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Zheng Z, Yu X. Insulin resistance in the retina: possible implications for certain ocular diseases. Front Endocrinol (Lausanne) 2024; 15:1415521. [PMID: 38952394 PMCID: PMC11215121 DOI: 10.3389/fendo.2024.1415521] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/10/2024] [Accepted: 06/05/2024] [Indexed: 07/03/2024] Open
Abstract
Insulin resistance (IR) is becoming a worldwide medical and public health challenge as an increasing prevalence of obesity and metabolic disorders. Accumulated evidence has demonstrated a strong relationship between IR and a higher incidence of several dramatically vision-threatening retinal diseases, including diabetic retinopathy, age-related macular degeneration, and glaucoma. In this review, we provide a schematic overview of the associations between IR and certain ocular diseases and further explore the possible mechanisms. Although the exact causes explaining these associations have not been fully elucidated, underlying mechanisms of oxidative stress, chronic low-grade inflammation, endothelial dysfunction and vasoconstriction, and neurodegenerative impairments may be involved. Given that IR is a modifiable risk factor, it may be important to identify patients at a high IR level with prompt treatment, which may decrease the risk of developing certain ocular diseases. Additionally, improving IR through the activation of insulin signaling pathways could become a potential therapeutic target.
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Affiliation(s)
- Zhaoxia Zheng
- Department of Ophthalmology, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing, China
- Graduate School of Peking Union Medical College, Beijing, China
| | - Xiaobing Yu
- Department of Ophthalmology, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing, China
- Graduate School of Peking Union Medical College, Beijing, China
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2
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Liu Y, Wang D, Liu YP. Metabolite profiles of diabetes mellitus and response to intervention in anti-hyperglycemic drugs. Front Endocrinol (Lausanne) 2023; 14:1237934. [PMID: 38027178 PMCID: PMC10644798 DOI: 10.3389/fendo.2023.1237934] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/10/2023] [Accepted: 10/16/2023] [Indexed: 12/01/2023] Open
Abstract
Type 2 diabetes mellitus (T2DM) has become a major health problem, threatening the quality of life of nearly 500 million patients worldwide. As a typical multifactorial metabolic disease, T2DM involves the changes and interactions of various metabolic pathways such as carbohydrates, amino acid, and lipids. It has been suggested that metabolites are not only the endpoints of upstream biochemical processes, but also play a critical role as regulators of disease progression. For example, excess free fatty acids can lead to reduced glucose utilization in skeletal muscle and induce insulin resistance; metabolism disorder of branched-chain amino acids contributes to the accumulation of toxic metabolic intermediates, and promotes the dysfunction of β-cell mitochondria, stress signal transduction, and apoptosis. In this paper, we discuss the role of metabolites in the pathogenesis of T2DM and their potential as biomarkers. Finally, we list the effects of anti-hyperglycemic drugs on serum/plasma metabolic profiles.
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Affiliation(s)
| | | | - Yi-Ping Liu
- Provincial University Key Laboratory of Sport and Health Science, School of Physical Education and Sport Sciences, Fujian Normal University, Fuzhou, China
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3
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Sadikan MZ, Abdul Nasir NA, Lambuk L, Mohamud R, Reshidan NH, Low E, Singar SA, Mohmad Sabere AS, Iezhitsa I, Agarwal R. Diabetic retinopathy: a comprehensive update on in vivo, in vitro and ex vivo experimental models. BMC Ophthalmol 2023; 23:421. [PMID: 37858128 PMCID: PMC10588156 DOI: 10.1186/s12886-023-03155-1] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2023] [Accepted: 09/26/2023] [Indexed: 10/21/2023] Open
Abstract
Diabetic retinopathy (DR), one of the leading causes of visual impairment and blindness worldwide, is one of the major microvascular complications in diabetes mellitus (DM). Globally, DR prevalence among DM patients is 25%, and 6% have vision-threatening problems among them. With the higher incidence of DM globally, more DR cases are expected to be seen in the future. In order to comprehend the pathophysiological mechanism of DR in humans and discover potential novel substances for the treatment of DR, investigations are typically conducted using various experimental models. Among the experimental models, in vivo models have contributed significantly to understanding DR pathogenesis. There are several types of in vivo models for DR research, which include chemical-induced, surgical-induced, diet-induced, and genetic models. Similarly, for the in vitro models, there are several cell types that are utilised in DR research, such as retinal endothelial cells, Müller cells, and glial cells. With the advancement of DR research, it is essential to have a comprehensive update on the various experimental models utilised to mimic DR environment. This review provides the update on the in vitro, in vivo, and ex vivo models used in DR research, focusing on their features, advantages, and limitations.
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Affiliation(s)
- Muhammad Zulfiqah Sadikan
- Department of Pharmacology, Faculty of Medicine, Manipal University College Malaysia (MUCM), Bukit Baru, 75150, Melaka, Malaysia
| | - Nurul Alimah Abdul Nasir
- Centre for Neuroscience Research (NeuRon), Faculty of Medicine, Universiti Teknologi MARA, 47000, Sungai Buloh, Selangor, Malaysia.
| | - Lidawani Lambuk
- Department of Immunology, School of Medical Sciences, Universiti Sains Malaysia, 16150, Kubang Kerian, Kelantan, Malaysia
| | - Rohimah Mohamud
- Department of Immunology, School of Medical Sciences, Universiti Sains Malaysia, 16150, Kubang Kerian, Kelantan, Malaysia
| | - Nur Hidayah Reshidan
- School of Biology, Faculty of Applied Sciences, Universiti Teknologi MARA, 40450, Shah Alam, Selangor, Malaysia
| | - Evon Low
- Ageing Biology Centre, Newcastle University, NE1 7RU, Newcastle upon Tyne, UK
| | - Saiful Anuar Singar
- Department of Nutrition and Integrative Physiology, College of Health and Human Sciences, Florida State University, 32306, Tallahassee, FL, USA
| | - Awis Sukarni Mohmad Sabere
- Kulliyyah of Pharmacy, International Islamic University Malaysia, Jalan Sultan Ahmad Shah, Bandar Indera Mahkota, 25200, Kuantan, Pahang, Malaysia
| | - Igor Iezhitsa
- School of Medicine, International Medical University, 57000, Bukit Jalil, Kuala Lumpur, Malaysia
- Department of Pharmacology and Bioinformatics, Volgograd State Medical University, Pavshikh Bortsov sq. 1, 400131 , Volgograd, Russian Federation
| | - Renu Agarwal
- School of Medicine, International Medical University, 57000, Bukit Jalil, Kuala Lumpur, Malaysia
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Hayden MR. Overview and New Insights into the Metabolic Syndrome: Risk Factors and Emerging Variables in the Development of Type 2 Diabetes and Cerebrocardiovascular Disease. Medicina (B Aires) 2023; 59:medicina59030561. [PMID: 36984562 PMCID: PMC10059871 DOI: 10.3390/medicina59030561] [Citation(s) in RCA: 22] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2023] [Revised: 03/04/2023] [Accepted: 03/10/2023] [Indexed: 03/16/2023] Open
Abstract
Metabolic syndrome (MetS) is considered a metabolic disorder that has been steadily increasing globally and seems to parallel the increasing prevalence of obesity. It consists of a cluster of risk factors which traditionally includes obesity and hyperlipidemia, hyperinsulinemia, hypertension, and hyperglycemia. These four core risk factors are associated with insulin resistance (IR) and, importantly, the MetS is known to increase the risk for developing cerebrocardiovascular disease and type 2 diabetes mellitus. The MetS had its early origins in IR and syndrome X. It has undergone numerous name changes, with additional risk factors and variables being added over the years; however, it has remained as the MetS worldwide for the past three decades. This overview continues to add novel insights to the MetS and suggests that leptin resistance with hyperleptinemia, aberrant mitochondrial stress and reactive oxygen species (ROS), impaired folate-mediated one-carbon metabolism with hyperhomocysteinemia, vascular stiffening, microalbuminuria, and visceral adipose tissues extracellular vesicle exosomes be added to the list of associated variables. Notably, the role of a dysfunctional and activated endothelium and deficient nitric oxide bioavailability along with a dysfunctional and attenuated endothelial glycocalyx, vascular inflammation, systemic metainflammation, and the important role of ROS and reactive species interactome are discussed. With new insights and knowledge regarding the MetS comes the possibility of new findings through further research.
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Affiliation(s)
- Melvin R Hayden
- Department of Internal Medicine, Endocrinology Diabetes and Metabolism, Diabetes and Cardiovascular Disease Center, University of Missouri School of Medicine, One Hospital Drive, Columbia, MO 65211, USA
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Retinitis Pigmentosa (RP): The Role of Oxidative Stress in the Degenerative Process Progression. Biomedicines 2022; 10:biomedicines10030582. [PMID: 35327384 PMCID: PMC8945005 DOI: 10.3390/biomedicines10030582] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2022] [Revised: 02/20/2022] [Accepted: 02/23/2022] [Indexed: 02/05/2023] Open
Abstract
Purpose: Retinitis Pigmentosa is a term that includes a group of inherited bilateral and progressive retinal degenerations, with the involvement of rod photoreceptors, which frequently leads to blindness; oxidative stress may be involved in the degeneration progression as proposed by several recent studies. The goal of this study is to evaluate whether circulating free radicals taken from capillary blood are related to one of the most important features of Retinitis pigmentosa that can affect frequently patients: cystoid macular oedema (CME). Materials: A total of 186 patients with Retinitis Pigmentosa (range: 25−69 years) were enrolled; all patients completed an ophthalmologic examination and SD-OCT at baseline and were divided into three subgroups according to the SD-OCT features. ROS blood levels were determined using FORT with monitoring of free oxygen radicals. Results: Test levels of free oxygen radicals were significantly increased, almost twice, in RP patients showing cystoid macular oedema and significantly increased compared to the control group. (p < 0.001). Discussion: Our findings suggest that oxidative stress may speed cone photoreceptors’ morphological damage (CMT); because long lasting oxidative stress in the RP may cause oxidative damage, with animal models of RP suggesting this is a micromolecular mechanism of photoreceptors’ (cone) death, it can be similar to cone damage in human RP eyes. The limitations of this paper are the relatively small sample, the horizontal design of the study, and the lack of data about the levels of ROS in the vitreous body.
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Pitale PM, Gorbatyuk MS. Diabetic Retinopathy: From Animal Models to Cellular Signaling. Int J Mol Sci 2022; 23:ijms23031487. [PMID: 35163410 PMCID: PMC8835767 DOI: 10.3390/ijms23031487] [Citation(s) in RCA: 29] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2021] [Revised: 01/24/2022] [Accepted: 01/26/2022] [Indexed: 12/24/2022] Open
Abstract
Diabetic retinopathy (DR) is an ocular complication of diabetes mellitus (DM), a metabolic disorder characterized by elevation in blood glucose level. The pathogenesis of DR includes vascular, neuronal, and inflammatory components leading to activation of complex cellular molecular signaling. If untreated, the disease can culminate in vision loss that eventually leads to blindness. Animal models mimicking different aspects of DM complications have been developed to study the development and progression of DR. Despite the significant contribution of the developed DR models to discovering the mechanisms of DR and the recent achievements in the research field, the sequence of cellular events in diabetic retinas is still under investigation. Partially, this is due to the complexity of molecular mechanisms, although the lack of availability of models that adequately mimic all the neurovascular pathobiological features observed in patients has also contributed to the delay in determining a precise molecular trigger. In this review, we provide an update on the status of animal models of DR to help investigators choose an appropriate system to validate their hypothesis. We also discuss the key cellular and physiological events of DR in these models.
