactive oxygen species, the regulation of inflammatory process, and how resveratrol can prevent ocular diseases through a potential epigenetic action by the activation of sirtuin-1. Lastly, various new forms of resveratrol delivery are emerging at the same time as some clinical trials are raising more questions about the future of resveratrol as a potential tool for prevention or in therapeutic strategies against ocular diseases. More preclinical studies are required to provide further insights into RSV's potential adjuvant activity.
Collapse
Affiliation(s)
- Dominique Delmas
- Université de Bourgogne Franche-Comté, F-21000 Dijon, France; (C.C.); (F.C.); (V.A.)
- INSERM Research Center U1231, Cancer and Adaptive Immune Response Team, Bioactive Molecules and Health Research Group, F-21000 Dijon, France
- Centre Anticancéreux Georges François Leclerc, F-21000 Dijon, France
| | - Clarisse Cornebise
- Université de Bourgogne Franche-Comté, F-21000 Dijon, France; (C.C.); (F.C.); (V.A.)
- INSERM Research Center U1231, Cancer and Adaptive Immune Response Team, Bioactive Molecules and Health Research Group, F-21000 Dijon, France
| | - Flavie Courtaut
- Université de Bourgogne Franche-Comté, F-21000 Dijon, France; (C.C.); (F.C.); (V.A.)
- INSERM Research Center U1231, Cancer and Adaptive Immune Response Team, Bioactive Molecules and Health Research Group, F-21000 Dijon, France
| | - Jianbo Xiao
- Nutrition and Bromatology Group, Department of Analytical Chemistry and Food Science, Faculty of Food Science and Technology, University of Vigo-Ourense Campus, E-32004 Ourense, Spain;
- College of Food Science and Technology, Guangdong Ocean University, Zhanjiang 524088, China
- International Research Center for Food Nutrition and Safety, Jiangsu University, Zhenjiang 212013, China
| | - Virginie Aires
- Université de Bourgogne Franche-Comté, F-21000 Dijon, France; (C.C.); (F.C.); (V.A.)
- INSERM Research Center U1231, Cancer and Adaptive Immune Response Team, Bioactive Molecules and Health Research Group, F-21000 Dijon, France
| |
Collapse
|
|
11
|
Ikonne EU, Ikpeazu VO, Ugbogu EA. The potential health benefits of dietary natural plant products in age related eye diseases. Heliyon 2020; 6:e04408. [PMID: 32685729 PMCID: PMC7355812 DOI: 10.1016/j.heliyon.2020.e04408] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2020] [Revised: 06/21/2020] [Accepted: 07/03/2020] [Indexed: 12/11/2022] Open
Abstract
In the past decade, there has been a tremendous increase in the number of cases of age-related eye diseases such as age-related macular degeneration (AMD), cataract, diabetic retinopathy and glaucoma. These diseases are the leading causes of visual impairment and blindness all over the world and are associated with many pathological risk factors such as aging, pollution, high levels of glucose (hyperglycaemia), high metabolic rates, and light exposure. These risk factors lead to the generation of uncontrollable reactive oxygen species (ROS), which causes oxidative stress. Oxidative stress plays a crucial role in the pathogenesis of age-related eye diseases through the activation of nuclear factor kappa B (NF-κB), vascular endothelial growth factor (VEGF), and lipid peroxidation, which leads to the production of inflammatory cytokines, angiogenesis, protein and DNA damages, apoptosis that causes macular degeneration (AMD), cataract, diabetic retinopathy and glaucoma. This review provides updated information on the beneficial effects of dietary natural plant products (DPNPs) against age-related eye diseases. In this review, supplementation of DPNPs demonstrated preventive and therapeutic effects on people at risk of or with age-related eye diseases due to their capacity to scavenge free radicals, ameliorate inflammatory molecules, neutralize the oxidation reaction that occurs in photoreceptor cells, decrease vascular endothelial growth factor and the blood-retinal barrier and increase the antioxidant defence system. However, further experiments and clinical trials are required to establish the daily doses of DPNPs that will safely and effectively prevent age-related eye diseases.
Collapse
Affiliation(s)
| | - Victor Okezie Ikpeazu
- Department of Biochemistry, Abia State University, P.M.B 2000, Uturu, Abia State, Nigeria
| | - Eziuche Amadike Ugbogu
- Department of Biochemistry, Abia State University, P.M.B 2000, Uturu, Abia State, Nigeria
| |
Collapse
|
|
12
|
Update on the Effects of Antioxidants on Diabetic Retinopathy: In Vitro Experiments, Animal Studies and Clinical Trials. Antioxidants (Basel) 2020; 9:antiox9060561. [PMID: 32604941 PMCID: PMC7346101 DOI: 10.3390/antiox9060561] [Citation(s) in RCA: 39] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2020] [Revised: 06/22/2020] [Accepted: 06/23/2020] [Indexed: 12/14/2022] Open
Abstract
Current therapies for diabetic retinopathy (DR) incorporate blood glucose and blood pressure control, vitrectomy, photocoagulation, and intravitreal injections of anti-vascular endothelial growth factors or corticosteroids. Nonetheless, these techniques have not been demonstrated to completely stop the evolution of this disorder. The pathophysiology of DR is not fully known, but there is more and more evidence indicating that oxidative stress is an important mechanism in the progression of DR. In this sense, antioxidants have been suggested as a possible therapy to reduce the complications of DR. In this review we aim to assemble updated information in relation to in vitro experiments, animal studies and clinical trials dealing with the effect of the antioxidants on DR.
