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Mühle A, Schnichels S, Hurst J. Introducing a Porcine Inflammatory Ex Vivo Retina Model for Diabetic Retinopathy. Int J Mol Sci 2025; 26:3919. [PMID: 40332752 PMCID: PMC12027530 DOI: 10.3390/ijms26083919] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2025] [Revised: 04/07/2025] [Accepted: 04/11/2025] [Indexed: 05/08/2025] Open
Abstract
This study aimed to develop an ex vivo retinal model to examine inflammatory processes in diabetic retinopathy (DR) without animal testing. Porcine eyes were collected from a local abattoir, dissected, and cultivated for four days in five experimental groups: control group (Co), 25 mM and 50 mM mannitol groups (Man25, Man50) as osmotic controls, and 25 mM and 50 mM glucose groups (Glc25, Glc50) as diabetic groups. A TUNEL assay was used to determine relative cell death. Immunofluorescence and quantitative real-time polymerase chain reaction (qRT-PCR) were performed to detect inflammatory markers. An increase in the cell death rate in Man50 (30%), Glc25 (36%) and Glc50 (37%) compared to Co (12%) (p < 0.01, p < 0.001, p < 0.001, respectively) and between Glc25 and Man25 (21%) (p < 0.01) was found. Immunofluorescence staining and qRT-PCR analysis revealed a TNF-α increase in Glc25 compared to Man25 and Co. iNOS was increased in Glc25 vs. Man25 but not in Co vs. Glc25. iNOS gene expression was upregulated with Glc25 treatment compared to Co and Man25 groups. Expression levels of IL-6 and CD31 were significantly higher in Glc25 than in Co and Man25. Glucose treatment increased cell death and inflammation, prompting us to present a DR model for better understanding DR and testing new therapies.
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Affiliation(s)
| | - Sven Schnichels
- Section for Translational Research in Ophthalmology, Centre for Ophthalmology, University Eye Hospital Tübingen, Elfriede-Aulhorn-Str. 7, 72076 Tübingen, Germany; (A.M.); (J.H.)
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Robles-Rivera RR, Pacheco-Moisés FP, Olvera-Montaño C, Castellanos-González JA, Barley-Villaseñor AL, Cardona-Muñoz EG, Rodríguez-Carrizalez AD. Mitochondrial Function and Oxidative Stress Biomarkers in Diabetic Retinopathy Development: An Analytical Cross-Sectional Study. Int J Mol Sci 2024; 25:13084. [PMID: 39684793 DOI: 10.3390/ijms252313084] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2024] [Revised: 11/30/2024] [Accepted: 12/02/2024] [Indexed: 12/18/2024] Open
Abstract
DR is a complex complication of DM with multiple biochemical pathways implicated in its genesis and progression. Circulating OS and mitochondrial function biomarkers represent potential candidates in the DR staging system. We conducted a comparative cross-sectional study comparing the OS biomarkers: TAC, GR, NOS, CARB, and hydroperoxydes, as well as mitochondrial function biomarkers: ATP synthase and ATPase activity in healthy volunteers, DM w/o DR, Moderate and Severe NPDR, and PDR. TAC is progressively diminished the more DR progresses to its proliferative stages. GR and NOS may function as biomarkers to differentiate the progression from S NPDR to PDR. CARB may correlate with the progression from M NPDR to S NPDR. Hydroperoxide levels were higher in patients with DR compared to DM w/o DR expressing OS in the early development of DR. ATPase activity is increasingly augmented the more DR progresses and may function as a biomarker that reflects the difference between N PDR and PDR, and ATP synthesis was lower the more DR progressed, being significantly lower compared to DM w/o DR. The behavior of OS and mitochondrial function in several stages of DR may aid in the staging and the prognosis of DR.
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Affiliation(s)
- Ricardo Raúl Robles-Rivera
- Institute of Clinical and Experimental Therapeutics, Department of Physiology, Health Sciences University Center, University of Guadalajara, Guadalajara 44340, Jalisco, Mexico
| | - Fermín Paul Pacheco-Moisés
- Department of Chemistry, University Centre of Exact and Engineering Sciences, University of Guadalajara, Guadalajara 44430, Jalisco, Mexico
| | - Cecilia Olvera-Montaño
- Institute of Clinical and Experimental Therapeutics, Department of Physiology, Health Sciences University Center, University of Guadalajara, Guadalajara 44340, Jalisco, Mexico
| | - José Alberto Castellanos-González
- Department of Ophthalmology, Specialties Hospital of the National Occidental Medical Center, Mexican Institute of Social Security, Guadalajara 44349, Jalisco, Mexico
| | - Andre Leonardo Barley-Villaseñor
- Institute of Clinical and Experimental Therapeutics, Department of Physiology, Health Sciences University Center, University of Guadalajara, Guadalajara 44340, Jalisco, Mexico
| | - Ernesto Germán Cardona-Muñoz
- Institute of Clinical and Experimental Therapeutics, Department of Physiology, Health Sciences University Center, University of Guadalajara, Guadalajara 44340, Jalisco, Mexico
| | - Adolfo Daniel Rodríguez-Carrizalez
- Institute of Clinical and Experimental Therapeutics, Department of Physiology, Health Sciences University Center, University of Guadalajara, Guadalajara 44340, Jalisco, Mexico
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Sheemar A, Goel P, Thakur PS, Takkar B, Kaur I, Rani PK, Tyagi M, Basu S, Venkatesh P. Diabetes, Diabetic Retinopathy, and Inflammatory Disorders. Ocul Immunol Inflamm 2024; 32:1155-1168. [PMID: 37159104 DOI: 10.1080/09273948.2023.2203742] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2022] [Revised: 04/11/2023] [Accepted: 04/12/2023] [Indexed: 05/10/2023]
Abstract
This review summarizes the impact of systemic and ocular inflammatory disorders on diabetes mellitus (DM) and diabetic retinopathy (DR). Local inflammation is a key pathology in diabetic retinopathy (DR) and is also an evolving target for clinical therapy. The legacy effects of local inflammation at the intracellular level make DR a persistent self-driven vicious process. Ocular inflammation is accompanied as well as incited by systemic inflammation due to diabetes mellitus (DM) itself. Over the years, a multitude of studies have evaluated the impact of systemic inflammatory disorders (SIDs, like rheumatoid arthritis, lupus, psoriasis, etc.) and anti-inflammatory drugs prescribed for managing them on manifestations of DM. Recent studies have indicated increased insulin resistance to be a result of chronic inflammation, and the anti-inflammatory drugs to have a protective effect towards DM. Very few studies have evaluated the impact of SIDs on DR. Furthermore, the evidence from these studies is conflicting, and while local anti-inflammatory therapy has shown a lot of clinical potential for use in DR, the results of systemic anti-inflammatory therapies have been inconsistent. The impact of local ocular inflammation due to uveitis on DR is a crucial aspect that has not been evaluated well at present. Initial pre-clinical studies and small-sized clinical reports have shown a strong and positive relationship between the presence of uveitis and the severity of DR as well as its progression, while larger cross-sectional patient surveys have refuted the same. The long term impact of ocular inflammation due to uveitis on DR needs to be studied while adjusting for confounders.
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Affiliation(s)
- Abhishek Sheemar
- Department of Ophthalmology, Moorfields Eye Hospital NHS Foundation Trust, London, UK
| | - Pallavi Goel
- Brien Holden Eye Research Centre, L V Prasad Eye Institute, Hyderabad, India
| | | | - Brijesh Takkar
- Anant Bajaj Retina Institute, L V Prasad Eye Institute, Hyderabad, India
- Indian Health Outcomes, Public Health, and Economics Research (IHOPE) Centre, L V Prasad Eye Institute, Hyderabad, India
| | - Inderjeet Kaur
- Brien Holden Eye Research Centre, L V Prasad Eye Institute, Hyderabad, India
| | - Padmaja K Rani
- Anant Bajaj Retina Institute, L V Prasad Eye Institute, Hyderabad, India
| | - Mudit Tyagi
- Uveitis Services, L V Prasad Eye Institute, Kallam Anji Reddy Campus, Hyderabad, India
| | - Soumyava Basu
- Uveitis Services, L V Prasad Eye Institute, Kallam Anji Reddy Campus, Hyderabad, India
| | - Pradeep Venkatesh
- Dr. RP Centre for Ophthalmic Sciences, All India Institute of Medical Sciences, New Delhi, India
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Serikbaeva A, Li Y, Ma S, Yi D, Kazlauskas A. Resilience to diabetic retinopathy. Prog Retin Eye Res 2024; 101:101271. [PMID: 38740254 PMCID: PMC11262066 DOI: 10.1016/j.preteyeres.2024.101271] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2022] [Revised: 05/03/2024] [Accepted: 05/10/2024] [Indexed: 05/16/2024]
Abstract
Chronic elevation of blood glucose at first causes relatively minor changes to the neural and vascular components of the retina. As the duration of hyperglycemia persists, the nature and extent of damage increases and becomes readily detectable. While this second, overt manifestation of diabetic retinopathy (DR) has been studied extensively, what prevents maximal damage from the very start of hyperglycemia remains largely unexplored. Recent studies indicate that diabetes (DM) engages mitochondria-based defense during the retinopathy-resistant phase, and thereby enables the retina to remain healthy in the face of hyperglycemia. Such resilience is transient, and its deterioration results in progressive accumulation of retinal damage. The concepts that co-emerge with these discoveries set the stage for novel intellectual and therapeutic opportunities within the DR field. Identification of biomarkers and mediators of protection from DM-mediated damage will enable development of resilience-based therapies that will indefinitely delay the onset of DR.