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Affiliation(s)
- Priyamvada M. Pitale
- Department of Ophthalmology, Baylor College of Medicine, Houston, TX 77030, USA;
| | - Marina S. Gorbatyuk
- Department of Optometry and Vision Science, School of Optometry, University of Alabama at Birmingham, Birmingham, AL 35294, USA
- Correspondence: ; Tel.: +1-205-934-6762; Fax: +1-205-934-3425
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Hayden MR, Tyagi SC. Impaired Folate-Mediated One-Carbon Metabolism in Type 2 Diabetes, Late-Onset Alzheimer's Disease and Long COVID. MEDICINA (KAUNAS, LITHUANIA) 2021; 58:16. [PMID: 35056324 PMCID: PMC8779539 DOI: 10.3390/medicina58010016] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/11/2021] [Revised: 12/18/2021] [Accepted: 12/21/2021] [Indexed: 12/25/2022]
Abstract
Impaired folate-mediated one-carbon metabolism (FOCM) is associated with many pathologies and developmental abnormalities. FOCM is a metabolic network of interdependent biosynthetic pathways that is known to be compartmentalized in the cytoplasm, mitochondria and nucleus. Currently, the biochemical mechanisms and causal metabolic pathways responsible for the initiation and/or progression of folate-associated pathologies have yet to be fully established. This review specifically examines the role of impaired FOCM in type 2 diabetes mellitus, Alzheimer's disease and the emerging Long COVID/post-acute sequelae of SARS-CoV-2 (PASC). Importantly, elevated homocysteine may be considered a biomarker for impaired FOCM, which is known to result in increased oxidative-redox stress. Therefore, the incorporation of hyperhomocysteinemia will be discussed in relation to impaired FOCM in each of the previously listed clinical diseases. This review is intended to fill gaps in knowledge associated with these clinical diseases and impaired FOCM. Additionally, some of the therapeutics will be discussed at this early time point in studying impaired FOCM in each of the above clinical disease states. It is hoped that this review will allow the reader to better understand the role of FOCM in the development and treatment of clinical disease states that may be associated with impaired FOCM and how to restore a more normal functional role for FOCM through improved nutrition and/or restoring the essential water-soluble B vitamins through oral supplementation.
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Affiliation(s)
- Melvin R. Hayden
- Departments of Internal Medicine, Endocrinology Diabetes and Metabolism Diabetes and Cardiovascular Disease Center, University of Missouri School of Medicine, Columbia, MO 65212, USA
| | - Suresh C. Tyagi
- Department of Physiology, University of Louisville School of Medicine, Louisville, KY 40202, USA;
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Gut microbiota: A potential therapeutic target for management of diabetic retinopathy? Life Sci 2021; 286:120060. [PMID: 34666038 DOI: 10.1016/j.lfs.2021.120060] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2021] [Revised: 10/04/2021] [Accepted: 10/12/2021] [Indexed: 12/12/2022]
Abstract
Diabetic Retinopathy (DR) is one of the main complications of Diabetes Mellitus (DM), drastically impacting individuals of working age over the years, being one of the main causes of blindness in the world. The existing therapies for its treatment consist of measures that aim only to alleviate the existing clinical signs, associated with the microvasculature. These treatments are limited only to the advanced stages and not to the preclinical ones. In response to a treatment with little resolution and limited for many patients with DM, investigations of alternative therapies that make possible the improvement of the glycemic parameters and the quality of life of subjects with DR, become extremely necessary. Recent evidence has shown that deregulation of the microbiota (dysbiosis) can lead to low-grade, local and systemic inflammation, directly impacting the development of DM and its microvascular complications, including DR, in an axis called the intestine-retina. In this regard, the present review seeks to comprehensively describe the biochemical pathways involved in DR as well as the association of the modulation of these mechanisms by the intestinal microbiota, since direct changes in the microbiota can have a drastic impact on various physiological processes. Finally, emphasize the strong potential for modulation of the gut-retina axis, as therapeutic and prophylactic target for the treatment of DR.
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Rodríguez ML, Millán I, Ortega ÁL. Cellular targets in diabetic retinopathy therapy. World J Diabetes 2021; 12:1442-1462. [PMID: 34630899 PMCID: PMC8472497 DOI: 10.4239/wjd.v12.i9.1442] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/26/2021] [Revised: 05/08/2021] [Accepted: 08/03/2021] [Indexed: 02/06/2023] Open
Abstract
Despite the existence of treatment for diabetes, inadequate metabolic control triggers the appearance of chronic complications such as diabetic retinopathy. Diabetic retinopathy is considered a multifactorial disease of complex etiology in which oxidative stress and low chronic inflammation play essential roles. Chronic exposure to hyperglycemia triggers a loss of redox balance that is critical for the appearance of neuronal and vascular damage during the development and progression of the disease. Current therapies for the treatment of diabetic retinopathy are used in advanced stages of the disease and are unable to reverse the retinal damage induced by hyperglycemia. The lack of effective therapies without side effects means there is an urgent need to identify an early action capable of preventing the development of the disease and its pathophysiological consequences in order to avoid loss of vision associated with diabetic retinopathy. Therefore, in this review we propose different therapeutic targets related to the modulation of the redox and inflammatory status that, potentially, can prevent the development and progression of the disease.
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Affiliation(s)
- María Lucía Rodríguez
- Department of Physiology, Faculty of Pharmacy, University of Valencia, Burjassot 46100, Valencia, Spain
| | - Iván Millán
- Neonatal Research Group, Health Research Institute La Fe, Valencia 46026, Valencia, Spain
| | - Ángel Luis Ortega
- Department of Physiology, Faculty of Pharmacy, University of Valencia, Burjassot 46100, Valencia, Spain
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Quiroz J, Yazdanyar A. Animal models of diabetic retinopathy. ANNALS OF TRANSLATIONAL MEDICINE 2021; 9:1272. [PMID: 34532409 PMCID: PMC8421981 DOI: 10.21037/atm-20-6737] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/04/2020] [Accepted: 12/23/2020] [Indexed: 12/16/2022]
Abstract
The retina is the posterior neuro-integrated layer of the eye that conducts impulses induced by light to the optic nerve for human vision. Diseases of the retina often leads to diminished vision and in some cases blindness. Diabetes mellitus (DM) is a worldwide public health issue and globally, there is an estimated 463 million people that are affected by DM and its consequences. Diabetic retinopathy (DR) is a blinding complication of chronic uncontrolled DM and is the most common cause of blindness in the United States between the ages 24-75. It is estimated that the global prevalence of DR will increase to 191.0 million by 2030, of those 56.3 million possessing vision-threatening diabetic retinopathy (VTDR). For the most part, current treatment modalities control the complications of DR without addressing the underlying pathophysiology of the disease. Therefore, there is an unmet need for new therapeutics that not only repair the damaged retinal tissue, but also reverse the course of DR. The key element in developing these treatments is expanding our basic knowledge by studying DR pathogenesis in animal models of proliferative and non-proliferative DR (PDR and NPDR). There are numerous models available for the research of both PDR and NPDR with substantial overlap. Animal models available include those with genetic backgrounds prone to hyperglycemic states, immunologic etiologies, or environmentally induced disease. In this review we aimed to comprehensively summarize the available animal models for DR while also providing insight to each model's ocular therapeutic potential for drug discovery.
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Affiliation(s)
- Jose Quiroz
- Medical Scientist Training Program, Albert Einstein College of Medicine, Bronx, NY, USA
| | - Amirfarbod Yazdanyar
- Department of Ophthalmology and Visual Sciences, State University of New York (SUNY), Upstate Medical University, Syracuse, NY, USA
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Suksathan R, Rachkeeree A, Puangpradab R, Kantadoung K, Sommano SR. Phytochemical and nutritional compositions and antioxidants properties of wild edible flowers as sources of new tea formulations. NFS JOURNAL 2021. [DOI: 10.1016/j.nfs.2021.06.001] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
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Suo LG, Qin RX, Cui YY, Qin XJ. Decreased expression of TIPE2 in the eye under high-glucose conditions tested in vivo and in vitro. Int Immunopharmacol 2021; 95:107517. [PMID: 33725633 DOI: 10.1016/j.intimp.2021.107517] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2020] [Revised: 01/29/2021] [Accepted: 02/15/2021] [Indexed: 10/21/2022]
Abstract
AIMS Inflammation is important in the development of angiogenesis diabetic retinopathy (DR). Anti-inflammation is promising strategy in early DR management. This study aimed to evaluate the level of tumour necrosis factor (TNF)-α-induced protein-8 like-2 (TIPE2), a formerly anti-inflammatory factor, under high-glucose conditions. METHODS TIPE2 was detected in the ① retina from db/db and streptozotocin-induced diabetic mice; ② vitreous fluid of patients with proliferative diabetic retinopathy (PDR) and ③ mouse retinal microendothelial cells (RMEC) cultured in glucose of varying concentrations. In situ expression was evaluated by immunohistochemistry and immunofluorescence assay. The expression of protein was analysed by Western blot or ELISA and mRNA by qRT-PCR. RESULTS TIPE2 was down-regulated in the retina of the mice with diabetes. TIPE2 was present in the cytoplasm of RMEC and down-regulated in high-glucose conditions in line with concentration and time. The expression of TIPE2 in the vitreous fluid of patients with PDR was significantly lower than that without diabetes. Silencing TIPE2 by an siRNA resulted in increased expression of vascular endothelial growth factor (a vital factor in the development of DR), TNF-α and IL-1β. CONCLUSIONS TIPE2 down-expressed and exerted anti-VEGF and anti-inflammatory function in the high-glucose environment. TIPE2 was verified to be involved in the process of DR and might be a potential regulator for DR development.
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Affiliation(s)
- Ling-Ge Suo
- Department of Ophthalmology, Qilu Hospital of Shandong University, China; Department of Ophthalmology, Peking University Third Hospital, China
| | - Rui-Xi Qin
- Department of Pathology, Qilu Hospital of Shandong University, China
| | - Yan-Yan Cui
- Department of Ophthalmology, Qilu Hospital of Shandong University, China
| | - Xue-Jiao Qin
- Department of Ophthalmology, Qilu Hospital of Shandong University, China.
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Yang B, Ma G, Liu Y. Z-Ligustilide Ameliorates Diabetic Rat Retinal Dysfunction Through Anti-Apoptosis and an Antioxidation Pathway. Med Sci Monit 2020; 26:e925087. [PMID: 33011733 PMCID: PMC7542994 DOI: 10.12659/msm.925087] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
Background Diabetic retinopathy (DR) is one of the major causes of vision impairment. Z-ligustilide (3-butylidene-4,5-dihydrophthalide; Z-LIG) is an important volatile oil from the Chinese herb Angelica sinensis (Oliv.) Diels. It has been extensively studied and reportedly has anti-inflammatory, antioxidant, antitumor, analgesic, vasodilatory, and neuroprotective effects. Its effects on DR, however, remain obscure. In this study, we attempted to explore the protective effects of Z-LIG on retinal dysfunction and the potential underlying mechanisms. Material/Methods A diabetic rat model was constructed with streptozotocin injection. Three study groups were constituted: control (CON), diabetic model (DM), and DM+Z-LIG. The DM+Z-LIG group was injected intraperitoneally with 10 mg/kg of Z-LIG. The other groups received the same volume of 3% solution of polysorbate 80. After a 12-week intervention, a series of assessments were performed, including tests for retinal function, morphology, and molecular biology. Results Z-LIG treatment significantly elevated b-wave and OPs2-wave amplitude and thickened the inner layer of the nucleus of the retina, and the outer plexiform and nuclear layers (INL+OPL+ONL). Moreover, the rate of apoptosis and expression of bcl-2- associated X protein (BAX) and cleaved-Caspase-3 were clearly reduced, and the expression of bcl-2 was raised by Z-LIG in retinas of diabetic mice. In addition, the levels of retinal proinflammatory cytokines interleukin-1 and tumor necrosis factor-α were downregulated by Z-LIG. Furthermore, Z-LIG inhibited expression of vascular endothelial growth factor-α (VEGF-α) at the mRNA and protein levels. Conclusions Z-LIG can inhibit inflammatory response and cell apoptosis in retinas of diabetic rats by repressing the VEGF-α pathway. Therefore, it may serve as a potential therapeutic agent for DR.