Collapse
|
|
13
|
Huang DD, Shi G, Jiang Y, Yao C, Zhu C. A review on the potential of Resveratrol in prevention and therapy of diabetes and diabetic complications. Biomed Pharmacother 2020; 125:109767. [PMID: 32058210 DOI: 10.1016/j.biopha.2019.109767] [Citation(s) in RCA: 135] [Impact Index Per Article: 27.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2019] [Revised: 11/18/2019] [Accepted: 11/29/2019] [Indexed: 02/08/2023] Open
Abstract
Diabetes mellitus (DM) is a major world health problem and one of the most studied diseases, which are highly prevalent in the whole world, it is frequently associated with severe clinical complications, such as diabetic cardiomyopathy, nephropathy, retinopathy, neuropathy etc. Scientific research is continuously casting about for new monomer molecules from Chinese herbal medicine that could be invoked as candidate drugs for fighting against diabetes and its complications. Resveratrol (RES), a polyphenol phytoalexin, possesses diverse biochemical and physiological actions, including antiplatelet, estrogenic, and anti-inflammatory properties. It is recently gaining scientific interest for RES in controlling blood sugar and fighting against diabetes and its complications properties in various types of diabetic models. These beneficial effects seem to be due to the multiple actions of RES on cellular functions, which make RES become a promising molecule for the treatment of diabetes and diabetic complications. Here, we review the mechanism of action and potential therapeutic use of RES in prevention and mitigation of these diseases in recent ten years to provide a reference for further research and development of RES.
Collapse
Affiliation(s)
- Dan-Dan Huang
- Department of Pharmacy, The Second Affiliated Hospital of Fujian Medical University, Fujian, 362000, China
| | - Guangjiang Shi
- School of pharmacy, China Pharmaceutical University, Nanjing, 211198, China
| | - Yaping Jiang
- School of Pharmacology, Ningxia Hui Medicine Modern Engineering Research Center and Collaborative Innovation Center, Ningxia Medical University, Yinchuan, 750004, China
| | - Chao Yao
- State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Drug Discovery for Metabolic Disease, Center for New Drug Safety Evaluation and Research, China Pharmaceutical University, Nanjing, 211198, China
| | - Chuanlin Zhu
- Department of Laboratory Medicine, Chongqing Hospital of Traditional Chinese Medicine, Chongqing, 400021, China.
| |
Collapse
|
|
14
|
Attenuation of diabetic retinopathy and neuropathy by resveratrol: Review on its molecular mechanisms of action. Life Sci 2020; 245:117350. [PMID: 31982401 DOI: 10.1016/j.lfs.2020.117350] [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: 11/09/2019] [Revised: 01/13/2020] [Accepted: 01/21/2020] [Indexed: 12/16/2022]
Abstract
Resveratrol is an important phenolic phytochemical from the therapeutic perspective. It has therapeutic impacts over wide range of diseases, especially the ones related to oxidative stress. Resveratrol, being primarily a potent anti-oxidant phytochemical, has significant impact against major diseases as inflammatory disorders, diabetes, and cancer. In the current review article, we intend to highlight the molecular aspects of the mechanism of action of resveratrol against major diabetic implications, namely, retinopathy and neuropathy. Both these diabetic implications are among the first fallouts of chronic hyperglycaemia. Resveratrol, via multiple molecular pathways, tend to attenuate and reverse these deformity and other disease-causing implications.
Collapse
|
|
15
|
Fathalipour M, Eghtedari M, Borges F, Silva T, Moosavi F, Firuzi O, Mirkhani H. Caffeic Acid Alkyl Amide Derivatives Ameliorate Oxidative Stress and Modulate ERK1/2 and AKT Signaling Pathways in a Rat Model of Diabetic Retinopathy. Chem Biodivers 2019; 16:e1900405. [PMID: 31566891 DOI: 10.1002/cbdv.201900405] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2019] [Accepted: 07/21/2019] [Indexed: 12/14/2022]
Abstract
The purpose of this study was to examine the neuroprotective effects of caffeic acid hexyl (CAF6) and dodecyl (CAF12) amide derivatives on the early stage of retinopathy in streptozotocin-induced diabetic rats. Animals were divided in five groups (n=8/group); one group consisted of non-diabetic rats as control, while the other four were diabetic animals either non-treated or treated with CAF6, CAF12 or resveratrol intravitreally for four weeks. Retinal superoxide dismutase (SOD) activity and 8-iso-prostaglandin F2α (iPF2α ) levels were evaluated by an ELISA assay. Phosphorylation of ERK1/2 and AKT was determined by immunoblotting in retinal homogenates. Retinal morphology was also examined using light microscopy. Treatment with CAF6 and CAF12 increased retinal SOD activity, while it decreased iPF2α levels in diabetic rats. Phosphorylation of ERK1/2 was increased, while AKT phosphorylation was decreased in diabetic rats compared to normal control and these alterations were significantly reversed in diabetic rats treated with CAF6 and CAF12. Furthermore, thickness of the whole retinal layer, outer nuclear layer, and ganglion cell count were decreased in diabetic rats compared to control and CAF6 and CAF12 treatments prevented these changes. CAF6 and CAF12 seem to be effective agents for treatment of diabetic retinopathy via attenuation of retinal oxidative stress and improvement of neuronal survival signaling.