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Affiliation(s)
- Anara Serikbaeva
- Department of Physiology and Biophysics, University of Illinois at Chicago, 1905 W Taylor St, Chicago, IL 60612, USA
| | - Yanliang Li
- Department of Ophthalmology and Visual Sciences, University of Illinois at Chicago, 1905 W Taylor St, Chicago, IL 60612, USA
| | - Simon Ma
- Department of Bioengineering, University of Illinois at Chicago, 1905 W Taylor St, Chicago, IL 60612, USA
| | - Darvin Yi
- Department of Ophthalmology and Visual Sciences, University of Illinois at Chicago, 1905 W Taylor St, Chicago, IL 60612, USA; Department of Bioengineering, University of Illinois at Chicago, 1905 W Taylor St, Chicago, IL 60612, USA
| | - Andrius Kazlauskas
- Department of Physiology and Biophysics, University of Illinois at Chicago, 1905 W Taylor St, Chicago, IL 60612, USA; Department of Ophthalmology and Visual Sciences, University of Illinois at Chicago, 1905 W Taylor St, Chicago, IL 60612, USA.
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Hu Y, Wei T, Gao S, Gao N, Chen L, Cheng Q. CD200R promotes high glucose-induced oxidative stress and damage in human retinal pigment epithelial cells by activating the mTOR signaling pathway. Tissue Cell 2024; 88:102381. [PMID: 38692160 DOI: 10.1016/j.tice.2024.102381] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2023] [Revised: 04/01/2024] [Accepted: 04/09/2024] [Indexed: 05/03/2024]
Abstract
Diabetic retinopathy (DR) is established as the primary cause of visual impairment and preventable blindness, posing significant social and economic burdens on healthcare systems worldwide. Oxidative stress has been identified as a major contributor to DR, yet the precise role of the transmembrane glycoprotein CD200R in this context remains elusive. We studied human retinal pigment epithelia ARPE-19 cells to investigate the role of CD200R in high-glucose (HG) induced oxidative stress. Under HG conditions, we found a significant increase in CD200R expression in a time-dependent pattern. Conversely, knockdown of CD200R effectively alleviated oxidative stress and restored cell viability in HG-treated ARPE-19 cells, a phenomenon corroborated by the addition of a reactive oxygen species (ROS) scavenger. Exploration of the AKT/mTOR signaling pathway confirmed its mediating role regarding CD200R knockdown suppression of the expression of key proteins induced by HG conditions. Additionally, we found that the inhibition of mTOR signaling with Rapamycin effectively countered HG-induced oxidative stress in ARPE-19 cells, suggesting a promising therapeutic target against oxidative stress in the context of DR. This study establishes the crucial role of CD200R in HG-induced oxidative stress and identifies potential therapeutic avenues for the treatment of DR.
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Affiliation(s)
- Yaguang Hu
- Department of Ophthalmology, The First Affiliated Hospital of Xi'an Jiaotong University, No. 277, Yanta West Road, Xi'an, Shaanxi Province 710061, PR China
| | - Ting Wei
- Department of Ophthalmology, The First Affiliated Hospital of Xi'an Jiaotong University, No. 277, Yanta West Road, Xi'an, Shaanxi Province 710061, PR China
| | - Shan Gao
- Department of Ophthalmology, The First Affiliated Hospital of Xi'an Jiaotong University, No. 277, Yanta West Road, Xi'an, Shaanxi Province 710061, PR China
| | - Ning Gao
- Department of Ophthalmology, The First Affiliated Hospital of Xi'an Jiaotong University, No. 277, Yanta West Road, Xi'an, Shaanxi Province 710061, PR China
| | - Li Chen
- Department of Ophthalmology, The First Affiliated Hospital of Xi'an Jiaotong University, No. 277, Yanta West Road, Xi'an, Shaanxi Province 710061, PR China
| | - Qiaochu Cheng
- Department of Ophthalmology, The First Affiliated Hospital of Xi'an Jiaotong University, No. 277, Yanta West Road, Xi'an, Shaanxi Province 710061, PR China.
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Wang J, Lai DA, Wang JJ, Zhang SX. Effects of Nox4 upregulation on PECAM-1 expression in a mouse model of diabetic retinopathy. PLoS One 2024; 19:e0303010. [PMID: 38748682 PMCID: PMC11095704 DOI: 10.1371/journal.pone.0303010] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2023] [Accepted: 04/17/2024] [Indexed: 05/19/2024] Open
Abstract
Diabetic Retinopathy (DR) is the leading cause of vision loss in working-age adults. The hallmark features of DR include vascular leakage, capillary loss, retinal ischemia, and aberrant neovascularization. Although the pathophysiology is not fully understood, accumulating evidence supports elevated reactive oxygen species associated with increased activity of NADPH oxidase 4 (Nox4) as major drivers of disease progression. Previously, we have shown that Nox4 upregulation in retinal endothelial cells by diabetes leads to increased vascular leakage by an unknown mechanism. Platelet endothelial cell adhesion molecule 1 (PECAM-1) is a cell surface molecule that is highly expressed in endothelial cells and regulates endothelial barrier function. In the present study, using endothelial cell-specific human Nox4 transgenic (TG) mice and endothelial cell-specific Nox4 conditional knockout (cKO) mice, we investigated the impact of Nox4 upregulation on PECAM-1 expression in mouse retinas and brain microvascular endothelial cells (BMECs). Additionally, cultured human retinal endothelial cells (HRECs) transduced with adenovirus overexpressing human Nox4 were used in the study. We found that overexpression of Nox4 increases PECAM-1 mRNA but has no effect on its protein expression in the mouse retina, BMECs, or HRECs. Furthermore, PECAM-1 mRNA and protein expression was unchanged in BMECs isolated from cKO mice compared to wild type (WT) mice with or without 2 months of diabetes. Together, these findings do not support a significant role of Nox4 in the regulation of PECAM-1 expression in the diabetic retina and endothelial cells. Further studies are warranted to elucidate the mechanism of Nox4-induced vascular leakage by investigating other intercellular junctional proteins in endothelial cells and their implications in the pathophysiology of diabetic retinopathy.
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Affiliation(s)
- Jinli Wang
- Department of Ophthalmology and Ross Eye Institute, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, State University of New York, Buffalo, NY, United States of America
| | - Daniel A. Lai
- Department of Ophthalmology and Ross Eye Institute, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, State University of New York, Buffalo, NY, United States of America
| | - Joshua J. Wang
- Department of Ophthalmology and Ross Eye Institute, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, State University of New York, Buffalo, NY, United States of America
| | - Sarah X. Zhang
- Department of Ophthalmology and Ross Eye Institute, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, State University of New York, Buffalo, NY, United States of America
- Department of Biochemistry, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, State University of New York, Buffalo, NY, United States of America
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Morya AK, Ramesh PV, Kaur K, Gurnani B, Heda A, Bhatia K, Sinha A. Diabetes more than retinopathy, it's effect on the anterior segment of eye. World J Clin Cases 2023; 11:3736-3749. [PMID: 37383113 PMCID: PMC10294174 DOI: 10.12998/wjcc.v11.i16.3736] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/23/2023] [Revised: 04/25/2023] [Accepted: 05/06/2023] [Indexed: 06/02/2023] Open
Abstract
Diabetes mellitus (DM) is one of the chronic metabolic noncommunicable diseases that has attained worldwide epidemics. It threatens healthy life around the globe, with mild-to-severe secondary complications and leads to significant illness including nephropathy, neuropathy, retinopathy, and macrovascular abnormalities including peripheral vasculopathy, and ischaemic heart disease. Research into diabetic retinopathy (DR), which affects one-third of persons with diabetes, has made considerable strides in recent years. In addition, it can lead to several anterior segment complications such as glaucoma, cataract, cornea, conjunctiva, lacrimal glands and other ocular surface diseases. Uncontrolled DM also caused gradual damage to corneal nerves and epithelial cells, which raises the likelihood of anterior segment diseases including corneal ulcers, dry eye disease, and chronic epithelial abnormalities. Although DR and other associated ocular complications are well-known, the complexity of its aetiology and diagnosis makes therapeutic intervention challenging. Strict glycaemic control, early detection and regular screening, and meticulous management is the key to halting the progression of the disease. In this review manuscript, we aim to provide an in-depth understanding of the broad spectrum of diabetic complications in the anterior segment of the ocular tissues and illustrate the progression of diabetes and its pathophysiology, epidemiology, and prospective therapeutic targets. This first such review article will highlight the role of diagnosing and treating patients with a plethora of anterior segment diseases associated with diabetes, which are often neglected.