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Affiliation(s)
- Bing Yang
- Department of Endocrinology and Metabolism, 3201 Hospital, Xi'an Jiaotong University Health Science Center, Hanzhong, Shaanxi, China (mainland)
| | - Guobin Ma
- Department of Endocrinology and Metabolism, 3201 Hospital, Xi'an Jiaotong University Health Science Center, Hanzhong, Shaanxi, China (mainland)
| | - Yang Liu
- Department of Endocrinology and Metabolism, 3201 Hospital, Xi'an Jiaotong University Health Science Center, Hanzhong, Shaanxi, China (mainland)
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Role of Arginase 2 in Murine Retinopathy Associated with Western Diet-Induced Obesity. J Clin Med 2020; 9:jcm9020317. [PMID: 31979105 PMCID: PMC7073940 DOI: 10.3390/jcm9020317] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2019] [Revised: 01/08/2020] [Accepted: 01/18/2020] [Indexed: 12/19/2022] Open
Abstract
Western diet-induced obesity is linked to the development of metabolic dysfunctions, including type 2 diabetes and complications that include retinopathy, a leading cause of blindness. Aberrant activation of the inflammasome cascade leads to the progression of obesity-induced pathologies. Our lab showed the critical role of arginase 2 (A2), the mitochondrial isoform of this ureahydrolase, in obesity-induced metabolic dysfunction and inflammation. A2 deletion also has been shown to be protective against retinal inflammation in models of ischemic retinopathy and multiple sclerosis. We investigated the effect of A2 deletion on western diet-induced retinopathy. Wild-type mice fed a high-fat, high-sucrose western diet for 16 weeks exhibited elevated retinal expression of A2, markers of the inflammasome pathway, oxidative stress, and activation of microglia/macrophages. Western diet feeding induced exaggerated retinal light responses without affecting visual acuity or retinal morphology. These effects were reduced or absent in mice with global A2 deletion. Exposure of retinal endothelial cells to palmitate and high glucose, a mimic of the obese state, increased expression of A2 and inflammatory mediators and induced cell death. These effects, except for A2, were prevented by pretreatment with an arginase inhibitor. Collectively, our study demonstrated a substantial role of A2 in early manifestations of diabetic retinopathy.
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Sharma S, Plotkin M. Id1 expression in kidney endothelial cells protects against diabetes-induced microvascular injury. FEBS Open Bio 2020; 10:1447-1462. [PMID: 31957231 PMCID: PMC7396439 DOI: 10.1002/2211-5463.12793] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2019] [Revised: 11/25/2019] [Accepted: 01/16/2020] [Indexed: 11/08/2022] Open
Abstract
The inhibitor of differentiation (Id) transcription regulators, which are induced in response to oxidative stress, promote cell proliferation and inhibit senescence. Inhibitor of differentiation 1 (Id1) expression is limited to endothelial cells (EC) in the normal mouse kidney and is required for a normal response to injury. Endothelial dysfunction leads to the development of diabetic nephropathy, and so, we hypothesized that endothelial Id1 may help protect against hyperglycemia-induced microvascular injury and nephropathy. Here, we tested this hypothesis by using streptozotocin to induce diabetes in Id1 knockout (KO) mice and WT B6;129 littermates and examining the mice at 3 months. Expression of Id1 was observed to be increased 15-fold in WT kidney EC, and Id1 KO mice exhibited increased mesangial and myofibroblast proliferation, matrix deposition, and albuminuria compared with WT mice. Electron microscopy demonstrated peritubular capillary EC injury and lumen narrowing, and fluorescence microangiography showed a 45% reduction in capillary perfusion area with no reduction in CD31-stained areas in Id1 KO mice. Microarray analysis of EC isolated from WT and KO control and diabetic mice demonstrated activation of senescence pathways in KO cells. Kidneys from KO diabetic mice showed increased histological expression of senescence markers. In addition, premature senescence in cultured KO EC was also seen in response to oxidative stress. In conclusion, endothelial Id1 upregulation with hyperglycemia protects against microvascular injury and senescence and subsequent nephropathy.
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Affiliation(s)
| | - Matthew Plotkin
- Department of Nephrology, John L. McClellan VA Hospital, University of Arkansas for Medical Sciences, Little Rock, AR, USA
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Oxidative Stress and Microvascular Alterations in Diabetic Retinopathy: Future Therapies. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2019; 2019:4940825. [PMID: 31814880 PMCID: PMC6878793 DOI: 10.1155/2019/4940825] [Citation(s) in RCA: 133] [Impact Index Per Article: 22.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/28/2019] [Revised: 09/06/2019] [Accepted: 09/14/2019] [Indexed: 02/07/2023]
Abstract
Diabetes is a disease that can be treated with oral antidiabetic agents and/or insulin. However, patients' metabolic control is inadequate in a high percentage of them and a major cause of chronic diseases like diabetic retinopathy. Approximately 15% of patients have some degree of diabetic retinopathy when diabetes is first diagnosed, and most will have developed this microvascular complication after 20 years. Early diagnosis of the disease is the best tool to prevent or delay vision loss and reduce the involved costs. However, diabetic retinopathy is an asymptomatic disease and its development to advanced stages reduces the effectiveness of treatments. Today, the recommended treatment for severe nonproliferative and proliferative diabetic retinopathy is photocoagulation with an argon laser and intravitreal injections of anti-VEGF associated with, or not, focal laser for diabetic macular oedema. The use of these therapeutic approaches is severely limited, such as uncomfortable administration for patients, long-term side effects, the costs they incur, and the therapeutic effectiveness of the employed management protocols. Hence, diabetic retinopathy is the widespread diabetic eye disease and a leading cause of blindness in adults in developed countries. The growing interest in using polyphenols, e.g., resveratrol, in treatments related to oxidative stress diseases has spread to diabetic retinopathy. This review focuses on analysing the sources and effects of oxidative stress and inflammation on vascular alterations and diabetic retinopathy development. Furthermore, current and antioxidant therapies, together with new molecular targets, are postulated for diabetic retinopathy treatment.
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Vuori N, Sandholm N, Kumar A, Hietala K, Syreeni A, Forsblom C, Juuti-Uusitalo K, Skottman H, Imamura M, Maeda S, Summanen PA, Lehto M, Groop PH. CACNB2 Is a Novel Susceptibility Gene for Diabetic Retinopathy in Type 1 Diabetes. Diabetes 2019; 68:2165-2174. [PMID: 31439644 PMCID: PMC6804633 DOI: 10.2337/db19-0130] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/06/2019] [Accepted: 08/07/2019] [Indexed: 01/03/2023]
Abstract
Diabetic retinopathy is a common diabetes complication that threatens the eyesight and may eventually lead to acquired visual impairment or blindness. While a substantial heritability has been reported for proliferative diabetic retinopathy (PDR), only a few genetic risk factors have been identified. Using genome-wide sib pair linkage analysis including 361 individuals with type 1 diabetes, we found suggestive evidence of linkage with PDR at chromosome 10p12 overlapping the CACNB2 gene (logarithm of odds = 2.73). Evidence of association between variants in CACNB2 and PDR was also found in association analysis of 4,005 individuals with type 1 diabetes with an odds ratio of 0.83 and P value of 8.6 × 10-4 for rs11014284. Sequencing of CACNB2 revealed two coding variants, R476C/rs202152674 and S502L/rs137886839. CACNB2 is abundantly expressed in retinal cells and encodes the β2 subunit of the L-type calcium channel. Blocking vascular endothelial growth factor (VEGF) by intravitreous anti-VEGF injections is a promising clinical therapy to treat PDR. Our data show that L-type calcium channels regulate VEGF expression and secretion from retinal pigment epithelial cells (ARPE19) and support the role of CACNB2 via regulation of VEGF in the pathogenesis of PDR. However, further genetic and functional studies are necessary to consolidate the findings.
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Affiliation(s)
- Nadja Vuori
- Folkhälsan Institute of Genetics, Folkhälsan Research Center, Helsinki, Finland
- Abdominal Center Nephrology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
- Research Program for Clinical and Molecular Metabolism, Faculty of Medicine, University of Helsinki, Helsinki, Finland
| | - Niina Sandholm
- Folkhälsan Institute of Genetics, Folkhälsan Research Center, Helsinki, Finland
- Abdominal Center Nephrology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
- Research Program for Clinical and Molecular Metabolism, Faculty of Medicine, University of Helsinki, Helsinki, Finland
| | - Anmol Kumar
- Folkhälsan Institute of Genetics, Folkhälsan Research Center, Helsinki, Finland
- Abdominal Center Nephrology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
- Research Program for Clinical and Molecular Metabolism, Faculty of Medicine, University of Helsinki, Helsinki, Finland
| | | | - Anna Syreeni
- Folkhälsan Institute of Genetics, Folkhälsan Research Center, Helsinki, Finland
- Abdominal Center Nephrology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
- Research Program for Clinical and Molecular Metabolism, Faculty of Medicine, University of Helsinki, Helsinki, Finland
| | - Carol Forsblom
- Folkhälsan Institute of Genetics, Folkhälsan Research Center, Helsinki, Finland
- Abdominal Center Nephrology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
- Research Program for Clinical and Molecular Metabolism, Faculty of Medicine, University of Helsinki, Helsinki, Finland
| | - Kati Juuti-Uusitalo
- Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland
| | - Heli Skottman
- Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland
| | - Minako Imamura
- Laboratory for Endocrinology, Metabolism and Kidney Diseases, RIKEN Center for Integrative Medical Sciences, Kanagawa, Japan
- Department of Advanced Genomic and Laboratory Medicine, Graduate School of Medicine, University of the Ryukyus, Okinawa, Japan
- Division of Clinical Laboratory and Blood Transfusion, University of the Ryukyus Hospital, Okinawa, Japan
| | - Shiro Maeda
- Laboratory for Endocrinology, Metabolism and Kidney Diseases, RIKEN Center for Integrative Medical Sciences, Kanagawa, Japan
- Department of Advanced Genomic and Laboratory Medicine, Graduate School of Medicine, University of the Ryukyus, Okinawa, Japan
- Division of Clinical Laboratory and Blood Transfusion, University of the Ryukyus Hospital, Okinawa, Japan
| | - Paula A. Summanen
- Ophthalmology, University of Helsinki, Helsinki University Hospital, Helsinki, Finland
| | - Markku Lehto
- Folkhälsan Institute of Genetics, Folkhälsan Research Center, Helsinki, Finland
- Abdominal Center Nephrology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
- Research Program for Clinical and Molecular Metabolism, Faculty of Medicine, University of Helsinki, Helsinki, Finland
| | - Per-Henrik Groop
- Folkhälsan Institute of Genetics, Folkhälsan Research Center, Helsinki, Finland
- Abdominal Center Nephrology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
- Research Program for Clinical and Molecular Metabolism, Faculty of Medicine, University of Helsinki, Helsinki, Finland
- Department of Diabetes, Central Clinical School, Monash University, Melbourne, Victoria, Australia
- Corresponding author: Per-Henrik Groop,
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Li R, Wang F, Zhang Y, Li C, Xia C, Chen H, Lu X, Liu F. Comparison of hematologic and biochemical reference values in specific-pathogen-free 1-month-old Yorkshire pigs and Yorkshire-Landrace crossbred pigs. CANADIAN JOURNAL OF VETERINARY RESEARCH = REVUE CANADIENNE DE RECHERCHE VETERINAIRE 2019; 83:285-290. [PMID: 31571729 PMCID: PMC6753882] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Subscribe] [Scholar Register] [Received: 08/31/2018] [Accepted: 01/09/2019] [Indexed: 06/10/2023]
Abstract
Analysis of hematologic and biochemical values in pigs is an important basis for biomedical research and veterinary clinical diagnosis. Reference values for specific-pathogen-free (SPF) 1-month-old Yorkshire (Y) pigs and Yorkshire-Landrace crossbred (YL) pigs are limited. The present research aimed to describe and compare the reference values for hematologic and biochemical parameters in such pigs. Blood samples were obtained from 90 Y pigs (52 males and 38 females) and 88 YL pigs (55 males and 33 females), all 1 month old and bred in an SPF environment. Among the 16 hematologic and 15 serum biochemical parameters tested, no significant differences between the Y and YL pigs were found except in the concentration of triglyceride (P < 0.05), and heterosis was not observed. Thus, the values determined in this study can be used as basic reference values for 1-month-old Y and YL pigs and will contribute to the use of SPF pigs in biomedical research.