Collapse
Affiliation(s)
- Mohammad Fathalipour
- Department of Pharmacology, Faculty of Medicine, Medicinal and Natural Products Chemistry Research Center, Shiraz University of Medical Sciences, Shiraz, 71348-45794, Iran.,Medicinal and Natural Products Chemistry Research Center, Shiraz University of Medical Sciences, Shiraz, 71348-53734, Iran
| | - Masoomeh Eghtedari
- Department of Ophthalmology, Shiraz University of Medical Sciences, Shiraz, 71348-14336, Iran
| | - Fernanda Borges
- CIQUP/Department of Chemistry and Biochemistry, Faculty of Sciences, University of Porto, Porto, 4169-007, Portugal
| | - Tiago Silva
- CIQUP/Department of Chemistry and Biochemistry, Faculty of Sciences, University of Porto, Porto, 4169-007, Portugal
| | - Fatemeh Moosavi
- Medicinal and Natural Products Chemistry Research Center, Shiraz University of Medical Sciences, Shiraz, 71348-53734, Iran
| | - Omidreza Firuzi
- Medicinal and Natural Products Chemistry Research Center, Shiraz University of Medical Sciences, Shiraz, 71348-53734, Iran
| | - Hossein Mirkhani
- Department of Pharmacology, Faculty of Medicine, Medicinal and Natural Products Chemistry Research Center, Shiraz University of Medical Sciences, Shiraz, 71348-45794, Iran.,Medicinal and Natural Products Chemistry Research Center, Shiraz University of Medical Sciences, Shiraz, 71348-53734, Iran
| |
Collapse
|
|
16
|
Jiang T, Gu J, Chen W, Chang Q. Resveratrol inhibits high-glucose-induced inflammatory "metabolic memory" in human retinal vascular endothelial cells through SIRT1-dependent signaling. Can J Physiol Pharmacol 2019; 97:1141-1151. [PMID: 31638409 DOI: 10.1139/cjpp-2019-0201] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
Abstract
Diabetes induces vascular endothelial damage and this study investigated high-glucose-induced inflammation "metabolic memory" of human retinal vascular endothelial cells (HRVECs), the effects of resveratrol on HRVECs, and the underlying signaling. HRVECs were grown under various conditions and assayed for levels of sirtuin 1 (SIRT1); acetylated nuclear factor κB (Ac-NF-κB); NOD-like receptor family, pyrin domain containing 3 (NLRP3); and other inflammatory cytokines; and cell viability. A high glucose concentration induced HRVEC inflammation metabolic memory by decreasing SIRT1 and increasing Ac-NF-κB, NLRP3, caspase 1, interleukin-1β, inducible nitric oxide synthase, and tumor necrosis factor α, whereas exposure of HRVECs to a high glucose medium for 4 days, followed by a normal glucose concentration for an additional 4 days, failed to reverse these changes. A high glucose concentration also significantly reduced HRVEC viability. In contrast, resveratrol, a selective SIRT1 activator, markedly enhanced HRVEC viability and reduced the inflammatory cytokines expressions. In addition, high glucose reduced AMP-activated protein kinase (AMPK) phosphorylation and retained during the 4 days of the reversal period of culture. The effects of resveratrol were abrogated after co-treatment with the SIRT1 inhibitor nicotinamide and the AMPK inhibitor compound C. In conclusion, resveratrol was able to reverse high-glucose-induced inflammation "metabolic memory" of HRVECs by activation of the SIRT1/AMPK/NF-κB pathway.
Collapse
Affiliation(s)
- Tingting Jiang
- Department of Ophthalmology, Eye and ENT Hospital, Fudan University, Shanghai 200031, China.,Shanghai Key Laboratory of Visual Impairment and Restoration, Shanghai 200031, China.,Key Laboratory of Myopia of National Health Commission, Fudan University, Shanghai 200000, China.,Key Laboratory of Myopia, Chinese Academy of Medical Sciences, Shanghai 200000, China
| | - Junxiang Gu
- Department of Ophthalmology, Eye and ENT Hospital, Fudan University, Shanghai 200031, China.,Shanghai Key Laboratory of Visual Impairment and Restoration, Shanghai 200031, China.,Key Laboratory of Myopia of National Health Commission, Fudan University, Shanghai 200000, China.,Key Laboratory of Myopia, Chinese Academy of Medical Sciences, Shanghai 200000, China
| | - Wenwen Chen
- Department of Ophthalmology, Eye and ENT Hospital, Fudan University, Shanghai 200031, China.,Shanghai Key Laboratory of Visual Impairment and Restoration, Shanghai 200031, China.,Key Laboratory of Myopia of National Health Commission, Fudan University, Shanghai 200000, China.,Key Laboratory of Myopia, Chinese Academy of Medical Sciences, Shanghai 200000, China
| | - Qing Chang
- Department of Ophthalmology, Eye and ENT Hospital, Fudan University, Shanghai 200031, China.,Shanghai Key Laboratory of Visual Impairment and Restoration, Shanghai 200031, China.,Key Laboratory of Myopia of National Health Commission, Fudan University, Shanghai 200000, China.,Key Laboratory of Myopia, Chinese Academy of Medical Sciences, Shanghai 200000, China
| |
Collapse
|
|
17
|
Effect of Resveratrol on In Vitro and In Vivo Models of Diabetic Retinophathy: A Systematic Review. Int J Mol Sci 2019; 20:ijms20143503. [PMID: 31319465 PMCID: PMC6678653 DOI: 10.3390/ijms20143503] [Citation(s) in RCA: 27] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2019] [Revised: 06/19/2019] [Accepted: 07/11/2019] [Indexed: 12/21/2022] Open
Abstract
A large number of preclinical studies suggest the involvement of resveratrol in the prevention and treatment of eye diseases induced by oxidative stress and inflammation. We tested the hypothesis that resveratrol influences many pathways of in vitro and in vivo models of diabetic retinopathy through a systematic literature review of original articles. The review was conducted in accordance with the PRISMA guidelines. A literature search of all original articles published until April 2019 was performed. The terms “resveratrol” in combination with “retina”, “retinal pathology”, “diabetic retinopathy” and “eye” were searched. Possible biases were identified with the adopted SYRCLE’s tool. Eighteen articles met inclusion/exclusion criteria for full-text review. Eleven of them included in vitro experiments, 11 studies reported in vivo data and 3 studies described both in vitro and in vivo experiments. Most of the in vivo studies did not include data that would allow exclusion of bias risks, according to SYRCLE’s risk of bias tool. Both in vitro and in vivo data suggest anti-apoptotic, anti-inflammatory and anti-oxidative actions of resveratrol in models of diabetic retinopathy. However, results on its anti-angiogenic effects are contradictory and need more rigorous studies.