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Affiliation(s)
- Arvind Kumar Morya
- Department of Ophthalmology, All India Institute of Medical Sciences, Hyderabad 508126, Telangana, India
| | - Prasanna Venkatesh Ramesh
- Glaucoma and Research, Mahathma Eye Hospital Private Limited, Tennur, Trichy 620001, Tamil Nadu, India
| | - Kirandeep Kaur
- Pediatric Ophthalmology and Strabismus, Sadguru Netra Chikitsalaya, Sadguru Seva Sangh Trust, Janaki-Kund, Chitrakoot 485334, Madhya Pradesh, India
| | - Bharat Gurnani
- Cornea and Refractive Services, Sadguru Netra Chikitsalaya, Sadguru Seva Sangh Trust, Janaki- Kund, Chitrakoot 485334, Madhya Pradesh, India
| | - Aarti Heda
- Department of Ophthalmology, National Institute of Ophthalmology, Pune 411000, Maharashtra, India
| | - Karan Bhatia
- Department of Ophthalmology, Manaktala Eye and Maternity Home, Meerut 250001, Uttar Pradesh, India
| | - Aprajita Sinha
- Department of Ophthalmology, Worcestershire Acute Hospital, Worcestershire 01601, United Kingdom
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Calbiague García V, Cadiz B, Herrera P, Díaz A, Schmachtenberg O. Evaluation of Photobiomodulation and Boldine as Alternative Treatment Options in Two Diabetic Retinopathy Models. Int J Mol Sci 2023; 24:ijms24097918. [PMID: 37175628 PMCID: PMC10178531 DOI: 10.3390/ijms24097918] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2023] [Revised: 04/18/2023] [Accepted: 04/19/2023] [Indexed: 05/15/2023] Open
Abstract
Diabetic retinopathy causes progressive and irreversible damage to the retina through activation of inflammatory processes, overproduction of oxidative species, and glial reactivity, leading to changes in neuronal function and finally ischemia, edema, and hemorrhages. Current treatments are invasive and mostly applied at advanced stages, stressing the need for alternatives. To this end, we tested two unconventional and potentially complementary non-invasive treatment options: Photobiomodulation, the stimulation with near-infrared light, has shown promising results in ameliorating retinal pathologies and insults in several studies but remains controversial. Boldine, on the other hand, is a potent natural antioxidant and potentially useful to prevent free radical-induced oxidative stress. To establish a baseline, we first evaluated the effects of diabetic conditions on the retina with immunofluorescence, histological, and ultrastructural analysis in two diabetes model systems, obese LepRdb/db mice and organotypic retinal explants, and then tested the potential benefits of photobiomodulation and boldine treatment in vitro on retinal explants subjected to high glucose concentrations, mimicking diabetic conditions. Our results suggest that the principal subcellular structures affected by these conditions were mitochondria in the inner segment of photoreceptors, which displayed morphological changes in both model systems. In retinal explants, lactate metabolism, assayed as an indicator of mitochondrial function, was altered, and decreased photoreceptor viability was observed, presumably as a consequence of increased oxidative-nitrosative stress. The latter was reduced by boldine treatment in vitro, while photobiomodulation improved mitochondrial metabolism but was insufficient to prevent retinal structural damage caused by high glucose. These results warrant further research into alternative and complementary treatment options for diabetic retinopathy.
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Affiliation(s)
- Víctor Calbiague García
- Ph. D. Program in Neuroscience, Facultad de Ciencias, Universidad de Valparaíso, Valparaíso 2360102, Chile
- Centro Interdisciplinario de Neurociencias de Valparaíso (CINV), Facultad de Ciencias, Universidad de Valparaíso, Valparaíso 2360102, Chile
| | - Bárbara Cadiz
- Centro Interdisciplinario de Neurociencias de Valparaíso (CINV), Facultad de Ciencias, Universidad de Valparaíso, Valparaíso 2360102, Chile
| | - Pablo Herrera
- Instituto de Biología, Facultad de Ciencias, Universidad de Valparaíso, Valparaíso 2360102, Chile
| | - Alejandra Díaz
- Centro Interdisciplinario de Neurociencias de Valparaíso (CINV), Facultad de Ciencias, Universidad de Valparaíso, Valparaíso 2360102, Chile
| | - Oliver Schmachtenberg
- Centro Interdisciplinario de Neurociencias de Valparaíso (CINV), Facultad de Ciencias, Universidad de Valparaíso, Valparaíso 2360102, Chile
- Instituto de Biología, Facultad de Ciencias, Universidad de Valparaíso, Valparaíso 2360102, Chile
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Saadane A, Veenstra AA, Minns MS, Tang J, Du Y, Abubakr Elghazali F, Lessieur EM, Pearlman E, Kern TS. CCR2-positive monocytes contribute to the pathogenesis of early diabetic retinopathy in mice. Diabetologia 2023; 66:590-602. [PMID: 36698021 PMCID: PMC9892100 DOI: 10.1007/s00125-022-05860-w] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/17/2022] [Accepted: 09/13/2022] [Indexed: 01/27/2023]
Abstract
AIMS/HYPOTHESIS Accumulating evidence suggests that leucocytes play a critical role in diabetes-induced vascular lesions and other abnormalities that characterise the early stages of diabetic retinopathy. However, the role of monocytes has yet to be fully investigated; therefore, we used Ccr2-/- mice to study the role of CCR2+ inflammatory monocytes in the pathogenesis of diabetes-induced degeneration of retinal capillaries. METHODS Experimental diabetes was induced in wild-type and Ccr2-/- mice using streptozotocin. After 2 months, superoxide levels, expression of inflammatory genes, leucostasis, leucocyte- and monocyte-mediated cytotoxicity against retinal endothelial cell death, retinal thickness and visual function were evaluated. Retinal capillary degeneration was determined after 8 months of diabetes. Flow cytometry of peripheral blood for differential expression of CCR2 in monocytes was assessed. RESULTS In nondiabetic mice, CCR2 was highly expressed on monocytes, and Ccr2-/- mice lack CCR2+ monocytes in the peripheral blood. Diabetes-induced retinal superoxide, expression of proinflammatory genes Inos and Icam1, leucostasis and leucocyte-mediated cytotoxicity against retinal endothelial cells were inhibited in diabetic Ccr2-deficient mice and in chimeric mice lacking Ccr2 only from myeloid cells. In order to focus on monocytes, these cells were immuno-isolated after 2 months of diabetes, and they significantly increased monocyte-mediated endothelial cell cytotoxicity ex vivo. Monocytes from Ccr2-deficient mice caused significantly less endothelial cell death. The diabetes-induced retinal capillary degeneration was inhibited in Ccr2-/- mice and in chimeric mice lacking Ccr2 only from myeloid cells. CONCLUSIONS/INTERPRETATION CCR2+ inflammatory monocytes contribute to the pathogenesis of early lesions of diabetic retinopathy.
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Affiliation(s)
- Aicha Saadane
- Department of Ophthalmology, University of California-Irvine, Irvine, CA, USA.
| | | | - Martin S Minns
- Institute for Immunology, University of California-Irvine, Irvine, CA, USA
| | - Jie Tang
- Department of Pharmacology, Case Western Reserve University, Cleveland, OH, USA
| | - Yunpeng Du
- Department of Ophthalmology, University of California-Irvine, Irvine, CA, USA
| | | | - Emma M Lessieur
- Department of Ophthalmology, University of California-Irvine, Irvine, CA, USA
| | - Eric Pearlman
- Institute for Immunology, University of California-Irvine, Irvine, CA, USA
| | - Timothy S Kern
- Department of Ophthalmology, University of California-Irvine, Irvine, CA, USA
- Veterans Administration Medical Center Research Service, Long Beach, CA, USA
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Ramos H, Bogdanov P, Huerta J, Deàs-Just A, Hernández C, Simó R. Antioxidant Effects of DPP-4 Inhibitors in Early Stages of Experimental Diabetic Retinopathy. Antioxidants (Basel) 2022; 11:antiox11071418. [PMID: 35883908 PMCID: PMC9312245 DOI: 10.3390/antiox11071418] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2022] [Revised: 07/19/2022] [Accepted: 07/19/2022] [Indexed: 12/03/2022] Open
Abstract
Hyperglycemia-induced oxidative stress plays a key role in the impairment of the retinal neurovascular unit, an early event in the pathogenesis of DR. The aim of this study was to assess the antioxidant properties of topical administration (eye drops) of sitagliptin in the diabetic retina. For this purpose, db/db mice received sitagliptin or vehicle eye drops twice per day for two weeks. Age-matched db/+ mice were used as the control group. We evaluated retinal mRNA (RT-PCR) and protein levels (Western blotting and immunohistochemistry) of different components from both the antioxidant system (NRF2, CAT, GPX, GR, CuZnSOD, and MnSOD) and the prooxidant machinery (PKC and TXNIP). We also studied superoxide levels (dihydroethidium staining) and oxidative damage to DNA/RNA (8-hydroxyguanosine immunostaining) and proteins (nitrotyrosine immunostaining). Finally, NF-кB translocation and IL-1β production were assessed through Western blotting and/or immunohistochemistry. We found that sitagliptin protected against diabetes-induced oxidative stress by reducing superoxide, TXNIP, PKC, and DNA/RNA/protein oxidative damage, and it prevented the downregulation of NRF2 and antioxidant enzymes, with the exception of catalase. Sitagliptin also exerted anti-inflammatory effects, avoiding both NF-кB translocation and IL-1β production. Sitagliptin prevents the diabetes-induced imbalance between ROS production and antioxidant defenses that occurs in diabetic retinas.
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Affiliation(s)
- Hugo Ramos
- Diabetes and Metabolism Research Unit, Vall d’Hebron Research Institute (VHIR), 08035 Barcelona, Spain; (H.R.); (P.B.); (J.H.); (A.D.-J.)
- Center for Networked Biomedical Research of Diabetes and Associated Metabolic Diseases (CIBERDEM), Carlos III Health Institute (ICSIII), 28029 Madrid, Spain
| | - Patricia Bogdanov
- Diabetes and Metabolism Research Unit, Vall d’Hebron Research Institute (VHIR), 08035 Barcelona, Spain; (H.R.); (P.B.); (J.H.); (A.D.-J.)
- Center for Networked Biomedical Research of Diabetes and Associated Metabolic Diseases (CIBERDEM), Carlos III Health Institute (ICSIII), 28029 Madrid, Spain
| | - Jordi Huerta
- Diabetes and Metabolism Research Unit, Vall d’Hebron Research Institute (VHIR), 08035 Barcelona, Spain; (H.R.); (P.B.); (J.H.); (A.D.-J.)
| | - Anna Deàs-Just
- Diabetes and Metabolism Research Unit, Vall d’Hebron Research Institute (VHIR), 08035 Barcelona, Spain; (H.R.); (P.B.); (J.H.); (A.D.-J.)
- Center for Networked Biomedical Research of Diabetes and Associated Metabolic Diseases (CIBERDEM), Carlos III Health Institute (ICSIII), 28029 Madrid, Spain
| | - Cristina Hernández
- Diabetes and Metabolism Research Unit, Vall d’Hebron Research Institute (VHIR), 08035 Barcelona, Spain; (H.R.); (P.B.); (J.H.); (A.D.-J.)