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Affiliation(s)
- Rui Li
- Department of Basic Veterinary Science, College of Veterinary Medicine, Northeast Agricultural University, 600 Changjiang Road, Harbin 150030, Heilongjiang Province, P.R. China (R. Li, Wang, Zhang, Liu); Heilongjiang Key Laboratory for Animal Disease Control and Pharmaceutical Development, Harbin, China (R. Li, Liu); Harbin Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Harbin, China (C. Li, Xia, Chen, Lu)
| | - Feng Wang
- Department of Basic Veterinary Science, College of Veterinary Medicine, Northeast Agricultural University, 600 Changjiang Road, Harbin 150030, Heilongjiang Province, P.R. China (R. Li, Wang, Zhang, Liu); Heilongjiang Key Laboratory for Animal Disease Control and Pharmaceutical Development, Harbin, China (R. Li, Liu); Harbin Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Harbin, China (C. Li, Xia, Chen, Lu)
| | - Yuanyuan Zhang
- Department of Basic Veterinary Science, College of Veterinary Medicine, Northeast Agricultural University, 600 Changjiang Road, Harbin 150030, Heilongjiang Province, P.R. China (R. Li, Wang, Zhang, Liu); Heilongjiang Key Laboratory for Animal Disease Control and Pharmaceutical Development, Harbin, China (R. Li, Liu); Harbin Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Harbin, China (C. Li, Xia, Chen, Lu)
| | - Changwen Li
- Department of Basic Veterinary Science, College of Veterinary Medicine, Northeast Agricultural University, 600 Changjiang Road, Harbin 150030, Heilongjiang Province, P.R. China (R. Li, Wang, Zhang, Liu); Heilongjiang Key Laboratory for Animal Disease Control and Pharmaceutical Development, Harbin, China (R. Li, Liu); Harbin Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Harbin, China (C. Li, Xia, Chen, Lu)
| | - Changyou Xia
- Department of Basic Veterinary Science, College of Veterinary Medicine, Northeast Agricultural University, 600 Changjiang Road, Harbin 150030, Heilongjiang Province, P.R. China (R. Li, Wang, Zhang, Liu); Heilongjiang Key Laboratory for Animal Disease Control and Pharmaceutical Development, Harbin, China (R. Li, Liu); Harbin Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Harbin, China (C. Li, Xia, Chen, Lu)
| | - Hongyan Chen
- Department of Basic Veterinary Science, College of Veterinary Medicine, Northeast Agricultural University, 600 Changjiang Road, Harbin 150030, Heilongjiang Province, P.R. China (R. Li, Wang, Zhang, Liu); Heilongjiang Key Laboratory for Animal Disease Control and Pharmaceutical Development, Harbin, China (R. Li, Liu); Harbin Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Harbin, China (C. Li, Xia, Chen, Lu)
| | - Xiaoye Lu
- Department of Basic Veterinary Science, College of Veterinary Medicine, Northeast Agricultural University, 600 Changjiang Road, Harbin 150030, Heilongjiang Province, P.R. China (R. Li, Wang, Zhang, Liu); Heilongjiang Key Laboratory for Animal Disease Control and Pharmaceutical Development, Harbin, China (R. Li, Liu); Harbin Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Harbin, China (C. Li, Xia, Chen, Lu)
| | - Fangping Liu
- Department of Basic Veterinary Science, College of Veterinary Medicine, Northeast Agricultural University, 600 Changjiang Road, Harbin 150030, Heilongjiang Province, P.R. China (R. Li, Wang, Zhang, Liu); Heilongjiang Key Laboratory for Animal Disease Control and Pharmaceutical Development, Harbin, China (R. Li, Liu); Harbin Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Harbin, China (C. Li, Xia, Chen, Lu)
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Hayden MR. Type 2 Diabetes Mellitus Increases The Risk of Late-Onset Alzheimer's Disease: Ultrastructural Remodeling of the Neurovascular Unit and Diabetic Gliopathy. Brain Sci 2019; 9:brainsci9100262. [PMID: 31569571 PMCID: PMC6826500 DOI: 10.3390/brainsci9100262] [Citation(s) in RCA: 45] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2019] [Revised: 09/17/2019] [Accepted: 09/27/2019] [Indexed: 12/11/2022] Open
Abstract
Type 2 diabetes mellitus (T2DM) and late-onset Alzheimer’s disease–dementia (LOAD) are increasing in global prevalence and current predictions indicate they will only increase over the coming decades. These increases may be a result of the concurrent increases of obesity and aging. T2DM is associated with cognitive impairments and metabolic factors, which increase the cellular vulnerability to develop an increased risk of age-related LOAD. This review addresses possible mechanisms due to obesity, aging, multiple intersections between T2DM and LOAD and mechanisms for the continuum of progression. Multiple ultrastructural images in female diabetic db/db models are utilized to demonstrate marked cellular remodeling changes of mural and glia cells and provide for the discussion of functional changes in T2DM. Throughout this review multiple endeavors to demonstrate how T2DM increases the vulnerability of the brain’s neurovascular unit (NVU), neuroglia and neurons are presented. Five major intersecting links are considered: i. Aging (chronic age-related diseases); ii. metabolic (hyperglycemia advanced glycation end products and its receptor (AGE/RAGE) interactions and hyperinsulinemia-insulin resistance (a linking linchpin); iii. oxidative stress (reactive oxygen–nitrogen species); iv. inflammation (peripheral macrophage and central brain microglia); v. vascular (macrovascular accelerated atherosclerosis—vascular stiffening and microvascular NVU/neuroglial remodeling) with resulting impaired cerebral blood flow.
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Affiliation(s)
- Melvin R Hayden
- Diabetes and Cardiovascular Center, University of Missouri School of Medicine, Columbia, MO 65212, USA.
- Division of Endocrinology and Metabolism, Department of Medicine, University of Missouri, Columbia, MO 65212, USA.
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Park SW, Ghim W, Oh S, Kim Y, Park UC, Kang J, Yu HG. Association of vitreous vitamin C depletion with diabetic macular ischemia in proliferative diabetic retinopathy. PLoS One 2019; 14:e0218433. [PMID: 31216331 PMCID: PMC6583975 DOI: 10.1371/journal.pone.0218433] [Citation(s) in RCA: 25] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2019] [Accepted: 06/02/2019] [Indexed: 12/11/2022] Open
Abstract
Purpose Vitreous vitamin C, as an anti-oxidant, is responsible for regulating oxygen tension and oxidative stress in the eye. Oxidative stress and retinal ischemia are implicated in the development of proliferative diabetic retinopathy (PDR). In this study, we aimed to determine whether vitreous level of vitamin C is compromised in patients with PDR and to investigate the association of diabetic macular ischemia and vitamin C. Methods This prospective study enrolled forty patients who underwent pars plana vitrectomy for the treatment of PDR (PDR group, n = 20) and idiopathic epiretinal membrane (control group, n = 20). Serum, aqueous humor, and the vitreous were collected for the analysis of vitamin C level by HPLC. Diabetic macular ischemia (DMI) in PDR group was evaluated with fluorescein angiography (FA). Results PDR patients (60.4 ± 2.1 y) were younger than non-diabetic control patients (67.4 ± 1.2 y). Serum, aqueous, and vitreous levels of vitamin C in PDR were 38.7%, 22.5%, and 11.1% of non-diabetic control group, respectively. All PDR patients had DMI (grade 1: 25%, grade 2: 30%, grade 3: 30%, grade 4: 15%). DMI grade was inversely correlated with the level of vitreous vitamin C (r = -0.546, P = 0.019), not with HbA1C, serum, or aqueous vitamin C level. In addition, the level of vitreous vitamin C (4.5 ± 2.6 μg/ml) in high DMI group (Gr 3 &4) was lower than that (31.0 ± 9.1 μg/ml) in low DMI group (Gr 1&2) (P = 0.015). Conclusions Vitreous level of vitamin C in PDR patients showed a tenfold decrease, which was associated with the degree of macular ischemia. This suggests that vitreous vitamin C depletion may cause macula ischemia in PDR patients.
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Affiliation(s)
- Sung Wook Park
- Department of Ophthalmology, Seoul National University College of Medicine, Seoul, Republic of Korea
- Department of Ophthalmology, Seoul National University Hospital, Seoul, Republic of Korea
- Retinal Degeneration Laboratory, Biomedical Research Institute, Seoul National University Hospital, Seoul, Republic of Korea
| | - Woonhyung Ghim
- Department of Ophthalmology, Seoul National University College of Medicine, Seoul, Republic of Korea
- Department of Ophthalmology, Seoul National University Hospital, Seoul, Republic of Korea
- Retinal Degeneration Laboratory, Biomedical Research Institute, Seoul National University Hospital, Seoul, Republic of Korea
| | - Sanghyeon Oh
- Retinal Degeneration Laboratory, Biomedical Research Institute, Seoul National University Hospital, Seoul, Republic of Korea
- Interdisciplinary Program in Stem Cell Biology, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Yejin Kim
- Department of Anatomy, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Un Chul Park
- Department of Ophthalmology, Seoul National University College of Medicine, Seoul, Republic of Korea
- Department of Ophthalmology, Seoul National University Hospital, Seoul, Republic of Korea
- Retinal Degeneration Laboratory, Biomedical Research Institute, Seoul National University Hospital, Seoul, Republic of Korea
| | - Jaeseung Kang
- Department of Anatomy, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Hyeong Gon Yu
- Department of Ophthalmology, Seoul National University College of Medicine, Seoul, Republic of Korea
- Department of Ophthalmology, Seoul National University Hospital, Seoul, Republic of Korea
- Retinal Degeneration Laboratory, Biomedical Research Institute, Seoul National University Hospital, Seoul, Republic of Korea
- * E-mail:
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Rachkeeree A, Kantadoung K, Suksathan R, Puangpradab R, Page PA, Sommano SR. Nutritional Compositions and Phytochemical Properties of the Edible Flowers from Selected Zingiberaceae Found in Thailand. Front Nutr 2018; 5:3. [PMID: 29450200 PMCID: PMC5799243 DOI: 10.3389/fnut.2018.00003] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2017] [Accepted: 01/15/2018] [Indexed: 11/13/2022] Open
Abstract
The nutritional compositions and phytochemical properties of eight edible flowers of the ginger family (Zingiberaceae) commonly found in Thailand are reported herein. The plant genera investigated were Zingiber (Ginger, Phlai Dam, Krathue), Hedychium (two morphological filament forms), Curcuma (Ao), Etlingera (Torch ginger), Amomum (Chi Kuk), and Alpinia (Galangal), which are eaten fresh or cooked as ingredients in the preparation of many Thai dishes. The proximate compositions (moisture, ash, fiber, protein, fat, and carbohydrate contents) varied among the different genera. The plants sampled were generally low in fat content (<1%), which contributed as little as 30% of the total caloric energy. Edible plant parts contained substantially high amounts of potassium (max. 737.21 mg/100 g), calcium (max. 140.15 mg/100 g), and iron (~0.32 mg/100 g). Among the tested samples, torch ginger had the highest vitamin C content (1.05 mg/100 g), total phenolic and total flavonoid contents, as well as 2,2-diphenyl-1-picrylhydrazyl activity. On the other hand, the 2,2'-azino-bis (3-ethylbenzothiazoline-6-sulfonic acid) assay suggested that Hedychium species possessed the highest antioxidant activity (~5.38 mg TEAC/g extract). Our results prove that edible plants of the Zingiberaceae family found in Thailand are rich sources of potentially important nutrients.