Collapse
|
|
18
|
Bungau S, Abdel-Daim MM, Tit DM, Ghanem E, Sato S, Maruyama-Inoue M, Yamane S, Kadonosono K. Health Benefits of Polyphenols and Carotenoids in Age-Related Eye Diseases. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2019; 2019:9783429. [PMID: 30891116 PMCID: PMC6390265 DOI: 10.1155/2019/9783429] [Citation(s) in RCA: 120] [Impact Index Per Article: 20.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/20/2018] [Revised: 09/20/2018] [Accepted: 12/18/2018] [Indexed: 12/19/2022]
Abstract
Oxidative stress and inflammation play a critical role in the initiation and progression of age-related ocular abnormalities as cataract, glaucoma, diabetic retinopathy, and macular degeneration. Therefore, phytochemicals with proven antioxidant and anti-inflammatory activities, such as carotenoids and polyphenols, could be of benefit in these diseases. We searched PubMed and Web of Science databases for original studies investigating the benefits of different carotenoids and polyphenols in age-related ophthalmic diseases. Our results showed that several polyphenols (such as anthocyanins, Ginkgo biloba, quercetin, and resveratrol) and carotenoids (such as lutein, zeaxanthin, and mezoxanthin) have shown significant preventive and therapeutic benefits against the aforementioned conditions. The involved mechanisms in these findings include mitigating the production of reactive oxygen species, inhibiting the tumor necrosis factor-α and vascular endothelial growth factor pathways, suppressing p53-dependent apoptosis, and suppressing the production of inflammatory markers, such as interleukin- (IL-) 8, IL-6, IL-1a, and endothelial leucocyte adhesion molecule-1. Consumption of products containing these phytochemicals may be protective against these diseases; however, adequate human data are lacking. This review discusses the role and mechanisms of polyphenols and carotenoids and their possible synergistic effects on the prevention and treatment of age-related eye diseases that are induced or augmented by oxidative stress and inflammation.
Collapse
Affiliation(s)
- Simona Bungau
- Pharmacy Department, Faculty of Medicine and Pharmacy, University of Oradea, Oradea, Romania
| | - Mohamed M. Abdel-Daim
- Pharmacology Department, Faculty of Veterinary Medicine, Suez Canal University, Ismailia, Egypt
- Department of Ophthalmology and Micro-technology, Yokohama City University, Yokohama, Japan
| | - Delia Mirela Tit
- Pharmacy Department, Faculty of Medicine and Pharmacy, University of Oradea, Oradea, Romania
| | - Esraa Ghanem
- Faculty of Medicine, Al-Azhar University, Cairo, Egypt
| | - Shimpei Sato
- Department of Ophthalmology and Micro-technology, Yokohama City University, Yokohama, Japan
| | - Maiko Maruyama-Inoue
- Department of Ophthalmology and Micro-technology, Yokohama City University, Yokohama, Japan
| | - Shin Yamane
- Department of Ophthalmology and Micro-technology, Yokohama City University, Yokohama, Japan
| | - Kazuaki Kadonosono
- Department of Ophthalmology and Micro-technology, Yokohama City University, Yokohama, Japan
| |
Collapse
|
|
19
|
Koushki M, Amiri‐Dashatan N, Ahmadi N, Abbaszadeh H, Rezaei‐Tavirani M. Resveratrol: A miraculous natural compound for diseases treatment. Food Sci Nutr 2018; 6:2473-2490. [PMID: 30510749 PMCID: PMC6261232 DOI: 10.1002/fsn3.855] [Citation(s) in RCA: 173] [Impact Index Per Article: 24.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2017] [Revised: 09/24/2018] [Accepted: 09/26/2018] [Indexed: 12/11/2022] Open
Abstract
Resveratrol (3, 5, 4'-trihydroxystilbene) is a nonflavonoid polyphenol that naturally occurs as phytoalexin. It is produced by plant sources such as grapes, apples, blueberries, plums, and peanut. This compound has critical roles in human health and is well known for its diverse biological activities such as antioxidant and anti-inflammatory properties. Nowadays, due to rising incidence of different diseases such as cancer and diabetes, efforts to find novel and effective disease-protective agents have led to the identification of plant-derived compounds such as resveratrol. Furthermore, several in vitro and in vivo studies have revealed the effectiveness of resveratrol in various diseases such as diabetes mellitus, cardiovascular disease, metabolic syndrome, obesity, inflammatory, neurodegenerative, and age-related diseases. This review presents an overview of currently available studies on preventive properties and essential molecular mechanisms involved in various diseases.
Collapse
Affiliation(s)
- Mehdi Koushki
- Department of BiochemistryFaculty of MedicineTehran University of Medical SciencesTehranIran
| | - Nasrin Amiri‐Dashatan
- Student Research CommitteeProteomics Research CenterShahid Beheshti University of Medical SciencesTehranIran
| | - Nayebali Ahmadi
- Proteomics Research CenterFaculty of Paramedical SciencesShahid Beheshti University of Medical SciencesTehranIran
| | | | - Mostafa Rezaei‐Tavirani
- Proteomics Research CenterFaculty of Paramedical SciencesShahid Beheshti University of Medical SciencesTehranIran
| |
Collapse
|
|
20
|
Nabavi SF, Barber AJ, Spagnuolo C, Russo GL, Daglia M, Nabavi SM, Sobarzo-Sánchez E. Nrf2 as molecular target for polyphenols: A novel therapeutic strategy in diabetic retinopathy. Crit Rev Clin Lab Sci 2016; 53:293-312. [PMID: 26926494 DOI: 10.3109/10408363.2015.1129530] [Citation(s) in RCA: 66] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
Diabetic retinopathy is a microvascular complication of diabetes that is considered one of the leading causes of blindness among adults. More than 4.4 million people suffer from this disorder throughout the world. Growing evidence suggests that oxidative stress plays a crucial role in the pathophysiology of diabetic retinopathy. Nuclear factor erythroid 2-related factor 2 (Nrf2), a redox sensitive transcription factor, plays an essential protective role in regulating the physiological response to oxidative and electrophilic stress via regulation of multiple genes encoding antioxidant proteins and phase II detoxifying enzymes. Many studies suggest that dozens of natural compounds, including polyphenols, can supress oxidative stress and inflammation through targeting Nrf2 and consequently activating the antioxidant response element-related cytoprotective genes. Therefore, Nrf2 may provide a new therapeutic target for treatment of diabetic retinopathy. In the present article, we will focus on the role of Nrf2 in diabetic retinopathy and the ability of polyphenols to target Nrf2 as a therapeutic strategy.