- Center for Networked Biomedical Research of Diabetes and Associated Metabolic Diseases (CIBERDEM), Carlos III Health Institute (ICSIII), 28029 Madrid, Spain
- Department of Medicine, Autonomous University of Barcelona, 08193 Barcelona, Spain
- Correspondence: (C.H.); (R.S.); Tel.: +34-934-894-172 (C.H.)
| | - Rafael Simó
- Diabetes and Metabolism Research Unit, Vall d’Hebron Research Institute (VHIR), 08035 Barcelona, Spain; (H.R.); (P.B.); (J.H.); (A.D.-J.)
- Center for Networked Biomedical Research of Diabetes and Associated Metabolic Diseases (CIBERDEM), Carlos III Health Institute (ICSIII), 28029 Madrid, Spain
- Department of Medicine, Autonomous University of Barcelona, 08193 Barcelona, Spain
- Correspondence: (C.H.); (R.S.); Tel.: +34-934-894-172 (C.H.)
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11
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Sobrin L, Susarla G, Stanwyck L, Rouhana JM, Li A, Pollack S, Igo RP, Jensen RA, Li X, Ng MCY, Smith AV, Kuo JZ, Taylor KD, Freedman BI, Bowden DW, Penman A, Chen CJ, Craig JE, Adler SG, Chew EY, Cotch MF, Yaspan B, Mitchell P, Wang JJ, Klein BEK, Wong TY, Rotter JI, Burdon KP, Iyengar SK, Segrè AV. Gene Set Enrichment Analsyes Identify Pathways Involved in Genetic Risk for Diabetic Retinopathy. Am J Ophthalmol 2022; 233:111-123. [PMID: 34166655 PMCID: PMC8678352 DOI: 10.1016/j.ajo.2021.06.014] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2020] [Revised: 04/19/2021] [Accepted: 06/12/2021] [Indexed: 01/03/2023]
Abstract
To identify functionally related genes associated with diabetic retinopathy (DR) risk using gene set enrichment analyses applied to genome-wide association study meta-analyses. METHODS We analyzed DR GWAS meta-analyses performed on 3246 Europeans and 2611 African Americans with type 2 diabetes. Gene sets relevant to 5 key DR pathophysiology processes were investigated: tissue injury, vascular events, metabolic events and glial dysregulation, neuronal dysfunction, and inflammation. Keywords relevant to these processes were queried in 4 pathway and ontology databases. Two GSEA methods, Meta-Analysis Gene set Enrichment of variaNT Associations (MAGENTA) and Multi-marker Analysis of GenoMic Annotation (MAGMA), were used. Gene sets were defined to be enriched for gene associations with DR if the P value corrected for multiple testing (Pcorr) was <.05. RESULTS Five gene sets were significantly enriched for numerous modest genetic associations with DR in one method (MAGENTA or MAGMA) and also at least nominally significant (uncorrected P < .05) in the other method. These pathways were regulation of the lipid catabolic process (2-fold enrichment, Pcorr = .014); nitric oxide biosynthesis (1.92-fold enrichment, Pcorr = .022); lipid digestion, mobilization, and transport (1.6-fold enrichment, P = .032); apoptosis (1.53-fold enrichment, P = .041); and retinal ganglion cell degeneration (2-fold enrichment, Pcorr = .049). The interferon gamma (IFNG) gene, previously implicated in DR by protein-protein interactions in our GWAS, was among the top ranked genes in the nitric oxide pathway (best variant P = .0001). CONCLUSIONS These GSEA indicate that variants in genes involved in oxidative stress, lipid transport and catabolism, and cell degeneration are enriched for genes associated with DR risk. NOTE: Publication of this article is sponsored by the American Ophthalmological Society.
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Affiliation(s)
- Lucia Sobrin
- From the Department of Ophthalmology, Harvard Medical School, Massachusetts Eye and Ear Infirmary.
| | - Gayatri Susarla
- From the Department of Ophthalmology, Harvard Medical School, Massachusetts Eye and Ear Infirmary
| | - Lynn Stanwyck
- From the Department of Ophthalmology, Harvard Medical School, Massachusetts Eye and Ear Infirmary
| | - John M Rouhana
- From the Department of Ophthalmology, Harvard Medical School, Massachusetts Eye and Ear Infirmary
| | - Ashley Li
- From the Department of Ophthalmology, Harvard Medical School, Massachusetts Eye and Ear Infirmary
| | - Samuela Pollack
- Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts
| | - Robert P Igo
- Department of Population and Quantitative Health Sciences, Case Western University, Cleveland, Ohio
| | - Richard A Jensen
- Cardiovascular Health Research Unit, Department of Medicine, Epidemiology and Health Services, University of Washington, Seattle, Washington
| | - Xiaohui Li
- Institute for Translational Genomics and Population Sciences, Department of Pediatrics, the Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, California
| | - Maggie C Y Ng
- Center for Genomics and Personalized Medicine Research, Wake Forest School of Medicine; Department of Biochemistry, Wake Forest School of Medicine, Winston-Salem, North Carolina, USA; Vanderbilt Genetics Institute and Division of Genetic Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | - Albert V Smith
- Department of Medicine, University of Iceland, Reykjavík, Iceland
| | - Jane Z Kuo
- Medical Affairs, Ophthalmology, Sun Pharmaceutical Industries, Inc, Princeton, New Jersey
| | - Kent D Taylor
- Institute for Translational Genomics and Population Sciences, Department of Pediatrics, the Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, California
| | - Barry I Freedman
- Center for Genomics and Personalized Medicine Research, Wake Forest School of Medicine; Department of Internal Medicine, Section on Nephrology, Wake Forest School of Medicine, Winston-Salem, North Carolina
| | - Donald W Bowden
- Center for Genomics and Personalized Medicine Research, Wake Forest School of Medicine; Department of Biochemistry, Wake Forest School of Medicine, Winston-Salem, North Carolina, USA
| | - Alan Penman
- Department of Preventive Medicine, John D. Bower School of Population Health (A.P.), Department of Ophthalmology
| | - Ching J Chen
- Department of Preventive Medicine, John D. Bower School of Population Health (A.P.), Department of Ophthalmology
| | - Jamie E Craig
- University of Mississippi Medical Center, Jackson, Mississippi, USA, FHMRI Eye & Vision, Flinders University, Bedford Park, SA, Australia
| | - Sharon G Adler
- Department of Nephrology and Hypertension, Los Angeles Biomedical Research Institute at Harbor-University of California, Torrance, California
| | - Emily Y Chew
- Division of Epidemiology and Clinical Applications, National Eye Institute, National Institutes of Health, Bethesda, Maryland
| | - Mary Frances Cotch
- Division of Epidemiology and Clinical Applications, National Eye Institute, National Institutes of Health, Bethesda, Maryland
| | - Brian Yaspan
- Genentech Inc, South San Francisco, California, USA
| | - Paul Mitchell
- Department of Ophthalmology, Centre for Vision Research, Westmead Institute for Medical Research, University of Sydney, Sydney, Australia
| | - Jie Jin Wang
- Department of Ophthalmology, Centre for Vision Research, Westmead Institute for Medical Research, University of Sydney, Sydney, Australia; Center of Clinician-Scientist Development, Duke-NUS Medical School, Singapore
| | - Barbara E K Klein
- Department of Ophthalmology and Visual Sciences, University of Wisconsin-Madison, Madison, Wisconsin, USA
| | - Tien Y Wong
- Center of Clinician-Scientist Development, Duke-NUS Medical School, Singapore; Singapore Eye Research Institute, Singapore National Eye Centre, Singapore
| | - Jerome I Rotter
- Institute for Translational Genomics and Population Sciences, Department of Pediatrics, the Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, California
| | - Kathyrn P Burdon
- Menzies Institute for Medical Research, University of Tasmania, Hobart, Australia
| | - Sudha K Iyengar
- Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts; Department of Population and Quantitative Health Sciences, Case Western University, Cleveland, Ohio
| | - Ayellet V Segrè
- From the Department of Ophthalmology, Harvard Medical School, Massachusetts Eye and Ear Infirmary; Broad Institute of Harvard and MIT, Cambridge, Massachusetts
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12
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Sheemar A, Soni D, Takkar B, Basu S, Venkatesh P. Inflammatory mediators in diabetic retinopathy: Deriving clinicopathological correlations for potential targeted therapy. Indian J Ophthalmol 2021; 69:3035-3049. [PMID: 34708739 PMCID: PMC8725076 DOI: 10.4103/ijo.ijo_1326_21] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2021] [Revised: 08/10/2021] [Accepted: 09/27/2021] [Indexed: 11/22/2022] Open
Abstract
The role of inflammation in diabetic retinopathy (DR) is well-established and dysregulation of a large number of inflammatory mediators is known. These include cytokines, chemokines, growth factors, mediators of proteogenesis, and pro-apoptotic molecules. This para-inflammation as a response is not directed to a particular pathogen or antigen but is rather directed toward the by-products of the diabetic milieu. The inflammatory mediators take part in cascades that result in cellular level responses like neurodegeneration, pericyte loss, leakage, capillary drop out, neovascularization, etc. There are multiple overlaps between the inflammatory pathways occurring within the diabetic retina due to a large number of mediators, their varied sources, and cross-interactions. This makes understanding the role of inflammation in clinical manifestations of DR difficult. Currently, mediator-based therapy for DR is being evaluated for interventions that target a specific step of the inflammatory cascade. We reviewed the role of inflammation in DR and derived a simplified clinicopathological correlation between the sources and stimuli of inflammation, the inflammatory mediators and pathways, and the clinical manifestations of DR. By doing so, we deliberate mediator-specific therapy for DR. The cross-interactions between inflammatory mediators and the molecular cycles influencing the inflammatory cascades are crucial challenges to such an approach. Future research should be directed to assess the feasibility of the pathology-based therapy for DR.