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Affiliation(s)
- Apinya Rachkeeree
- Queen Sirikit Botanic Garden, The Botanical Garden Organization, Chiang Mai, Thailand
| | - Kuttiga Kantadoung
- Queen Sirikit Botanic Garden, The Botanical Garden Organization, Chiang Mai, Thailand
| | - Ratchuporn Suksathan
- Queen Sirikit Botanic Garden, The Botanical Garden Organization, Chiang Mai, Thailand
| | | | - Paul Alexander Page
- Plant Bioactive Compound Laboratory, Department of Plant and Soil Sciences, Faculty of Agriculture, Chiang Mai University, Chiang Mai, Thailand
| | - Sarana Rose Sommano
- Plant Bioactive Compound Laboratory, Department of Plant and Soil Sciences, Faculty of Agriculture, Chiang Mai University, Chiang Mai, Thailand
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Selmi S, Rtibi K, Grami D, Sebai H, Marzouki L. Rosemary (Rosmarinus officinalis) essential oil components exhibit anti-hyperglycemic, anti-hyperlipidemic and antioxidant effects in experimental diabetes. ACTA ACUST UNITED AC 2017; 24:297-303. [PMID: 28928060 DOI: 10.1016/j.pathophys.2017.08.002] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2017] [Revised: 08/18/2017] [Accepted: 08/21/2017] [Indexed: 11/30/2022]
Abstract
INTRODUCTION The present study aims to investigate the protective effects of Rosemary (Rosmarinus officinalis L.) essential oils (ROEO) against alloxan-induced diabetes and oxidative stress in rats. METHODS The animals were divided into four groups: Healthy Control (HC); Diabetic Control (DC); Healthy+ROEO (H+ROEO) and Diabetic+ROEO (D+ROEO). RESULTS The use of GC/MS technique has allowed us to identify fifteen compounds in ROEO. We have found that alloxan administration induced hyperglycaemia, lipid metabolic parameters deregulation as well as liver and kidney dysfunctions. Alloxan administration has also induced an oxidative stress status as assessed by malondialdehyde (MDA) content increase, thiol groups (-SH) level decrease and antioxidant enzyme activities depletion such as catalase (CAT), total superoxide dismutase (SOD), Cu/Zn-SOD, Mn-SOD and Fe-SOD in both liver and kidney tissues. More importantly subacute (15days) ROEO administration has significantly corrected all biochemical alterations induced by alloxan intoxication. CONCLUSIONS We propose that Rosmarinus officinalis essential oils exhibit protective effects in alloxan-induced hyperglycaemia as well as protecting against liver and kidney oxidative stress in rats, reflecting its antioxidant properties.
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Affiliation(s)
- Slimen Selmi
- Laboratory Functional Physiology and Bio-resources Valorisation, Higher Institute of Biotechnology of Beja, University of Jendouba, Avenue Habib Bourguiba, BP, 382, 9000, Beja, Tunisia.
| | - Kais Rtibi
- Laboratory Functional Physiology and Bio-resources Valorisation, Higher Institute of Biotechnology of Beja, University of Jendouba, Avenue Habib Bourguiba, BP, 382, 9000, Beja, Tunisia
| | - Dhekra Grami
- Laboratory Functional Physiology and Bio-resources Valorisation, Higher Institute of Biotechnology of Beja, University of Jendouba, Avenue Habib Bourguiba, BP, 382, 9000, Beja, Tunisia
| | - Hichem Sebai
- Laboratory Functional Physiology and Bio-resources Valorisation, Higher Institute of Biotechnology of Beja, University of Jendouba, Avenue Habib Bourguiba, BP, 382, 9000, Beja, Tunisia
| | - Lamjed Marzouki
- Laboratory Functional Physiology and Bio-resources Valorisation, Higher Institute of Biotechnology of Beja, University of Jendouba, Avenue Habib Bourguiba, BP, 382, 9000, Beja, Tunisia
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Abstract
PURPOSE OF REVIEW Diabetic retinopathy (DR) is one of the most common complications associated with chronic hyperglycemia seen in patients with diabetes mellitus. While many facets of DR are still not fully understood, animal studies have contributed significantly to understanding the etiology and progression of human DR. This review provides a comprehensive discussion of the induced and genetic DR models in different species and the advantages and disadvantages of each model. RECENT FINDINGS Rodents are the most commonly used models, though dogs develop the most similar morphological retinal lesions as those seen in humans, and pigs and zebrafish have similar vasculature and retinal structures to humans. Nonhuman primates can also develop diabetes mellitus spontaneously or have focal lesions induced to simulate retinal neovascular disease observed in individuals with DR. DR results in vascular changes and dysfunction of the neural, glial, and pancreatic β cells. Currently, no model completely recapitulates the full pathophysiology of neuronal and vascular changes that occur at each stage of diabetic retinopathy; however, each model recapitulates many of the disease phenotypes.
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Affiliation(s)
- Ana Maria Olivares
- Schepens Eye Research Institute, Massachusetts Eye and Ear Infirmary, Department of Ophthalmology, Harvard Medical School, 20 Staniford Street, Boston, MA 02114 USA
| | - Kristen Althoff
- Schepens Eye Research Institute, Massachusetts Eye and Ear Infirmary, Department of Ophthalmology, Harvard Medical School, 20 Staniford Street, Boston, MA 02114 USA
| | - Gloria Fanghua Chen
- Schepens Eye Research Institute, Massachusetts Eye and Ear Infirmary, Department of Ophthalmology, Harvard Medical School, 20 Staniford Street, Boston, MA 02114 USA
| | - Siqi Wu
- Schepens Eye Research Institute, Massachusetts Eye and Ear Infirmary, Department of Ophthalmology, Harvard Medical School, 20 Staniford Street, Boston, MA 02114 USA
| | | | | | - Neena Haider
- Schepens Eye Research Institute, Massachusetts Eye and Ear Infirmary, Department of Ophthalmology, Harvard Medical School, 20 Staniford Street, Boston, MA 02114 USA
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Domanico D, Fragiotta S, Cutini A, Carnevale C, Zompatori L, Vingolo EM. Circulating levels of reactive oxygen species in patients with nonproliferative diabetic retinopathy and the influence of antioxidant supplementation: 6-month follow-up. Indian J Ophthalmol 2016; 63:9-14. [PMID: 25686055 PMCID: PMC4363979 DOI: 10.4103/0301-4738.151455] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022] Open
Abstract
Aims: The aim was to evaluate circulating levels of reactive oxygen species (ROS) and changes in central macular thickness (CMT) in patients with nonproliferative diabetic retinopathy (NPDR) after antioxidant supplementation. Materials and Methods: A total of 68 patients (68 eyes) with NPDR were enrolled. Patients were randomly divided into two groups: Treated with antioxidant supplement (Group A) and untreated control group (Group B). Each tablet, for oral administration, containing pycnogenol 50 mg, Vitamin E 30 mg and coenzyme Q10 20 mg. CMT and free oxygen radical test (FORT) were analyzed at baseline (T0), 3 (T1) and 6 (T2) months in both groups. Results: In Group A, FORT levels and CMT were significantly reduced over time (P < 0.001 for both). In Group B, FORT levels were increased (P < 0.001) and CMT did not vary significantly (P = 0.81) over 3 time points. Conclusions: This is the first study showing the reduction of ROS levels in patients with NPDR thanks to antioxidant therapy. Moreover, our findings have suggested also an influence on retinal thickness.
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Affiliation(s)
| | | | | | - Carmela Carnevale
- Department of Sense Organs UOC B, Policlinico Umberto I Hospital, Sapienza University of Rome, Viale del Policlinico 155, 00161 Rome, Italy
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Jian W, Yu S, Tang M, Duan H, Huang J. A combination of the main constituents of Fufang Xueshuantong Capsules shows protective effects against streptozotocin-induced retinal lesions in rats. JOURNAL OF ETHNOPHARMACOLOGY 2016; 182:50-56. [PMID: 26692279 DOI: 10.1016/j.jep.2015.11.021] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/04/2015] [Revised: 10/08/2015] [Accepted: 11/06/2015] [Indexed: 06/05/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Fufang Xueshuantong Capsule, an herbal formula licensed for clinical use in China, which is composed of Panax notoginseng (Burkill) F.H. Chen, Salvia miltiorrhiza Bunge, Astragalus membranaceus (Fisch.) Bunge, and Scrophularia ningpoensis Hemsl, has proven effective for the treatment of diabetic retinopathy. However, its bioactive constituents are still ambiguous. In this study, the therapeutic effects of a combination of the main constituents of Fufang Xueshuantong Capsule (cFXT) were evaluated in streptozotocin (STZ)-induced retinal lesions to identify the bioactive constituents. METHODS Sprague-Dawley rats, except for those in the control group (vehicle+vehicle), were administered a single injection of 60mg/kg STZ. One-week later, STZ-treated rats were randomly divided into three groups-one STZ group (STZ+vehicle) and two cFXT treatment groups (STZ+cFXT). The rats in the latter two groups received cFXT 44.8mg/kg or cFXT 22.4mg/kg by intragastric gavage once per day, for 24 consecutive weeks. The rats in the control and STZ groups received the vehicle in the same way. Body weights and fasting blood glucose levels were recorded every four weeks. After treatment, hemorheological tests were performed to record the erythrocyte aggregation indexes, blood viscosity, and plasma viscosity. The trypsin digestion method was used to observe pericyte and acellular capillary counts in the retina. Ultraviolet spectrophotometry was utilized to measure the activity of aldose reductase (AR) by measuring the nicotinamide adenine dinucleotide phosphate (NADPH) consumption at 340nm. An immunohistochemical assay was used to observe the expressions of vascular endothelial growth factor (VEGF) and pigment epithelium-derived factor (PEDF) in the retina. The expression levels of intercellular adhesion molecule-1 (ICAM-1), endothelin-1 (RT-1),and occludin in the retina were tested by the western blot assay. RESULTS cFXT is composed of 991.44mg/g saponins of Panax notoginseng, 1.62mg/g harpagoside, 0.70mg/g cryptotanshinone, 0.74mg/g tanshinone I, and 5.50mg/g astragaloside A. Although it showed no effects on the increased body weight and blood glucose levels induced by STZ in rats. However, it showed a tendency to attenuate the increase in erythrocyte aggregation, plasma viscosity, and acellular vessel and pericyte loss, paralleled with a reversal of the hyper-activation of AR, the hyper-expression of VEGF, ICAM-1, and ET-1, and the hypo-expression of PEDF and occludin in the retinas of STZ-treated rats. CONCLUSION The saponins of Panax notoginseng, harpagoside, cryptotanshinone, tanshinone I, and astragaloside A are the main bioactive constituents of Fufang Xueshuantong Capsule and contribute to the attenuation of STZ-induced retinal lesions in rats. These constituents can be used as the base to optimize a new drug for the treatment of diabetic retinopathy, and can be selected for quality control of Fufang Xueshuantong Capsules.