Collapse
Affiliation(s)
- Seyed Fazel Nabavi
- a Applied Biotechnology Research Center, Baqiyatallah University of Medical Sciences , Tehran , Iran
| | - Alistair J Barber
- b Department of Ophthalmology , Penn State Hershey Eye Center, Penn State Hershey College of Medicine , Hershey , PA , USA
| | - Carmela Spagnuolo
- c Institute of Food Sciences, National Research Council , Avellino , Italy
| | - Gian Luigi Russo
- c Institute of Food Sciences, National Research Council , Avellino , Italy
| | - Maria Daglia
- d Department of Drug Sciences , Medicinal Chemistry and Pharmaceutical Technology Section, University of Pavia , Pavia , Italy , and
| | - Seyed Mohammad Nabavi
- a Applied Biotechnology Research Center, Baqiyatallah University of Medical Sciences , Tehran , Iran
| | - Eduardo Sobarzo-Sánchez
- e Laboratory of Pharmaceutical Chemistry , Department of Organic Chemistry, Faculty of Pharmacy, University of Santiago De Compostela , Santiago De Compostela , Spain
| |
Collapse
|
|
21
|
Lee BY, Jee D, Epidemiology Survey Committee of the Korean Ophthalmology Society. Association between Grapes Intake and Diabetic Retinopathy: Inhibitory Effect of Resveratol on Diabetic Retinopathy. JOURNAL OF THE KOREAN OPHTHALMOLOGICAL SOCIETY 2016. [DOI: 10.3341/jkos.2016.57.2.276] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
Affiliation(s)
- Bo Young Lee
- Department of Ophthalmology and Visual Science, St. Vincent's Hospital, College of Medicine, The Catholic University of Korea, Suwon, Korea
| | - Donghyun Jee
- Department of Ophthalmology and Visual Science, St. Vincent's Hospital, College of Medicine, The Catholic University of Korea, Suwon, Korea
| | | |
Collapse
|
|
22
|
Hernández C, Dal Monte M, Simó R, Casini G. Neuroprotection as a Therapeutic Target for Diabetic Retinopathy. J Diabetes Res 2016; 2016:9508541. [PMID: 27123463 PMCID: PMC4830713 DOI: 10.1155/2016/9508541] [Citation(s) in RCA: 58] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/22/2015] [Revised: 02/29/2016] [Accepted: 03/16/2016] [Indexed: 02/07/2023] Open
Abstract
Diabetic retinopathy (DR) is a multifactorial progressive disease of the retina and a leading cause of vision loss. DR has long been regarded as a vascular disorder, although neuronal death and visual impairment appear before vascular lesions, suggesting an important role played by neurodegeneration in DR and the appropriateness of neuroprotective strategies. Upregulation of vascular endothelial growth factor (VEGF), the main target of current therapies, is likely to be one of the first responses to retinal hyperglycemic stress and VEGF may represent an important survival factor in early phases of DR. Of central importance for clinical trials is the detection of retinal neurodegeneration in the clinical setting, and spectral domain optical coherence tomography seems the most indicated technique. Many substances have been tested in animal studies for their neuroprotective properties and for possible use in humans. Perhaps, the most intriguing perspective is the use of endogenous neuroprotective substances or nutraceuticals. Together, the data point to the central role of neurodegeneration in the pathogenesis of DR and indicate neuroprotection as an effective strategy for treating this disease. However, clinical trials to determine not only the effectiveness and safety but also the compliance of a noninvasive route of drug administration are needed.