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Affiliation(s)
- Abhishek Sheemar
- Department of Ophthalmology, All India Institute of Medical Sciences, Jodhpur, Rajasthan, India
| | - Deepak Soni
- Department of Ophthalmology, All India Institute of Medical Sciences, Bhopal, Madhya Pradesh, India
| | - Brijesh Takkar
- Smt. Kanuri Santhamma Center for Vitreoretinal Diseases, L V Prasad Eye Institute, Hyderabad, India
- Indian Health Outcomes, Public Health and Economics Research (IHOPE) Centre, L V Prasad Eye Institute, Hyderabad, India
| | - Soumyava Basu
- Uveitis Service, L V Prasad Eye Institute, Hyderabad, Telangana, India
| | - Pradeep Venkatesh
- Dr.R.P.Centre for Ophthalmic Sciences, All India Institute of Medical Science, New Delhi, India
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13
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Saadane A, Du Y, Thoreson WB, Miyagi M, Lessieur EM, Kiser J, Wen X, Berkowitz BA, Kern TS. Photoreceptor Cell Calcium Dysregulation and Calpain Activation Promote Pathogenic Photoreceptor Oxidative Stress and Inflammation in Prodromal Diabetic Retinopathy. THE AMERICAN JOURNAL OF PATHOLOGY 2021; 191:1805-1821. [PMID: 34214506 PMCID: PMC8579242 DOI: 10.1016/j.ajpath.2021.06.006] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/17/2020] [Revised: 05/20/2021] [Accepted: 06/15/2021] [Indexed: 12/13/2022]
Abstract
This study tested the hypothesis that diabetes promotes a greater than normal cytosolic calcium level in rod cells that activates a Ca2+-sensitive protease, calpain, resulting in oxidative stress and inflammation, two pathogenic factors of early diabetic retinopathy. Nondiabetic and 2-month diabetic C57Bl/6J and calpain1 knockout (Capn1-/-) mice were studied; subgroups were treated with a calpain inhibitor (CI). Ca2+ content was measured in photoreceptors using Fura-2. Retinal calpain expression was studied by quantitative RT-PCR and immunohistochemistry. Superoxide and expression of inflammatory proteins were measured using published methods. Proteomic analysis was conducted on photoreceptors isolated from untreated diabetic mice or treated daily with CI for 2 months. Cytosolic Ca2+ content was increased twofold in photoreceptors of diabetic mice as compared with nondiabetic mice. Capn1 expression increased fivefold in photoreceptor outer segments of diabetic mice. Pharmacologic inhibition or genetic deletion of Capn1 significantly suppressed diabetes-induced oxidative stress and expression of proinflammatory proteins in retina. Proteomics identified a protein (WW domain-containing oxidoreductase [WWOX]) whose expression was significantly increased in photoreceptors from mice diabetic for 2 months and was inhibited with CI. Knockdown of Wwox using specific siRNA in vitro inhibited increase in superoxide caused by the high glucose. These results suggest that reducing Ca2+ accumulation, suppressing calpain activation, and/or reducing Wwox up-regulation are novel targets for treating early diabetic retinopathy.
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Affiliation(s)
- Aicha Saadane
- Department of Ophthalmology, University of California, Irvine, Irvine, California.
| | - Yunpeng Du
- Department of Ophthalmology, University of California, Irvine, Irvine, California
| | - Wallace B Thoreson
- Department of Ophthalmology and Visual Sciences, University of Nebraska Medical Center, Omaha, Nebraska; Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, Nebraska
| | - Masaru Miyagi
- Department of Pharmacology, Case Western Reserve University, Cleveland, Ohio
| | - Emma M Lessieur
- Department of Ophthalmology, University of California, Irvine, Irvine, California
| | - Jianying Kiser
- Department of Ophthalmology, University of California, Irvine, Irvine, California
| | - Xiangyi Wen
- Department of Ophthalmology and Visual Sciences, University of Nebraska Medical Center, Omaha, Nebraska
| | - Bruce A Berkowitz
- Department of Ophthalmology, Visual and Anatomical Sciences, Wayne State University School of Medicine, Detroit, Michigan
| | - Timothy S Kern
- Department of Ophthalmology, University of California, Irvine, Irvine, California; Veterans Administration Medical Center Research Service, Long Beach, California
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14
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Chang GR, Hou PH, Wang CM, Lin JW, Lin WL, Lin TC, Liao HJ, Chan CH, Wang YC. Imipramine Accelerates Nonalcoholic Fatty Liver Disease, Renal Impairment, Diabetic Retinopathy, Insulin Resistance, and Urinary Chromium Loss in Obese Mice. Vet Sci 2021; 8:189. [PMID: 34564583 PMCID: PMC8473438 DOI: 10.3390/vetsci8090189] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2021] [Revised: 08/23/2021] [Accepted: 09/07/2021] [Indexed: 12/12/2022] Open
Abstract
Imipramine is a tricyclic antidepressant that has been approved for treating depression and anxiety in patients and animals and that has relatively mild side effects. However, the mechanisms of imipramine-associated disruption to metabolism and negative hepatic, renal, and retinal effects are not well defined. In this study, we evaluated C57BL6/J mice subjected to a high-fat diet (HFD) to study imipramine's influences on obesity, fatty liver scores, glucose homeostasis, hepatic damage, distribution of chromium, and retinal/renal impairments. Obese mice receiving imipramine treatment had higher body, epididymal fat pad, and liver weights; higher serum triglyceride, aspartate and alanine aminotransferase, creatinine, blood urea nitrogen, renal antioxidant enzyme, and hepatic triglyceride levels; higher daily food efficiency; and higher expression levels of a marker of fatty acid regulation in the liver compared with the controls also fed an HFD. Furthermore, the obese mice that received imipramine treatment exhibited insulin resistance, worse glucose intolerance, decreased glucose transporter 4 expression and Akt phosphorylation levels, and increased chromium loss through urine. In addition, the treatment group exhibited considerably greater liver damage and higher fatty liver scores, paralleling the increases in patatin-like phospholipid domain containing protein 3 and the mRNA levels of sterol regulatory element-binding protein 1 and fatty acid-binding protein 4. Retinal injury worsened in imipramine-treated mice; decreases in retinal cell layer organization and retinal thickness and increases in nuclear factor κB and inducible nitric oxide synthase levels were observed. We conclude that administration of imipramine may result in the exacerbation of nonalcoholic fatty liver disease, diabetes, diabetic retinopathy, and kidney injury.
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Affiliation(s)
- Geng-Ruei Chang
- Department of Veterinary Medicine, National Chiayi University, 580 Xinmin Road, Chiayi 60054, Taiwan; (G.-R.C.); (C.-M.W.); (T.-C.L.); (H.-J.L.)
| | - Po-Hsun Hou
- Department of Psychiatry, Taichung Veterans General Hospital, 4 Section, 1650 Taiwan Boulevard, Taichung 40705, Taiwan;
- Faculty of Medicine, National Yang-Ming University, 2 Section, 155 Linong Street, Beitou District, Taipei 11221, Taiwan
- College of Medicine, National Chung Hsing University, 145 Xingda Road, South District, Taichung 40227, Taiwan
| | - Chao-Min Wang
- Department of Veterinary Medicine, National Chiayi University, 580 Xinmin Road, Chiayi 60054, Taiwan; (G.-R.C.); (C.-M.W.); (T.-C.L.); (H.-J.L.)
| | - Jen-Wei Lin
- Bachelor Degree Program in Animal Healthcare, Hungkuang University, 6 Section, 1018 Taiwan Boulevard, Shalu District, Taichung 433304, Taiwan; (J.-W.L.); (W.-L.L.)
| | - Wei-Li Lin
- Bachelor Degree Program in Animal Healthcare, Hungkuang University, 6 Section, 1018 Taiwan Boulevard, Shalu District, Taichung 433304, Taiwan; (J.-W.L.); (W.-L.L.)
- General Education Center, Chaoyang University of Technology, 168 Jifeng Eastern Road, Taichung 413310, Taiwan
| | - Tzu-Chun Lin
- Department of Veterinary Medicine, National Chiayi University, 580 Xinmin Road, Chiayi 60054, Taiwan; (G.-R.C.); (C.-M.W.); (T.-C.L.); (H.-J.L.)
| | - Huei-Jyuan Liao
- Department of Veterinary Medicine, National Chiayi University, 580 Xinmin Road, Chiayi 60054, Taiwan; (G.-R.C.); (C.-M.W.); (T.-C.L.); (H.-J.L.)
| | - Chee-Hong Chan
- Division of Nephrology, Chang Bing Show Chwan Memorial Hospital, 6 Lugong Road, Lukang Township, Changhua 50544, Taiwan
| | - Yu-Chen Wang
- Division of Cardiology, Asia University Hospital, 222 Fuxin Road, Wufeng District, Taichung 41354, Taiwan
- Department of Medical Laboratory Science and Biotechnology, Asia University, 500 Lioufeng Road, Wufeng District, Taichung 41354, Taiwan
- Division of Cardiovascular Medicine, China Medical University Hospital, 2 Yude Road, North District, Taichung 404332, Taiwan
- College of Medicine, China Medical University, 91 Hsueh-Shih Road, North District, Taichung 404333, Taiwan
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15
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Tonade D, Kern TS. Photoreceptor cells and RPE contribute to the development of diabetic retinopathy. Prog Retin Eye Res 2021; 83:100919. [PMID: 33188897 PMCID: PMC8113320 DOI: 10.1016/j.preteyeres.2020.100919] [Citation(s) in RCA: 111] [Impact Index Per Article: 27.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2020] [Revised: 10/27/2020] [Accepted: 10/31/2020] [Indexed: 12/26/2022]
Abstract
Diabetic retinopathy (DR) is a leading cause of blindness. It has long been regarded as vascular disease, but work in the past years has shown abnormalities also in the neural retina. Unfortunately, research on the vascular and neural abnormalities have remained largely separate, instead of being integrated into a comprehensive view of DR that includes both the neural and vascular components. Recent evidence suggests that the most predominant neural cell in the retina (photoreceptors) and the adjacent retinal pigment epithelium (RPE) play an important role in the development of vascular lesions characteristic of DR. This review summarizes evidence that the outer retina is altered in diabetes, and that photoreceptors and RPE contribute to retinal vascular alterations in the early stages of the retinopathy. The possible molecular mechanisms by which cells of the outer retina might contribute to retinal vascular damage in diabetes also are discussed. Diabetes-induced alterations in the outer retina represent a novel therapeutic target to inhibit DR.