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Affiliation(s)
- Weijie Jian
- School of Chinese Material Medica, Beijing University of Chinese Medicine, 6#, Wangjing Zhonghuan Nanlu, Chaoyang District, Beijing 100102, China
| | - Suyun Yu
- School of Chinese Material Medica, Beijing University of Chinese Medicine, 6#, Wangjing Zhonghuan Nanlu, Chaoyang District, Beijing 100102, China
| | - Minke Tang
- School of Chinese Material Medica, Beijing University of Chinese Medicine, 6#, Wangjing Zhonghuan Nanlu, Chaoyang District, Beijing 100102, China
| | - Huihui Duan
- School of Chinese Material Medica, Beijing University of Chinese Medicine, 6#, Wangjing Zhonghuan Nanlu, Chaoyang District, Beijing 100102, China
| | - Jianmei Huang
- School of Chinese Material Medica, Beijing University of Chinese Medicine, 6#, Wangjing Zhonghuan Nanlu, Chaoyang District, Beijing 100102, China.
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The Parkinsonism-associated protein DJ-1/Park7 prevents glycation damage in human keratinocyte. Biochem Biophys Res Commun 2016; 473:87-91. [PMID: 26995087 DOI: 10.1016/j.bbrc.2016.03.056] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2016] [Accepted: 03/14/2016] [Indexed: 11/24/2022]
Abstract
Reducing sugars and dicarbonyls form covalent adducts with proteins through a nonenzymatic process known as glycation, which inactivates proteins, is increased in diabetic patients and is associated with diabetic complications, including retinopathy, cataracts, nephropathy, neuropathy, cardiomyopathy and skin defects. We recently characterized DJ-1/Park7 as a protein deglycase that repairs proteins from glycation by glyoxal and methylglyoxal, two major glycating agents which are responsible for up to 65% of glycation events. In this study, we investigated the ability of DJ-1 to prevent protein glycation in keratinocytes. Glycation of collagen and keratinocyte proteins was tested by measuring ultraviolet absorption and fluorescence emission. Protein glycation in HaCaT keratinocytes was investigated by immunodetection with anti-advanced glycation endproduct antibodies, after DJ-1 depletion or overexpression. In vitro, DJ-1 prevented glycation of collagen and keratinocyte protein extracts. In cell culture, DJ-1 depletion by small interfering RNAs resulted in a 3-fold increase in protein glycation levels. Moreover, protein glycation levels were decreased several-fold in cells overexpressing DJ-1 after addition of the Nrf2 inducer sulforaphane or after transfection with a DJ-1 plasmid. Thus, the DJ-1 deglycase plays a major role in preventing protein glycation in eukaryotic cells and might be important for preventing skin glycation.
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Poh S, Mohamed Abdul RBB, Lamoureux EL, Wong TY, Sabanayagam C. Metabolic syndrome and eye diseases. Diabetes Res Clin Pract 2016; 113:86-100. [PMID: 26838669 DOI: 10.1016/j.diabres.2016.01.016] [Citation(s) in RCA: 36] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/20/2015] [Revised: 10/28/2015] [Accepted: 01/08/2016] [Indexed: 12/25/2022]
Abstract
Metabolic syndrome is becoming a worldwide medical and public health challenge as it has been seen increasing in prevalence over the years. Age-related eye diseases, the leading cause of blindness globally and visual impairment in developed countries, are also on the rise due to aging of the population. Many of the individual components of the metabolic syndrome have been shown to be associated with these eye diseases. However, the association of metabolic syndrome with eye diseases is not clear. In this review, we reviewed the evidence for associations between metabolic syndrome and certain ocular diseases in populations. We also reviewed the association of individual metabolic syndrome components with ocular diseases due to a paucity of research in this area. Besides, we also summarised the current understanding of etiological mechanisms of how metabolic syndrome or the individual components lead to these ocular diseases. With increasing evidence of such associations, it may be important to identify patients who are at risk of developing metabolic syndrome as prompt treatment and intervention may potentially decrease the risk of developing certain ocular diseases.
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Affiliation(s)
- Stanley Poh
- National University of Singapore, Singapore, Singapore
| | | | - Ecosse L Lamoureux
- Singapore Eye Research Institute, Singapore, Singapore; Duke-NUS Medical School, Singapore, Singapore
| | - Tien Y Wong
- Singapore Eye Research Institute, Singapore, Singapore; Duke-NUS Medical School, Singapore, Singapore; Singapore National Eye Center, Singapore, Singapore
| | - Charumathi Sabanayagam
- Singapore Eye Research Institute, Singapore, Singapore; Duke-NUS Medical School, Singapore, Singapore.
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Luo X, Wu J, Jing S, Yan LJ. Hyperglycemic Stress and Carbon Stress in Diabetic Glucotoxicity. Aging Dis 2016; 7:90-110. [PMID: 26816666 DOI: 10.14336/ad.2015.0702] [Citation(s) in RCA: 85] [Impact Index Per Article: 9.4] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2015] [Accepted: 07/02/2015] [Indexed: 12/16/2022] Open
Abstract
Diabetes and its complications are caused by chronic glucotoxicity driven by persistent hyperglycemia. In this article, we review the mechanisms of diabetic glucotoxicity by focusing mainly on hyperglycemic stress and carbon stress. Mechanisms of hyperglycemic stress include reductive stress or pseudohypoxic stress caused by redox imbalance between NADH and NAD(+) driven by activation of both the polyol pathway and poly ADP ribose polymerase; the hexosamine pathway; the advanced glycation end products pathway; the protein kinase C activation pathway; and the enediol formation pathway. Mechanisms of carbon stress include excess production of acetyl-CoA that can over-acetylate a proteome and excess production of fumarate that can over-succinate a proteome; both of which can increase glucotoxicity in diabetes. For hyperglycemia stress, we also discuss the possible role of mitochondrial complex I in diabetes as this complex, in charge of NAD(+) regeneration, can make more reactive oxygen species (ROS) in the presence of excess NADH. For carbon stress, we also discuss the role of sirtuins in diabetes as they are deacetylases that can reverse protein acetylation thereby attenuating diabetic glucotoxicity and improving glucose metabolism. It is our belief that targeting some of the stress pathways discussed in this article may provide new therapeutic strategies for treatment of diabetes and its complications.
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Affiliation(s)
- Xiaoting Luo
- 1 Department of Pharmaceutical Sciences, UNT System College of Pharmacy, University of North Texas Health Science Center, Fort Worth, TX 76107, USA; 2 Department of Biochemistry and Molecular Biology, Gannan Medical University, Ganzhou, Jiangxi province, China, 341000
| | - Jinzi Wu
- 1 Department of Pharmaceutical Sciences, UNT System College of Pharmacy, University of North Texas Health Science Center, Fort Worth, TX 76107, USA
| | - Siqun Jing
- 1 Department of Pharmaceutical Sciences, UNT System College of Pharmacy, University of North Texas Health Science Center, Fort Worth, TX 76107, USA; 3 College of Life Sciences and Technology, Xinjiang University, Urumqi, Xinjiang, China, 830046
| | - Liang-Jun Yan
- 1 Department of Pharmaceutical Sciences, UNT System College of Pharmacy, University of North Texas Health Science Center, Fort Worth, TX 76107, USA
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Gong X, Rubin LP. Role of macular xanthophylls in prevention of common neovascular retinopathies: retinopathy of prematurity and diabetic retinopathy. Arch Biochem Biophys 2015; 572:40-48. [PMID: 25701588 DOI: 10.1016/j.abb.2015.02.004] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2014] [Revised: 02/03/2015] [Accepted: 02/08/2015] [Indexed: 12/20/2022]
Abstract
Retinopathy of prematurity (ROP) and diabetic retinopathy (DR) are important causes of blindness among children and working-age adults, respectively. The development of both diseases involves retinal microvascular degeneration, vessel loss and consequent hypoxic and inflammatory pathologic retinal neovascularization. Mechanistic studies have shown that oxidative stress and subsequent derangement of cell signaling are important factors in disease progression. In eye and vision research, role of the dietary xanthophyll carotenoids, lutein and zeaxanthin, has been more extensively studied in adult onset macular degeneration than these other retinopathies. These carotenoids also may decrease severity of ROP in preterm infants and of DR in working-age adults. A randomized controlled clinical trial of carotenoid supplementation in preterm infants indicated that lutein has functional effects in the neonatal eye and is anti-inflammatory. Three multicenter clinical trials all showed a trend of decreased ROP severity in the lutein supplemented group. Prospective studies on patients with non-proliferative DR indicate serum levels of lutein and zeaxanthin are significantly lower in these patients compared to normal subjects. The present review describes recent advances in lutein and zeaxanthin modulation of oxidative stress and inflammation related to ROP and DR and discusses potential roles of lutein/zeaxanthin in preventing or lessening the risks of disease initiation or progression.
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Affiliation(s)
- Xiaoming Gong
- Department of Pediatrics, Texas Tech University Health Science Center, Paul L. Foster School of Medicine, El Paso, TX 79905, USA
| | - Lewis P Rubin
- Department of Pediatrics, Texas Tech University Health Science Center, Paul L. Foster School of Medicine, El Paso, TX 79905, USA.
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Mi XS, Yuan TF, Ding Y, Zhong JX, So KF. Choosing preclinical study models of diabetic retinopathy: key problems for consideration. DRUG DESIGN DEVELOPMENT AND THERAPY 2014; 8:2311-9. [PMID: 25429204 PMCID: PMC4242133 DOI: 10.2147/dddt.s72797] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Diabetic retinopathy (DR) is the most common complication of diabetes mellitus in the eye. Although the clinical treatment for DR has already developed to a relative high level, there are still many urgent problems that need to be investigated in clinical and basic science. Currently, many in vivo animal models and in vitro culture systems have been applied to solve these problems. Many approaches have also been used to establish different DR models. However, till now, there has not been a single study model that can clearly and exactly mimic the developmental process of the human DR. Choosing the suitable model is important, not only for achieving our research goals smoothly, but also, to better match with different experimental proposals in the study. In this review, key problems for consideration in choosing study models of DR are discussed. These problems relate to clinical relevance, different approaches for establishing models, and choice of different species of animals as well as of the specific in vitro culture systems. Attending to these considerations will deepen the understanding on current study models and optimize the experimental design for the final goal of preventing DR.