Collapse
Affiliation(s)
- Cristina Hernández
- CIBERDEM (CIBER de Diabetes y Enfermedades Metabolicas Asociadas) and Diabetes and Metabolism Research Unit, Vall d'Hebron Institut de Recerca (VHIR), Universitat Autonoma de Barcelona, Passeig Vall d'Hebron 119-129, 08035 Barcelona, Spain
- *Cristina Hernández: and
| | - Massimo Dal Monte
- Department of Biology, University of Pisa, Via San Zeno 31, 56127 Pisa, Italy
- Interdepartmental Research Center Nutrafood “Nutraceuticals and Food for Health”, University of Pisa, Via del Borghetto 80, 56124 Pisa, Italy
| | - Rafael Simó
- CIBERDEM (CIBER de Diabetes y Enfermedades Metabolicas Asociadas) and Diabetes and Metabolism Research Unit, Vall d'Hebron Institut de Recerca (VHIR), Universitat Autonoma de Barcelona, Passeig Vall d'Hebron 119-129, 08035 Barcelona, Spain
| | - Giovanni Casini
- Department of Biology, University of Pisa, Via San Zeno 31, 56127 Pisa, Italy
- Interdepartmental Research Center Nutrafood “Nutraceuticals and Food for Health”, University of Pisa, Via del Borghetto 80, 56124 Pisa, Italy
- *Giovanni Casini:
| |
Collapse
|
|
23
|
Modifying Choroidal Neovascularization Development with a Nutritional Supplement in Mice. Nutrients 2015; 7:5423-42. [PMID: 26153682 PMCID: PMC4517006 DOI: 10.3390/nu7075229] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2015] [Revised: 06/05/2015] [Accepted: 06/18/2015] [Indexed: 12/23/2022] Open
Abstract
We examined the effect of nutritional supplements (modified Age Related Eye Disease Study (AREDS)-II formulation containing vitamins, minerals, lutein, resveratrol, and omega-3 fatty acids) on choroidal neovascularization (CNV). Supplements were administered alone and combined with intravitreal anti-VEGF in an early-CNV (diode laser-induced) murine model. Sixty mice were evenly divided into group V (oral vehicle, intravitreal saline), group S (oral supplement, intravitreal saline), group V + aVEGF (oral vehicle, intravitreal anti-VEGF), and group S + aVEGF (oral supplement, intravitreal anti-VEGF). Vehicle and nutritional supplements were administered daily for 38 days beginning 10 days before laser. Intravitreal injections were administered 48 h after laser. Fluorescein angiography (FA) and flat-mount CD31 staining evaluated leakage and CNV lesion area. Expression of VEGF, MMP-2 and MMP-9 activity, and NLRP3 were evaluated with RT-PCR, zymography, and western-blot. Leakage, CNV size, VEGF gene and protein expression were lower in groups V + aVEGF, S + aVEGF, and S than in V (all p < 0.05). Additionally, MMP-9 gene expression differed between groups S + aVEGF and V (p < 0.05) and MMP-9 activity was lower in S + aVEGF than in V and S (both p < 0.01). Levels of MMP-2 and NLRP3 were not significantly different between groups. Nutritional supplements either alone or combined with anti-VEGF may mitigate CNV development and inhibit retinal disease involving VEGF overexpression and CNV.
Collapse
|
|
24
|
Cuenca N, Fernández-Sánchez L, Campello L, Maneu V, De la Villa P, Lax P, Pinilla I. Cellular responses following retinal injuries and therapeutic approaches for neurodegenerative diseases. Prog Retin Eye Res 2014; 43:17-75. [PMID: 25038518 DOI: 10.1016/j.preteyeres.2014.07.001] [Citation(s) in RCA: 316] [Impact Index Per Article: 28.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2014] [Revised: 07/03/2014] [Accepted: 07/07/2014] [Indexed: 01/17/2023]
Abstract
Retinal neurodegenerative diseases like age-related macular degeneration, glaucoma, diabetic retinopathy and retinitis pigmentosa each have a different etiology and pathogenesis. However, at the cellular and molecular level, the response to retinal injury is similar in all of them, and results in morphological and functional impairment of retinal cells. This retinal degeneration may be triggered by gene defects, increased intraocular pressure, high levels of blood glucose, other types of stress or aging, but they all frequently induce a set of cell signals that lead to well-established and similar morphological and functional changes, including controlled cell death and retinal remodeling. Interestingly, an inflammatory response, oxidative stress and activation of apoptotic pathways are common features in all these diseases. Furthermore, it is important to note the relevant role of glial cells, including astrocytes, Müller cells and microglia, because their response to injury is decisive for maintaining the health of the retina or its degeneration. Several therapeutic approaches have been developed to preserve retinal function or restore eyesight in pathological conditions. In this context, neuroprotective compounds, gene therapy, cell transplantation or artificial devices should be applied at the appropriate stage of retinal degeneration to obtain successful results. This review provides an overview of the common and distinctive features of retinal neurodegenerative diseases, including the molecular, anatomical and functional changes caused by the cellular response to damage, in order to establish appropriate treatments for these pathologies.
Collapse
Affiliation(s)
- Nicolás Cuenca
- Department of Physiology, Genetics and Microbiology, University of Alicante, Alicante, Spain; Multidisciplinary Institute for Environmental Studies "Ramon Margalef", University of Alicante, Alicante, Spain.
| | - Laura Fernández-Sánchez
- Department of Physiology, Genetics and Microbiology, University of Alicante, Alicante, Spain
| | - Laura Campello
- Department of Physiology, Genetics and Microbiology, University of Alicante, Alicante, Spain
| | - Victoria Maneu
- Department of Optics, Pharmacology and Anatomy, University of Alicante, Alicante, Spain
| | - Pedro De la Villa
- Department of Systems Biology, University of Alcalá, Alcalá de Henares, Spain
| | - Pedro Lax
- Department of Physiology, Genetics and Microbiology, University of Alicante, Alicante, Spain
| | - Isabel Pinilla
- Department of Ophthalmology, Lozano Blesa University Hospital, Aragon Institute of Health Sciences, Zaragoza, Spain
| |
Collapse
|
|
25
|
Ha JH, Shil PK, Zhu P, Gu L, Li Q, Chung S. Ocular inflammation and endoplasmic reticulum stress are attenuated by supplementation with grape polyphenols in human retinal pigmented epithelium cells and in C57BL/6 mice. J Nutr 2014; 144:799-806. [PMID: 24699803 PMCID: PMC6611528 DOI: 10.3945/jn.113.186957] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023] Open
Abstract
Inflammation and endoplasmic reticulum (ER) stress are common denominators for vision-threatening diseases such as diabetic retinopathy and age-related macular degeneration. Based on our previous study, supplementation with muscadine grape polyphenols (MGPs) alleviated systemic insulin resistance and proinflammatory responses. In this study, we hypothesized that MGPs would also be effective in attenuating ocular inflammation and ER stress. We tested this hypothesis using the human retinal pigmented epithelium (ARPE-19) cells and C57BL/6 mice. In ARPE-19 cells, tumor necrosis factor-α-induced proinflammatory gene expression of interleukin (IL)-1β, IL-6, and monocyte chemotactic protein-1 was decreased by 35.0%, 68.8%, and 62.5%, respectively, with MGP pretreatment, which was primarily due to the diminished mitogen-activated protein kinase activation and subsequent reduction of nuclear factor κ-B activation. Consistently, acute ocular inflammation and leukocyte infiltration were almost completely dampened (>95%) by MGP supplementation (100-200 mg/kg body weight) in C57BL/6 mice. Moreover, MGPs reduced inflammation-mediated loss of tight junctions and retinal permeability. To further investigate the protective roles of MGPs against ER stress, ARPE-19 cells were stimulated with thapsigargin. Pretreatment with MGPs significantly decreased the following: 1) ER stress-mediated vascular endothelial growth factor secretion (3.47 ± 0.06 vs. 1.58 ± 0.02 μg/L, P < 0.0001), 2) unfolded protein response, and 3) early apoptotic cell death (64.4 ± 6.85 vs. 33.7 ± 4.32%, P = 0.0003). Collectively, we have demonstrated that MGP is effective in attenuating ocular inflammation and ER stress. Our work also suggests that MGP may provide a novel dietary strategy to prevent vision-threatening retinal diseases.