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Affiliation(s)
- Deoye Tonade
- Department of Pharmacology, Case Western Reserve University, Cleveland, OH, USA
| | - Timothy S Kern
- Department of Pharmacology, Case Western Reserve University, Cleveland, OH, USA; Veterans Administration Medical Center Research Service, Cleveland, OH, USA; Gavin Herbert Eye Institute, University of California Irvine, Irvine, CA, USA; Veterans Administration Medical Center Research Service, Long Beach, CA, USA.
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16
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Chang GR, Liu HY, Yang WC, Wang CM, Wu CF, Lin JW, Lin WL, Wang YC, Lin TC, Liao HJ, Hou PH, Chan CH, Lin CF. Clozapine Worsens Glucose Intolerance, Nonalcoholic Fatty Liver Disease, Kidney Damage, and Retinal Injury and Increases Renal Reactive Oxygen Species Production and Chromium Loss in Obese Mice. Int J Mol Sci 2021; 22:ijms22136680. [PMID: 34206460 PMCID: PMC8268139 DOI: 10.3390/ijms22136680] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2021] [Revised: 06/09/2021] [Accepted: 06/18/2021] [Indexed: 12/18/2022] Open
Abstract
Clozapine is widely employed in the treatment of schizophrenia. Compared with that of atypical first-generation antipsychotics, atypical second-generation antipsychotics such as clozapine have less severe side effects and may positively affect obesity and blood glucose level. However, no systematic study of clozapine’s adverse metabolic effects—such as changes in kidney and liver function, body weight, glucose and triglyceride levels, and retinopathy—was conducted. This research investigated how clozapine affects weight, the bodily distribution of chromium, liver damage, fatty liver scores, glucose homeostasis, renal impairment, and retinopathy in mice fed a high fat diet (HFD). We discovered that obese mice treated with clozapine gained more weight and had greater kidney, liver, and retroperitoneal and epididymal fat pad masses; higher daily food efficiency; higher serum or hepatic triglyceride, aspartate aminotransferase, alanine aminotransferase, blood urea nitrogen, and creatinine levels; and higher hepatic lipid regulation marker expression than did the HFD-fed control mice. Furthermore, the clozapine group mice exhibited insulin resistance, poorer insulin sensitivity, greater glucose intolerance, and less Akt phosphorylation; their GLUT4 expression was lower, they had renal damage, more reactive oxygen species, and IL-1 expression, and, finally, their levels of antioxidative enzymes (superoxide dismutase, glutathione peroxidase, and catalase) were lower. Moreover, clozapine reduced the thickness of retinal cell layers and increased iNOS and NF-κB expression; a net negative chromium balance occurred because more chromium was excreted through urine, and this influenced chromium mobilization, which did not help overcome the hyperglycemia. Our clozapine group had considerably higher fatty liver scores, which was supported by the findings of lowered adiponectin protein levels and increased FASN protein, PNPLA3 protein, FABP4 mRNA, and SREBP1 mRNA levels. We conclude that clozapine can worsen nonalcoholic fatty liver disease, diabetes, and kidney and retinal injury. Therefore, long-term administration of clozapine warrants higher attention.
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Affiliation(s)
- Geng-Ruei Chang
- Department of Veterinary Medicine, National Chiayi University, 580 Xinmin Road, Chiayi 600023, Taiwan; (G.-R.C.); (C.-M.W.); (C.-F.W.); (T.-C.L.); (H.-J.L.)
| | - Hsien-Yueh Liu
- Bachelor Degree Program in Animal Healthcare, Hungkuang University, 6 Section, 1018 Taiwan Boulevard, Shalu District, Taichung 433304, Taiwan; (H.-Y.L.); (J.-W.L.); (W.-L.L.)
| | - Wei-Cheng Yang
- School of Veterinary Medicine, National Taiwan University, 4 Section, 1 Roosevelt Road, Taipei 100046, Taiwan;
| | - Chao-Min Wang
- Department of Veterinary Medicine, National Chiayi University, 580 Xinmin Road, Chiayi 600023, Taiwan; (G.-R.C.); (C.-M.W.); (C.-F.W.); (T.-C.L.); (H.-J.L.)
| | - Ching-Fen Wu
- Department of Veterinary Medicine, National Chiayi University, 580 Xinmin Road, Chiayi 600023, Taiwan; (G.-R.C.); (C.-M.W.); (C.-F.W.); (T.-C.L.); (H.-J.L.)
| | - Jen-Wei Lin
- Bachelor Degree Program in Animal Healthcare, Hungkuang University, 6 Section, 1018 Taiwan Boulevard, Shalu District, Taichung 433304, Taiwan; (H.-Y.L.); (J.-W.L.); (W.-L.L.)
| | - Wei-Li Lin
- Bachelor Degree Program in Animal Healthcare, Hungkuang University, 6 Section, 1018 Taiwan Boulevard, Shalu District, Taichung 433304, Taiwan; (H.-Y.L.); (J.-W.L.); (W.-L.L.)
- General Education Center, Chaoyang University of Technology, 168 Jifeng Eastern Road, Taichung 413310, Taiwan
| | - Yu-Chen Wang
- Division of Cardiology, Asia University Hospital, 222 Fuxin Road, Wufeng District, Taichung 413505, Taiwan;
- Department of Medical Laboratory Science and Biotechnology, Asia University, 500 Lioufeng Road, Wufeng District, Taichung 413305, Taiwan
- Division of Cardiovascular Medicine, China Medical University Hospital, 2 Yude Road, North District, Taichung 404332, Taiwan
- College of Medicine, China Medical University, 91 Hsueh-Shih Road, North District, Taichung 404333, Taiwan
| | - Tzu-Chun Lin
- Department of Veterinary Medicine, National Chiayi University, 580 Xinmin Road, Chiayi 600023, Taiwan; (G.-R.C.); (C.-M.W.); (C.-F.W.); (T.-C.L.); (H.-J.L.)
| | - Huei-Jyuan Liao
- Department of Veterinary Medicine, National Chiayi University, 580 Xinmin Road, Chiayi 600023, Taiwan; (G.-R.C.); (C.-M.W.); (C.-F.W.); (T.-C.L.); (H.-J.L.)
| | - Po-Hsun Hou
- Department of Psychiatry, Taichung Veterans General Hospital, 4 Section, 1650 Taiwan Boulevard, Taichung 407219, Taiwan
- Faculty of Medicine, National Yang Ming Chiao Tung University, 2 Section, 155 Linong Street, Beitou District, Taipei 112304, Taiwan
- Correspondence: (P.-H.H.); (C.-H.C.); (C.-F.L.); Tel.: +886-4-23592525 (P.-H.H.); +886-975-617071 (C.-H.C.); +886-8-7703202 (C.-F.L.)
| | - Chee-Hong Chan
- Division of Nephrology, Chang Bing Show Chwan Memorial Hospital, 6 Lugong Road, Lukang Township, Changhua 505029, Taiwan
- Correspondence: (P.-H.H.); (C.-H.C.); (C.-F.L.); Tel.: +886-4-23592525 (P.-H.H.); +886-975-617071 (C.-H.C.); +886-8-7703202 (C.-F.L.)
| | - Chuen-Fu Lin
- Department of Veterinary Medicine, College of Veterinary Medicine, National Pingtung University of Science and Technology, 1 Shuefu Road, Neipu, Pingtung 912301, Taiwan
- Correspondence: (P.-H.H.); (C.-H.C.); (C.-F.L.); Tel.: +886-4-23592525 (P.-H.H.); +886-975-617071 (C.-H.C.); +886-8-7703202 (C.-F.L.)
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17
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Couto SMF, da Fonseca CD, Watanabe M, de Fátima Fernandes Vattimo M. Protection of coenzyme Q10 against contrast-induced acute kidney injury in male diabetic rats. Diabetol Metab Syndr 2021; 13:69. [PMID: 34134745 PMCID: PMC8207798 DOI: 10.1186/s13098-021-00689-6] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/20/2021] [Accepted: 06/09/2021] [Indexed: 02/16/2023] Open
Abstract
BACKGROUND Diabetes mellitus (DM) is a major risk factor for contrast-induced acute kidney injury (CI-AKI). DM and CI-AKI result in oxidative damage and inflammation that can be reduced when treated with the coenzyme Q-10 (CoQ10). The aim of this study was to investigate the therapeutic potential of CoQ10 in renal function, renal hemodynamics, oxidative profile and renal histology in diabetic rats subjected to CI-AKI. METHODS Wistar rats, male, randomized into five groups: citrate: control animals received citrate buffer (streptozotocin vehicle, 0.4 mL); Tween: control animals of CoQ10 treatment received 1% Tween 80 (CoQ10 vehicle, 0.5 mL); DM: animals that received streptozotocin (60 mg/kg); DM + IC: DM animals treated with iodinated contrast (IC, 6 mL/kg); DM + IC + CoQ10: DM animals treated with CoQ10 (10 mg/kg) and that received IC (6 mL/kg). The protocols lasted 4 weeks. An evaluation was made to measure renal function, inulin clearance and serum creatinine, renal hemodynamics by renal blood flow (RBF) and renal vascular resistance (RVR), markers of oxidative stress such as urinary peroxides and nitrate, lipid peroxidation, thiols in renal tissue and renal histological analysis. RESULTS DM animals showed reduced renal function, which was followed by an increase inserum creatinine and significant reduction of inulin clearance and RBF. It was noticed an increase in RVR and redox imbalance with higher urinary peroxides and nitrate lipid peroxidation levels with depletion of thiols in renal tissue. IC treatment exacerbated these changes in DM + IC. CoQ10 administration ameliorated renal function, prevented hemodynamic changes and neutralized oxidative damage and progression of the histologic damage in the DM + IC + CoQ10 group. CONCLUSION This study demonstrated the renoprotection properties of CoQ10 in an experimental model of risk factor of DM for CI-AKI. CoQ10 presented an antioxidant effect on the CI-AKI in male diabetic rats by improving renal function and renal hemodynamics, preserving morphology and reducing oxidative stress.