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Affiliation(s)
- Xue-Song Mi
- Department of Ophthalmology, First Affiliated Hospital of Jinan University, Guangzhou, Guangdong, People's Republic of China ; Department of Anatomy, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, People's Republic of China
| | - Ti-Fei Yuan
- School of Psychology, Nanjing Normal University, Nanjing, People's Republic of China ; Department of Ophthalmology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong
| | - Yong Ding
- Department of Ophthalmology, First Affiliated Hospital of Jinan University, Guangzhou, Guangdong, People's Republic of China
| | - Jing-Xiang Zhong
- Department of Ophthalmology, First Affiliated Hospital of Jinan University, Guangzhou, Guangdong, People's Republic of China
| | - Kwok-Fai So
- Department of Ophthalmology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong ; Guangdong-Hongkong-Macau Institute of Central Nervous System, Jinan University, Guangzhou, People's Republic of China
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Yan LJ. Pathogenesis of chronic hyperglycemia: from reductive stress to oxidative stress. J Diabetes Res 2014; 2014:137919. [PMID: 25019091 PMCID: PMC4082845 DOI: 10.1155/2014/137919] [Citation(s) in RCA: 237] [Impact Index Per Article: 21.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/29/2014] [Accepted: 05/27/2014] [Indexed: 02/08/2023] Open
Abstract
Chronic overnutrition creates chronic hyperglycemia that can gradually induce insulin resistance and insulin secretion impairment. These disorders, if not intervened, will eventually be followed by appearance of frank diabetes. The mechanisms of this chronic pathogenic process are complex but have been suggested to involve production of reactive oxygen species (ROS) and oxidative stress. In this review, I highlight evidence that reductive stress imposed by overflux of NADH through the mitochondrial electron transport chain is the source of oxidative stress, which is based on establishments that more NADH recycling by mitochondrial complex I leads to more electron leakage and thus more ROS production. The elevated levels of both NADH and ROS can inhibit and inactivate glyceraldehyde 3-phosphate dehydrogenase (GAPDH), respectively, resulting in blockage of the glycolytic pathway and accumulation of glycerol 3-phospate and its prior metabolites along the pathway. This accumulation then initiates all those alternative glucose metabolic pathways such as the polyol pathway and the advanced glycation pathways that otherwise are minor and insignificant under euglycemic conditions. Importantly, all these alternative pathways lead to ROS production, thus aggravating cellular oxidative stress. Therefore, reductive stress followed by oxidative stress comprises a major mechanism of hyperglycemia-induced metabolic syndrome.
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Affiliation(s)
- Liang-Jun Yan
- Department of Pharmaceutical Sciences, UNT System College of Pharmacy, University of North Texas Health Science Center, 3500 Camp Bowie Boulevard, RES-314E, Fort Worth, TX 76107, USA
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Zeng J, Chen B. Epigenetic mechanisms in the pathogenesis of diabetic retinopathy. Ophthalmologica 2014; 232:1-9. [PMID: 24714375 DOI: 10.1159/000357824] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2013] [Accepted: 12/08/2013] [Indexed: 11/19/2022]
Abstract
Diabetic retinopathy (DR), which arises as a result of an increasing incidence of diabetes mellitus, has gradually become a common disease. Due to its complex pathogenesis, the treatment means of DR are very limited. The findings of several studies have shown that instituting tight glycemic control in diabetic patients does not immediately benefit the progression of retinopathy, and the benefits of good control persist beyond the period of good glycemic control. This has led to the concept of persistent epigenetic changes. Epigenetics has now become an increasingly important area of biomedical research. Recently, important roles of various epigenetic mechanisms have been identified in the pathogenesis of diabetes and its complications. The aim of this review is to provide an overview of the epigenetics and epigenetic mechanisms in diabetes and diabetes complications, and the focus is on the emerging evidence for aberrant epigenetic mechanisms in DR.
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Affiliation(s)
- Jun Zeng
- Department of Ophthalmology, Second Xiangya Hospital, Central South University, Changsha City, PR China
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Cooper CA, Moraes LE, Murray JD, Owens SD. Hematologic and biochemical reference intervals for specific pathogen free 6-week-old Hampshire-Yorkshire crossbred pigs. J Anim Sci Biotechnol 2014; 5:5. [PMID: 24410946 PMCID: PMC3898366 DOI: 10.1186/2049-1891-5-5] [Citation(s) in RCA: 46] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2013] [Accepted: 01/07/2014] [Indexed: 12/11/2022] Open
Abstract
BACKGROUND Hematologic and biochemical reference intervals depend on many factors, including age. A review of the literature highlights the lack of reference intervals for 6-wk-old specific pathogen free (SPF) Hampshire-Yorkshire crossbred pigs. For translational research, 6-wk-old pigs represent an important animal model for both human juvenile colitis and diabetes mellitus type 2 given the similarities between the porcine and human gastrointestinal maturation process. The aim of this study was to determine reference intervals for hematological and biochemical parameters in healthy 6-wk-old crossbred pigs. Blood samples were collected from 66 clinically healthy Hampshire-Yorkshire pigs. The pigs were 6 wks old, represented both sexes, and were housed in a SPF facility. Automated hematological and biochemical analysis were performed using an ADVIA 120 Hematology System and a Cobas 6000 C501 Clinical Chemistry Analyzer. RESULTS Reference intervals were calculated using both parametric and nonparametric methods. The mean, median, minimum, and maximum values were calculated. CONCLUSION As pigs are used more frequently as medical models of human disease, having reference intervals for commonly measured hematological and biochemical parameters in 6-wk-old pigs will be useful. The reference intervals calculated in this study will aid in the diagnosis and monitoring of both naturally occurring and experimentally induced disease. In comparison to published reference intervals for older non SPF pigs, notable differences in leukocyte populations, and in levels of sodium, potassium, glucose, protein, and alkaline phosphatase were observed.
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Affiliation(s)
| | | | | | - Sean D Owens
- Department of Pathology, Microbiology and Immunology, School of Veterinary Medicine, University of California, One Shields Avenue, Davis, CA 95616, USA.
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Yang Y, Yang K, Li Y, Li X, Sun Q, Meng H, Zeng Y, Hu Y, Zhang Y. Decursin inhibited proliferation and angiogenesis of endothelial cells to suppress diabetic retinopathy via VEGFR2. Mol Cell Endocrinol 2013; 378:46-52. [PMID: 23684887 DOI: 10.1016/j.mce.2013.04.021] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/17/2012] [Revised: 04/26/2013] [Accepted: 04/26/2013] [Indexed: 12/29/2022]
Abstract
Diabetes induces pathologic proliferation and angiogenesis in the retina that leads to catastrophic loss of vision. Decursin is a novel therapeutic that targets the vascular endothelial growth factor (VEGF) receptor (VEGFR) with putative anti-proliferative and anti-angiogenic activities. Thereby we utilized human retinal microvascular endothelial cells (HRMEC) and human umbilical vein endothelial cells (HUVEC) under conditions of excess glucose to explore dose-dependent responses of decursin on markers of migration, angiogenesis, and proliferation. Decursin dose-dependently inhibited tube formation, VEGFR-2 expression, along with relative metabolic activity and 5-bromo-2'-deoxy-uridine (BrdU) activity in both cell lines. We then correlated our findings to the streptozotocin-induced rat model of diabetes. Following three months of decursin treatment VEGFR-2 expression was significantly inhibited. Our data would suggest that decursin may be a potent anti-angiogenic and anti-proliferative agent targeting the VEGFR-2 signaling pathway, which significantly inhibits diabetic retinal neovascularization.
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Affiliation(s)
- Ying Yang
- Department of Endocrinology and Metabolism, Yunnan Province 2nd Hospital, Kunming 650031, China; Department of Internal Medicine, Division of Endocrinology, HSC Diabetes Center, University of Missouri, Columbia, MO 65201, USA; Laboratory for Conservation and Utilization of Bio-resources Yunnan University, Kunming 650021, China.
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Murray AR, Chen Q, Takahashi Y, Zhou KK, Park K, Ma JX. MicroRNA-200b downregulates oxidation resistance 1 (Oxr1) expression in the retina of type 1 diabetes model. Invest Ophthalmol Vis Sci 2013; 54:1689-97. [PMID: 23404117 DOI: 10.1167/iovs.12-10921] [Citation(s) in RCA: 75] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022] Open
Abstract
PURPOSE MicroRNAs (miRNAs) are known to participate in post-transcriptional regulation of gene expression and are involved in multiple pathogenic processes. Here, we identified miRNA expression changes in the retinas of Akita mice, a genetic model of type 1 diabetes, and investigated the potential role of miRNA in diabetic retinopathy. METHODS Visual function of Akita and control mice was evaluated by electroretinography. MiRNA expression changes in the retinas of Akita mice were identified by miRNA-specific microarray and confirmed by quantitative RT-PCR (qRT-PCR). The potential downstream targets of identified miRNAs were predicted by bioinformatic analysis using web-based applications and confirmed by dual luciferase assay. The mRNA and protein changes of identified downstream targets were examined by qRT-PCR and Western blot analysis. RESULTS MiRNA-specific microarray and qRT-PCR showed that miR-200b was upregulated significantly in the Akita mouse retina. Sequence analysis and luciferase assay identified oxidation resistance 1 (Oxr1) as a downstream target gene regulated by miR-200b. In a human Müller cell line, MIO-M1, transfection of a miR-200b mimic downregulated Oxr1 expression. Conversely, transfection of MIO-M1 with a miR-200b inhibitor resulted in upregulated Oxr1. Furthermore, overexpression of recombinant Oxr1 attenuated oxidative stress marker, nitration of cellular proteins, and ameliorated apoptosis induced by 4-hydroxynonenal (4-HNE), an oxidative stressor. Similarly, transfection of a miR-200b inhibitor decreased, whereas transfection of miR-200b mimic increased the number of apoptotic cells following 4-HNE treatment. CONCLUSIONS These results suggested that miR-200b-regulated Oxr1 potentially has a protective role in diabetic retinopathy.
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Affiliation(s)
- Anne R Murray
- Department of Physiology, University of Oklahoma Health Sciences Center, 941 Stanton L. Young Boulevard, Oklahoma City, OK 73104, USA
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Nikolopoulou A, Kadoglou NPE. Obesity and metabolic syndrome as related to cardiovascular disease. Expert Rev Cardiovasc Ther 2013; 10:933-9. [PMID: 22908926 DOI: 10.1586/erc.12.74] [Citation(s) in RCA: 103] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
The metabolic syndrome (MetS) constitutes a multifaceted disorder, including obesity, dyslipidemia, hyperglycemia and hypertension, associated with an increased propensity towards cardiovascular disease (CVD). Besides this, accumulating data suggest the involvement of nontraditional, novel, cardiovascular risk factors in MetS. Among them, insulin resistance seems to possess a predominant role in MetS-related CVD in obese patients. Furthermore, adipose tissue fatty acid metabolism, increased incidence of oxidative stress and endothelial dysfunction, and excessive production of adipocyte derivatives, known as adipokines, have all been proposed to contribute to the pathogenesis of CVD in obese patients with MetS. Lifestyle interventions, such as weight loss and increased physical activity, have long been the cornerstone for the treatment of obesity-related disorders. With the exception of obesity, pharmaceutical interventions targeting each disorder of MetS have yielded considerable improvement in cardiovascular morbidity and mortality. The long-term management of obesity and its complications seems promising but requires further investigation.
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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.