Collapse
Affiliation(s)
- Jung-Heun Ha
- Department of Food Science and Human Nutrition, University of Florida,
Gainesville, FL
| | | | - Ping Zhu
- Department of Ophthalmology, University of Florida, Gainesville, FL
| | - Liwei Gu
- Department of Food Science and Human Nutrition, University of Florida,
Gainesville, FL
| | - Qiuhong Li
- Department of Ophthalmology, University of Florida, Gainesville, FL
| | | |
Collapse
|
|
26
|
Bola C, Bartlett H, Eperjesi F. Resveratrol and the eye: activity and molecular mechanisms. Graefes Arch Clin Exp Ophthalmol 2014; 252:699-713. [DOI: 10.1007/s00417-014-2604-8] [Citation(s) in RCA: 58] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2013] [Revised: 02/17/2014] [Accepted: 02/20/2014] [Indexed: 12/27/2022] Open
|
|
27
|
Botanical compounds: effects on major eye diseases. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE 2013; 2013:549174. [PMID: 23843879 PMCID: PMC3703386 DOI: 10.1155/2013/549174] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/01/2013] [Accepted: 05/22/2013] [Indexed: 12/19/2022]
Abstract
Botanical compounds have been widely used throughout history as cures for various diseases and ailments. Many of these compounds exhibit strong antioxidative, anti-inflammatory, and antiapoptotic properties. These are also common damaging mechanisms apparent in several ocular diseases, including age-related macular degeneration (AMD), glaucoma, diabetic retinopathy, cataract, and retinitis pigmentosa. In recent years, there have been many epidemiological and clinical studies that have demonstrated the beneficial effects of plant-derived compounds, such as curcumin, lutein and zeaxanthin, danshen, ginseng, and many more, on these ocular pathologies. Studies in cell cultures and animal models showed promising results for their uses in eye diseases. While there are many apparent significant correlations, further investigation is needed to uncover the mechanistic pathways of these botanical compounds in order to reach widespread pharmaceutical use and provide noninvasive alternatives for prevention and treatments of the major eye diseases.
Collapse
|
|
28
|
Abstract
Diabetic retinopathy (DR) and age-related macular degeneration (AMD) are the leading causes of blindness in adults. The impact of these conditions on the quality of life is increasing in significance with a rise in life expectancy. The role of hyperglycemia, oxidative stress and inflammatory responses in the development and/or progression of DR and AMD, and several other sight threatening ocular diseases, is well established. In proliferative retinopathy, signals sent by the retina for nourishment, triggers the growth of fragile and abnormal blood vessels. Changes in ocular pressure may lead to rupture of these blood vessels causing severe vision problems. Recent in vitro and preclinical studies demonstrate that certain phytochemicals possessing potent antioxidant and anti-inflammatory activity and ocular blood flow enhancing properties may be very useful in the treatment of, or as a prophylactic measure for, DR and AMD. Apart from these properties they have also been investigated for their anti-bacterial, hormonal, enzyme stimulation, and anti-angiogenic activities. The attractive aspect of these potential therapeutic candidates is that they can act on multiple pathways identified in the etiology of DR, AMD, cataract and other ocular diseases. However, results from clinical trials have been somewhat ambiguous, raising questions about the concentrations of these bioflavonoids achieved in the neural retina following oral administration. Unfortunately, as of date, an efficient noninvasive means to deliver therapeutic agents/candidates to the back-of-the eye is still not available. This review examines some of these promising natural agents and discusses the challenges encountered in delivering them to the posterior segment ocular tissues through the oral route.
Collapse
|
|
29
|
Zhang W, Yan H. Dysfunction of circulating endothelial progenitor cells in type 1 diabetic rats with diabetic retinopathy. Graefes Arch Clin Exp Ophthalmol 2013; 251:1123-31. [PMID: 23385543 DOI: 10.1007/s00417-013-2267-x] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2012] [Revised: 12/27/2012] [Accepted: 01/15/2013] [Indexed: 12/27/2022] Open
Abstract
PURPOSE To investigate the role of endothelial progenitor cell (EPC) in the pathogenesis of diabetic retinopathy (DR) in streptozotocin (STZ)-induced type 1 diabetes mellitus (T1DM) rats. METHODS A total of 160 male Wistar rats (12 weeks old; 250-350 g) were randomly assigned into four groups (n = 40 for each), including control (group 1, no treatment), T1DM1 (group 2, 1 month after 50 mg/kg of STZ, single i.p.), T1DM3 (group 3, 3 months after 50 mg/kg of STZ, single i.p.), T1DM6 (group 4, 6 months after 50 mg/kg of STZ, single i.p.). Enumeration of circulating EPC from peripheral blood was measured by flow cytometry. EPC from bone marrow of rats was cultured in vitro to evaluate its function of proliferation, adhesion, and migration activities. Plasma levels of vascular endothelial growth factor (VEGF) and nitric oxide (NO) were measured by enzyme-linked immunosorbent assay (ELISA). Retinal sections were imaged by light microscopy and a transmission electron microscope (TEM). RESULTS The numbers of circulating EPC were significantly decreased in diabetic groups compared with the control group. Impaired proliferation, adhesion, and migratory activities of cultured EPC were observed in diabetic groups. There were significantly higher levels of plasma VEGF but lower levels of plasma NO in diabetic groups than those in non-diabetic controls. The significantly reduced thickness and obvious disorganized retinal cell layers were seen in T1DM DR rats. In the diabetic groups, we also found that T1DM rats developed telangiectatic vessels, vacuolar degeneration of ganglion cells, and thickened capillary basement membrane with capillary lumen stenosis in the retina. Significantly raised EPC numbers during DR formation and progression were also found. CONCLUSIONS The reduced numbers and impaired function of circulating EPC may contribute to the pathogenesis of DR in T1DM rats.