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Affiliation(s)
- Sheila Marques Fernandes Couto
- Laboratório Experimental de Modelos Animais (LEMA), Escola de Enfermagem da Universidade de São Paulo (EEUSP), Avenida Doutor Enéas de Carvalho Aguiar, 419, Cerqueira César, São Paulo, SP, 05403-000, Brazil.
| | - Cassiane Dezoti da Fonseca
- Laboratório Experimental de Modelos Animais (LEMA), Escola de Enfermagem da Universidade de São Paulo (EEUSP), Avenida Doutor Enéas de Carvalho Aguiar, 419, Cerqueira César, São Paulo, SP, 05403-000, Brazil
- Escola Paulista de Enfermagem da Universidade Federal de São Paulo, São Paulo, SP, Brazil
| | - Mirian Watanabe
- Laboratório Experimental de Modelos Animais (LEMA), Escola de Enfermagem da Universidade de São Paulo (EEUSP), Avenida Doutor Enéas de Carvalho Aguiar, 419, Cerqueira César, São Paulo, SP, 05403-000, Brazil
- Ciências da Saúde e Bem Estar (CISBEM), Centro Universitário das Faculdades Metropolitanas Unidas, São Paulo, SP, Brazil
| | - Maria de Fátima Fernandes Vattimo
- Laboratório Experimental de Modelos Animais (LEMA), Escola de Enfermagem da Universidade de São Paulo (EEUSP), Avenida Doutor Enéas de Carvalho Aguiar, 419, Cerqueira César, São Paulo, SP, 05403-000, Brazil
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18
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Maugeri G, Bucolo C, Drago F, Rossi S, Di Rosa M, Imbesi R, D'Agata V, Giunta S. Attenuation of High Glucose-Induced Damage in RPE Cells through p38 MAPK Signaling Pathway Inhibition. Front Pharmacol 2021; 12:684680. [PMID: 34025440 PMCID: PMC8138305 DOI: 10.3389/fphar.2021.684680] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2021] [Accepted: 04/26/2021] [Indexed: 12/18/2022] Open
Abstract
This study aimed to investigate the high glucose damage on human retinal pigment epithelial (RPE) cells, the role of p38 MAPK signaling pathway and how dimethyl fumarate can regulate that. We carried out in vitro studies on ARPE-19 cells exposed to physiological and high glucose (HG) conditions, to evaluate the effects of DMF on cell viability, apoptosis, and expression of inflammatory and angiogenic biomarkers such as COX-2, iNOS, IL-1β, and VEGF. Our data have demonstrated that DMF treatment attenuated HG-induced apoptosis, as confirmed by reduction of BAX/Bcl-2 ratio. Furthermore, in RPE cells exposed to HG we observed a significant increase of iNOS, COX-2, and IL-1β expression, that was reverted by DMF treatment. Moreover, DMF reduced the VEGF levels elicited by HG, inhibiting p38 MAPK signaling pathway. The present study demonstrated that DMF provides a remarkable protection against high glucose-induced damage in RPE cells through p38 MAPK inhibition and the subsequent down-regulation of VEGF levels, suggesting that DMF is a small molecule that represents a good candidate for diabetic retinopathy treatment and warrants further in vivo and clinical evaluation.
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Affiliation(s)
- Grazia Maugeri
- Section of Anatomy, Histology and Movement Sciences, Department of Biomedical and Biotechnological Sciences, University of Catania, Catania, Italy
| | - Claudio Bucolo
- Pharmacology Section, Department of Biomedical and Biotechnological Sciences, University of Catania, Catania, Italy.,Center for Research in Ocular Pharmacology (CERFO), University of Catania, Catania, Italy
| | - Filippo Drago
- Pharmacology Section, Department of Biomedical and Biotechnological Sciences, University of Catania, Catania, Italy.,Center for Research in Ocular Pharmacology (CERFO), University of Catania, Catania, Italy
| | - Settimio Rossi
- Eye Clinic, Multidisciplinary Department of Medical, Surgical and Dental Sciences, University of Campania "Luigi Vanvitelli", Napoli, Italy
| | - Michelino Di Rosa
- Section of Anatomy, Histology and Movement Sciences, Department of Biomedical and Biotechnological Sciences, University of Catania, Catania, Italy
| | - Rosa Imbesi
- Section of Anatomy, Histology and Movement Sciences, Department of Biomedical and Biotechnological Sciences, University of Catania, Catania, Italy
| | - Velia D'Agata
- Section of Anatomy, Histology and Movement Sciences, Department of Biomedical and Biotechnological Sciences, University of Catania, Catania, Italy
| | - Salvatore Giunta
- Section of Anatomy, Histology and Movement Sciences, Department of Biomedical and Biotechnological Sciences, University of Catania, Catania, Italy
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Subedi L, Gaire BP, Kim SY, Parveen A. Nitric Oxide as a Target for Phytochemicals in Anti-Neuroinflammatory Prevention Therapy. Int J Mol Sci 2021; 22:ijms22094771. [PMID: 33946349 PMCID: PMC8124914 DOI: 10.3390/ijms22094771] [Citation(s) in RCA: 30] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2021] [Revised: 04/27/2021] [Accepted: 04/27/2021] [Indexed: 12/23/2022] Open
Abstract
Nitric oxide (NO) is a neurotransmitter that mediates the activation and inhibition of inflammatory cascades. Even though physiological NO is required for defense against various pathogens, excessive NO can trigger inflammatory signaling and cell death through reactive nitrogen species-induced oxidative stress. Excessive NO production by activated microglial cells is specifically associated with neuroinflammatory and neurodegenerative conditions, such as Alzheimer’s and Parkinson’s disease, amyotrophic lateral sclerosis, ischemia, hypoxia, multiple sclerosis, and other afflictions of the central nervous system (CNS). Therefore, controlling excessive NO production is a desirable therapeutic strategy for managing various neuroinflammatory disorders. Recently, phytochemicals have attracted considerable attention because of their potential to counteract excessive NO production in CNS disorders. Moreover, phytochemicals and nutraceuticals are typically safe and effective. In this review, we discuss the mechanisms of NO production and its involvement in various neurological disorders, and we revisit a number of recently identified phytochemicals which may act as NO inhibitors. This review may help identify novel potent anti-inflammatory agents that can downregulate NO, specifically during neuroinflammation and neurodegeneration.
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20
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Nebbioso M, Lambiase A, Armentano M, Tucciarone G, Sacchetti M, Greco A, Alisi L. Diabetic retinopathy, oxidative stress, and sirtuins: an in depth look in enzymatic patterns and new therapeutic horizons. Surv Ophthalmol 2021; 67:168-183. [PMID: 33864872 DOI: 10.1016/j.survophthal.2021.04.003] [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: 05/01/2020] [Revised: 04/03/2021] [Accepted: 04/05/2021] [Indexed: 12/16/2022]
Abstract
Diabetic retinopathy (DR) is one of the leading causes of blindness in the world. DR represents the most common microvascular complication of diabetes, and its incidence is constantly rising. The complex interactions between inflammation, oxidative stress, and the production of free oxygen radicals caused by prolonged exposure to hyperglycemia determine the development of DR. Sirtuins (SIRTs) are a recently discovered class of 7 histone deacetylases involved in cellular senescence, regulation of cell cycle, metabolic pathways, and DNA repair. SIRTs participate in the progress of several pathologies such as cancer, neurodegeneration, and metabolic diseases. In DR sirtuins 1,3,5, and 6 play an important role as they regulate the activation of the inflammatory response, insulin sensibility, and both glycolysis and gluconeogenesis. A wide spectrum of direct and indirect activators of SIRTs pathways (e.g., antagomiR, resveratrol, or glycyrrhizin) is currently being developed to treat the inflammatory cascade occurring in DR. We focus on the main metabolic and inflammatory pathways involving SIRTs and DR, as well as recent evidence on SIRTs activators that may be employed as novel therapeutic approaches to DR.