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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:
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Hypoxia-induced oxidative stress in ischemic retinopathy. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2012; 2012:426769. [PMID: 23125893 PMCID: PMC3483772 DOI: 10.1155/2012/426769] [Citation(s) in RCA: 84] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/02/2012] [Revised: 08/24/2012] [Accepted: 09/17/2012] [Indexed: 12/28/2022]
Abstract
Oxidative stress plays a crucial role in the pathogenesis of retinal ischemia/hypoxia, a complication of ocular diseases such as diabetic retinopathy (DR) and retinopathy of prematurity (ROP). Oxidative stress refers to the imbalance between the production of reactive oxygen species (ROS) and the ability to scavenge these ROS by endogenous antioxidative systems. Free radicals and ROS are implicated in the irreversible damage to cell membrane, DNA, and other cellular structures by oxidizing lipids, proteins, and nucleic acids. Anti-oxidants that can inhibit the oxidative processes can protect retinal cells from ischemic/hypoxic insults. In particular, treatment using anti-oxidants such as vitamin E and lutein, inhibition of nicotinamide adenine dinucleotide phosphate oxidase (NADPH oxidase) or related signaling pathways, and administration of catalase and superoxide dismutase (SOD) are possible therapeutic regimens for DR, ROP, and other retinal ischemic diseases. The role of oxidative stress in the pathogenesis of DR and ROP as well as the underlying mechanisms involved in the hypoxia/ischemia-induced oxidative damage is discussed. The information provided will be beneficial in understanding the underlying mechanisms involved in the pathogenesis of the diseases as well as in developing effective therapeutic interventions to treat oxidative stress-induced damages.
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Cederlund M, Ghosh F, Arnér K, Andréasson S, Akerström B. Vitreous levels of oxidative stress biomarkers and the radical-scavenger α1-microglobulin/A1M in human rhegmatogenous retinal detachment. Graefes Arch Clin Exp Ophthalmol 2012; 251:725-32. [PMID: 22829194 DOI: 10.1007/s00417-012-2113-6] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2012] [Revised: 06/25/2012] [Accepted: 07/01/2012] [Indexed: 11/26/2022] Open
Abstract
PURPOSE To explore oxidative stress and the radical scavenger α(1)-microglobulin (A1M) in the vitreous body of human eyes with primary rhegmatogenous retinal detachment (RRD). METHODS Levels of carbonyl groups, a marker of oxidative stress, and A1M were measured by ELISA and RIA in 14 vitreous samples derived from patients suffering from RRD, and compared with 14 samples from macula hole (MH) patients. Carbonyl group and A1M levels in RRD samples were statistically related to detachment characteristics. Analysis of total protein level, SDS-PAGE, and Western blotting of A1M was also performed. In a separate experiment, mRNA expression of A1M was measured by RT-PCR in rat retina explants. RESULTS Levels of carbonyl groups and A1M varied widely in RRD vitreous samples, but were significantly higher in samples derived from eyes with large detachment area and macula-off status, while the presence of vitreous hemorrhage did not show any significant correlation. Compared with MH samples, RRD samples displayed significantly higher levels of A1M, whereas changes in total protein levels and carbonyl groups were not significant. Novel forms of A1M, not previously seen in plasma, were found in the vitreous body by Western blotting. Furthermore, A1M expression was seen in rat retina explants and was upregulated after 24 h of culturing. CONCLUSION Oxidative stress is a prominent feature of human eyes with primary RRD, and is directly related to detachment severity. Affected eyes can launch a protective response in the form of the radical scavenger A1M possibly derived from the retina. The results thus indicate potential therapeutic cell loss prevention in RRD by employing the endogeneous radical scavenger A1M.
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Affiliation(s)
- Martin Cederlund
- Division of Infection Medicine, Department of Clinical Sciences, Lund University, BMC B14, 221 84 Lund, Sweden
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Qiu X, Villalta J, Lin G, Lue TF. Role of hydrogen sulfide in the physiology of penile erection. JOURNAL OF ANDROLOGY 2012; 33:529-35. [PMID: 22016355 PMCID: PMC3541055 DOI: 10.2164/jandrol.111.014936] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Hydrogen sulfide (H(2)S), which is a well-known toxic gas, has recently been recognized as a biological messenger that plays an important role in physiological and pathophysiological conditions. Relatively high levels of H(2)S have been discovered in mammalian tissues. It is mainly synthesized by 2 enzymes, including cystathionine β-synthase and cystathionine γ-lysase, which utilize L-cysteine as substrate to produce H(2)S. H(2)S has been demonstrated to exhibit potent vasodilator activity both in vitro and in vivo by relaxing vascular smooth muscle. Recently, H(2)S has been discovered in penile tissue with smooth muscle relaxant effects. Furthermore, other effects of H(2)S could play a role in the physiology of erection. Understanding H(2)S in the physiology of erection might provide alternative erectile dysfunction strategies for those patients with poor or no response to type 5 phosphodiesterase inhibitors. This review intends to present the H(2)S pathway in penile tissue and the potential role of H(2)S in the physiology of erections.
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Affiliation(s)
- Xuefeng Qiu
- Knuppe Molecular Urology Laboratory, Department of Urology, University of California, San Francisco, California 94143-0738, USA
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Khodaie L, Bamdad S, Delazar A, Nazemiyeh H. Antioxidant, total phenol and flavonoid contents of two pedicularis L. Species from eastern azerbaijan, iran. BIOIMPACTS : BI 2012; 2:43-57. [PMID: 23678441 DOI: 10.5681/bi.2012.006] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Received: 02/13/2012] [Revised: 03/06/2012] [Accepted: 03/20/2012] [Indexed: 11/17/2022]
Abstract
INTRODUCTION Pedicularis sibthorpii and P. wilhelmsiana are endemic species mainly found in North-West of Iran. Plants of genus Pedicularis produce some important poly-phenols and flavonoids. In the present work, total phenol and flavonoid contents of the mentioned species as well as their antioxidant capacity have been evaluated. METHODS Methanol extract of samples was fractionated by SPE method using an ODS cartridge and their (1)H-NMR spectra were recorded. Total phenols and flavonoids of methanol extracts were determined using Folin- Ciocalteu and aluminum chloride methods. For determining antioxidant activity of the extracts and fractions, bleaching of purple color methanol solu-tion of 1, 1-diphenylpycryl hydrazyl (DPPH) was measured by spectrophotometric assay. RESULTS Total phenols of Pedicularis sibthorpii and P. wilhelmsiana were in the range of 8-30 mg g(-1) and 9-20 mg g(-1), respectively. The 40% and 60% fractions of P. sibthorpii and the 20%, 40% and 60% fractions of P. wilhelmsiana showed higher amounts of phenolic compounds. The total flavonoid contents of P. sibthorpii and P. wilhelmsiana were in the range of 0-215 mg g(-1) and 0-177 mg g(-1), respectively, whereas the 40% and 60% fractions showed higher flavonoid amounts. Antioxidant activity of P. sibthorpii and P. wil-helmsiana were in the range of 0.01-0.7 mg mL(-1) and 0.01-1.02 mg mL(-1). In the same manner, the 20% and 40% fractions of P. sibthorpii and the 40% and 60% fractions of P. wilhelmsiana had lower RC50 than that of other fractions. CONCLUSION Fractions with lower RC50 had higher contents of phenolic and flavonoid compounds. The results of NMR spectra were parallel with these findings and show that it is worth to do phytochemi-cal studies on P. sibthorpii and P. wilhelmsiana.
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Affiliation(s)
- Laleh Khodaie
- Drug Applied Research Center, Faculty of Pharmacy, Tabriz University of Medical Sciences, Tabriz, Iran ; Students' Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran
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Cilenšek I, Mankoč S, Globočnik Petrovič M, Petrovič D. The 4a/4a genotype of the VNTR polymorphism for endothelial nitric oxide synthase (eNOS) gene predicts risk for proliferative diabetic retinopathy in Slovenian patients (Caucasians) with type 2 diabetes mellitus. Mol Biol Rep 2012; 39:7061-7. [PMID: 22311033 DOI: 10.1007/s11033-012-1537-8] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2011] [Accepted: 01/24/2012] [Indexed: 11/30/2022]
Abstract
Thus far only a limited number of studies examined the association between endothelial nitric oxide synthase (eNOS) polymorphisms and proliferative diabetic retinopathy (PDR). In this report, two polymorphisms in the eNOS gene have been investigated, namely the 894G>T (Glu298Asp) and a 27 bp VNTR (4b/4a), to assess their possible relationships to PDR among Slovenian (Caucasians) type 2 diabetic patients. This cross-sectional case-control study enrolled 577 unrelated Slovenian subjects (Caucasians) with type 2 diabetes mellitus. The case group consisted of 172 patients with PDR and the control group had 405 patients who had no clinical signs of diabetic retinopathy (DR) but did have type 2 diabetes for more than 10 years' duration. Genotyping of eNOS polymorphisms was carried out with conventional and real-time PCR assays. A significantly higher frequency of the eNOS minor "4a" allele was found in patients with PDR than in controls (23.6 versus 17.7%, p = 0.01). Moreover, the univariate analysis showed a significant association of the 27 bp VNTR 4a/4a genotype and PDR in the recessive model. The odds ratio (OR) of PDR for the 4a/4a genotype to 4b/4a plus 4b/4b was 2.9 (95% CI 1.3-6.2, p = 0.005). Further, the presence of 4a/a genotype was associated with a 3.4-fold (95% CI 1.4-8.6, p = 0.009) increased risk for PDR while adjusted for other risk factors. This is the first study to implicate eNOS 4a/4a homozygous deletion, and hence the "4a" allele, as the genetic risk factors for PDR in Caucasians.
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Affiliation(s)
- Ines Cilenšek
- Medical Faculty Ljubljana, Institute of Histology and Embryology, University of Ljubljana, Ljubljana, Slovenia
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Zhu Y, Zhang XL, Zhu BF, Ding YN. Effect of antioxidant N-acetylcysteine on diabetic retinopathy and expression of VEGF and ICAM-1 from retinal blood vessels of diabetic rats. Mol Biol Rep 2011; 39:3727-35. [PMID: 21952821 DOI: 10.1007/s11033-011-1148-9] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2011] [Accepted: 06/24/2011] [Indexed: 11/26/2022]
Abstract
Diabetic retinopathy (DR) is a leading cause of blindness globally and its pathogenesis has still not been completely elucidated. Some studies show a close relation between oxidative stress and DR. This study was aimed to investigate the effects of anti-oxidant in DR and expression of vascular endothelial growth factor (VEGF) and intercellular adhesion molecule-1 (ICAM-1) from retinal blood vessels in diabetic rats. Diabetic rat models were established by intraperitoneal injection of streptozotocin (60 mg/kg) and confirmation of high serum glucose levels in the animals. Antioxidant N-acetylcysteine was given to diabetic rats to elicit antioxidative responses, and rats were sacrificed at 3 and 5 months. Ultrastructures of retinal vascular tissues were observed under transmission electron microscope, and pathology of retinal capillaries was examined using retinal vascular digest preparations. Changes in the expression of VEGF and ICAM-1 were examined by immunofluorescence; and reactive oxygen species contents in the retinas were detected using dichlorofluorescein assay. Compared with normal rats, diabetic rats displayed significant retinopathy both under electronic and light microscopy, accompanied by elevated reactive oxygen species contents in the retinas; N-acetylcysteine treatment alleviated the pathological changes and also decreased reactive oxygen species, most significantly at 5 months. VEGF and ICAM-1 expressions were significantly up-regulated in retinal blood vessels from diabetic rats, and such up-regulation was attenuated by N-acetylcysteine treatment. The expression of both factors returned to basal levels after 5-month treatment with N-acetylcysteine. Long-term N-acetylcysteine treatment exerts protective effects on the diabetic retinas, possibly through its down-regulation of the expression of VEGF and ICAM-1, and reduction of reactive oxygen species content in retinal vascular tissues in diabetic rats.
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Affiliation(s)
- Yuan Zhu
- Department of Ophthalmology, The First Affiliate Hospital of Xi'an Jiaotong University College of Medicine, Xi'an, 710061, Shaanxi, China
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