Collapse
Affiliation(s)
- Wei Zhang
- Department of Ophthalmology, Tianjin Medical University General Hospital, No. 154, Anshan Road, Tianjin 300052, China
| | | |
Collapse
|
|
30
|
Mohammad G, Mairaj Siddiquei M, Imtiaz Nawaz M, Abu El-Asrar AM. The ERK1/2 Inhibitor U0126 Attenuates Diabetes-Induced Upregulation of MMP-9 and Biomarkers of Inflammation in the Retina. J Diabetes Res 2013; 2013:658548. [PMID: 23671886 PMCID: PMC3647581 DOI: 10.1155/2013/658548] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/21/2013] [Accepted: 03/25/2013] [Indexed: 12/11/2022] Open
Abstract
This study was conducted to determine the expression of matrix metalloproteinase-9 (MMP-9) and tissue inhibitor of metalloproteinase-1 (TIMP-1) in a time-dependent manner and the effect of extracellular-signal-regulated kinases-1/2 (ERK1/2) inhibition on the expressions of MMP-9, TIMP-1, and inflammatory biomarkers in the retinas of diabetic rats. The expression of MMP-9 was quantified by zymography, and the mRNA level of MMP-9 and TIMP-1 was quantified by RT-PCR. The expression of inducible nitric oxide synthase (iNOS), interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF- α ) was examined by Western blot analysis. MMP-9 expression was significantly higher in diabetic rat retinas compared to controls at all time points.TIMP-1 expression was nonsignificantly upregulated at 1week of diabetes and was significantly downregulated at 4 and 12 weeks of diabetes. Intravitreal administration of the ERK1/2 inhibitor U0126 prior to induction of diabetes decreased ERK1/2 activation, attenuated diabetes-induced upregulation of MMP-9, iNOS, IL-6, and TNF- α and upregulated TIMP-1 expression. In MMP-9 knockout mice, diabetes had no effect on retinal iNOS expression and its level remained unchanged. These data provide evidence that ERK1/2 signaling pathway is involved in MMP-9, iNOS, IL-6, and TNF- α induction in diabetic retinas and suggest that ERK1/2 can be a novel therapeutic target in diabetic retinopathy.
Collapse
Affiliation(s)
- Ghulam Mohammad
- Department of Ophthalmology, College of Medicine, King Saud University, P.O. Box 245, Riyadh 11411, Saudi Arabia
- *Ghulam Mohammad:
| | - Mohammad Mairaj Siddiquei
- Department of Ophthalmology, College of Medicine, King Saud University, P.O. Box 245, Riyadh 11411, Saudi Arabia
| | - Mohammad Imtiaz Nawaz
- Department of Ophthalmology, College of Medicine, King Saud University, P.O. Box 245, Riyadh 11411, Saudi Arabia
| | - Ahmed M. Abu El-Asrar
- Department of Ophthalmology, College of Medicine, King Saud University, P.O. Box 245, Riyadh 11411, Saudi Arabia
| |
Collapse
|
|
31
|
Lai AKW, Lo ACY. Animal models of diabetic retinopathy: summary and comparison. J Diabetes Res 2013; 2013:106594. [PMID: 24286086 PMCID: PMC3826427 DOI: 10.1155/2013/106594] [Citation(s) in RCA: 142] [Impact Index Per Article: 11.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/10/2013] [Revised: 09/02/2013] [Accepted: 09/02/2013] [Indexed: 12/16/2022] Open
Abstract
Diabetic retinopathy (DR) is a microvascular complication associated with chronic exposure to hyperglycemia and is a major cause of blindness worldwide. Although clinical assessment and retinal autopsy of diabetic patients provide information on the features and progression of DR, its underlying pathophysiological mechanism cannot be deduced. In order to have a better understanding of the development of DR at the molecular and cellular levels, a variety of animal models have been developed. They include pharmacological induction of hyperglycemia and spontaneous diabetic rodents as well as models of angiogenesis without diabetes (to compensate for the absence of proliferative DR symptoms). In this review, we summarize the existing protocols to induce diabetes using STZ. We also describe and compare the pathological presentations, in both morphological and functional aspects, of the currently available DR animal models. The advantages and disadvantages of using different animals, ranging from zebrafish, rodents to other higher-order mammals, are also discussed. Until now, there is no single model that displays all the clinical features of DR as seen in human. Yet, with the understanding of the pathological findings in these animal models, researchers can select the most suitable models for mechanistic studies or drug screening.
Collapse
Affiliation(s)
- Angela Ka Wai Lai
- Department of Ophthalmology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong
| | - Amy C. Y. Lo
- Department of Ophthalmology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong
- Research Center of Heart, Brain, Hormone and Healthy Aging, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong
- *Amy C. Y. Lo:
| |
Collapse
|