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Affiliation(s)
- Marcella Nebbioso
- Department of Sense Organs, Faculty of Medicine and Odontology, Policlinico Umberto I. Sapienza University of Rome, v. le del Policlinico 155, 00161 Rome, Italy
| | - Alessandro Lambiase
- Department of Sense Organs, Faculty of Medicine and Odontology, Policlinico Umberto I. Sapienza University of Rome, v. le del Policlinico 155, 00161 Rome, Italy.
| | - Marta Armentano
- Department of Sense Organs, Faculty of Medicine and Odontology, Policlinico Umberto I. Sapienza University of Rome, v. le del Policlinico 155, 00161 Rome, Italy
| | - Giosuè Tucciarone
- Department of Sense Organs, Faculty of Medicine and Odontology, Policlinico Umberto I. Sapienza University of Rome, v. le del Policlinico 155, 00161 Rome, Italy
| | - Marta Sacchetti
- Department of Sense Organs, Faculty of Medicine and Odontology, Policlinico Umberto I. Sapienza University of Rome, v. le del Policlinico 155, 00161 Rome, Italy
| | - Antonio Greco
- Department of Sense Organs, Faculty of Medicine and Odontology, Policlinico Umberto I. Sapienza University of Rome, v. le del Policlinico 155, 00161 Rome, Italy
| | - Ludovico Alisi
- Department of Sense Organs, Faculty of Medicine and Odontology, Policlinico Umberto I. Sapienza University of Rome, v. le del Policlinico 155, 00161 Rome, Italy
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21
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Al-Shabrawey M, Hussein K, Wang F, Wan M, Elmasry K, Elsherbiny N, Saleh H, Yu PB, Tawfik A, Ibrahim AS. Bone Morphogenetic Protein-2 Induces Non-Canonical Inflammatory and Oxidative Pathways in Human Retinal Endothelial Cells. Front Immunol 2021; 11:568795. [PMID: 33584642 PMCID: PMC7878387 DOI: 10.3389/fimmu.2020.568795] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2020] [Accepted: 12/08/2020] [Indexed: 11/13/2022] Open
Abstract
The mechanisms of diabetic retinopathy (DR), are not yet fully understood. We previously demonstrated an upregulation of retinal bone morphogenetic protein-2 (BMP2) in experimental diabetes and in retinas of diabetic human subjects. The purpose of current study was to investigate the role of non-canonical inflammatory pathway in BMP2-induced retinal endothelial cell (REC) barrier dysfunction. For this purpose, we used RT-PCR and western blotting to evaluate the levels of BMP2 signaling components (BMP2, BMP4, BMP receptors), VEGF, phosphorylated p38 MAPK and NFκB, and oxidative stress markers in cultured human retinal endothelial cells (HRECs) subjected to BMP2 (50ng/ml) for up to 24 h. Also, effect of high glucose (HG, 30mM D-glucose) on the expression of BMP2 and its downstream genes was examined in HRECs. H2-DCF is a fluorogenic dye that measures the levels of cellular reactive oxygen species (ROS) was used to measure the pro-oxidative effect of BMP2. Moreover, we evaluated the effect of inhibiting p38 and VEGF signaling on BMP2-induced HRECs barrier dysfunction by measuring the trans-endothelial cell electrical resistance (TER) using electric cell-substrate impedance sensing (ECIS). We also tested the effect of HG on the integrity of HRECs barrier in the presence or absence of inhibitors of BMP2 signaling. Our data reveals that BMP2 and high glucose upregulates BMP components of the BMP signaling pathway (SMAD effectors, BMP receptors, and TGFβ ligand itself) and induces phosphorylation of p38 MAPK and NFκB with nuclear translocation of NFκB. Inhibition of p38 or NFκB attenuated BMP2-induced VEGF expression and barrier dysfunction in HRECs. Also, inhibition of VEGFR2 attenuated BMP2-induced barrier dysfunction. Moreover, BMP2 induces generation of ROS and endothelial nitric oxide synthase (eNOS) expression and activity in HRECs. Finally, HG upregulated BMP2 and its downstream genes (SMAD, BMP4, ALKs, and TGF-β) in HRECs and BMP2 inhibitors attenuated HG-induced HRECs barrier dysfunction. Our results suggest that in addition to the regular canonical SMAD signaling BMP2 induces non-canonical inflammatory pathway in HRECs via activation of p38/NFκB pathway that causes the upregulation of VEGF and the disruption of HRECs. Inhibition of BMP2 signaling is a potential therapeutic intervention to preserve endothelial cell barrier function in DR.
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Affiliation(s)
- Mohamed Al-Shabrawey
- Department of Oral Biology and Diagnostic Sciences, Dental College of Georgia, Augusta University, Augusta, GA, United States
- Department of Cellular Biology and Anatomy, Medical College of Georgia, Augusta University, Augusta, GA, United States
- Department of Ophthalmology and Culver Vision Discovery Institute, Medical College of Georgia, Augusta University, Augusta, GA, United States
- Department of Anatomy, Mansoura Faculty of Medicine, Mansoura University, Mansoura, Egypt
| | - Khaled Hussein
- Department of Oral Biology and Diagnostic Sciences, Dental College of Georgia, Augusta University, Augusta, GA, United States
- Department of Medicine and Surgery, Oral and Dental Research Division, National Research Centre, Cairo, Egypt
| | - Fang Wang
- Department of Oral Biology and Diagnostic Sciences, Dental College of Georgia, Augusta University, Augusta, GA, United States
- Department of Traditional Chinese Medicine, School of Medicine, Jianghan University, Wuhan, China
| | - Ming Wan
- Department of Oral Biology and Diagnostic Sciences, Dental College of Georgia, Augusta University, Augusta, GA, United States
- Department of Traditional Chinese Medicine, School of Medicine, Jianghan University, Wuhan, China
| | - Khaled Elmasry
- Department of Oral Biology and Diagnostic Sciences, Dental College of Georgia, Augusta University, Augusta, GA, United States
- Department of Anatomy, Mansoura Faculty of Medicine, Mansoura University, Mansoura, Egypt
| | - Nehal Elsherbiny
- Department of Oral Biology and Diagnostic Sciences, Dental College of Georgia, Augusta University, Augusta, GA, United States
- Department of Biochemistry, Faculty of Pharmacy, Mansoura University, Mansoura, Egypt
| | - Heba Saleh
- Department of Oral Biology and Diagnostic Sciences, Dental College of Georgia, Augusta University, Augusta, GA, United States
| | - Paul B. Yu
- Division of Cardiovascular Medicine, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, United States
| | - Amany Tawfik
- Department of Oral Biology and Diagnostic Sciences, Dental College of Georgia, Augusta University, Augusta, GA, United States
- Department of Cellular Biology and Anatomy, Medical College of Georgia, Augusta University, Augusta, GA, United States
- Department of Ophthalmology and Culver Vision Discovery Institute, Medical College of Georgia, Augusta University, Augusta, GA, United States
| | - Ahmed S. Ibrahim
- Department of Biochemistry, Faculty of Pharmacy, Mansoura University, Mansoura, Egypt
- Department of Ophthalmology, Visual, and Anatomical Sciences, Department of Pharmacology, Wayne State University, Detroit, MI, United States
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22
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Saadane A, Lessieur EM, Du Y, Liu H, Kern TS. Successful induction of diabetes in mice demonstrates no gender difference in development of early diabetic retinopathy. PLoS One 2020; 15:e0238727. [PMID: 32941450 PMCID: PMC7498040 DOI: 10.1371/journal.pone.0238727] [Citation(s) in RCA: 56] [Impact Index Per Article: 11.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2020] [Accepted: 08/21/2020] [Indexed: 01/29/2023] Open
Abstract
Purpose Female mice have been found to be resistant to streptozotocin (STZ)-induced diabetes, and pre-clinical research related to diabetic complications commonly omits females. The purpose of this study was to develop a method to induce diabetes in female mice, and to determine if retinas of diabetic female mice develop molecular changes and histopathological abnormalities comparable to those which develop in male diabetic mice. Methods To induce diabetes, animals of both sexes received daily intraperitoneal (i.p.) injection of STZ for 5 consecutive days at 55 mg/kg BW (a dose that is known to induce diabetes in male mice) or for females, 75 mg/kg BW of STZ. Retinal abnormalities that have been implicated in the development of the retinopathy (superoxide generation and expression of inflammatory proteins, iNOS and ICAM-1) were evaluated at 2 months of diabetes, and retinal capillary degeneration was evaluated at 8 months of diabetes. Results Daily i.p. injection of STZ for 5 consecutive days at a concentration of 55 mg/kg BW was sufficient to induce diabetes in 100% of male mice, but only 33% of female mice. However, females did become hyperglycemic when the dose of STZ administered was increased to 75 mg/kg BW. The resulting STZ-induced hyperglycemia in female and male mice was sustained for at least 8 months. After induction of the diabetes, both sexes responded similarly with respect to the oxidative stress, expression of iNOS, and degeneration of retinal capillaries, but differed in the limited population evaluated with respect to expression of ICAM-1. Conclusions The resistance of female mice to STZ-induced diabetes can be overcome by increasing the dose of STZ used. Female mice can, and should, be included in pre-clinical studies of diabetes and its complications.
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Affiliation(s)
- Aicha Saadane
- Department of Ophthalmology, University of California-Irvine, Irvine, California, United States of America
- * E-mail:
| | - Emma M. Lessieur
- Department of Ophthalmology, University of California-Irvine, Irvine, California, United States of America
| | - Yunpeng Du
- Department of Ophthalmology, University of California-Irvine, Irvine, California, United States of America
| | - Haitao Liu
- Department of Ophthalmology, Children's Hospital of University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, United States of America
| | - Timothy S. Kern
- Department of Ophthalmology, University of California-Irvine, Irvine, California, United States of America
- Veterans Administration Medical Center Research Service, Long Beach, California, United States of America
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23
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Wang F, Li R, Zhao L, Ma S, Qin G. Resveratrol ameliorates renal damage by inhibiting oxidative stress-mediated apoptosis of podocytes in diabetic nephropathy. Eur J Pharmacol 2020; 885:173387. [PMID: 32710953 DOI: 10.1016/j.ejphar.2020.173387] [Citation(s) in RCA: 33] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2019] [Revised: 07/14/2020] [Accepted: 07/20/2020] [Indexed: 02/07/2023]
Abstract
Diabetic nephropathy (DN) is the major cause of end-stage renal disease. Resveratrol (RSV) has been shown to exert a renoprotective effect against DN, but despite research progress, the protective mechanisms of RSV have not been fully elucidated. Here, we demonstrated that RSV relieved a series of pathological characteristics of DN and attenuated oxidative stress and apoptosis in the renal tissues of diabetic (db/db) mice. In addition, RSV inhibited oxidative stress production and apoptosis in human podocytes exposed to high glucose. Furthermore, inhibition of reactive oxygen species generation by reactive oxygen species scavengers N-acetylcysteine and 2,2,6,6-tetramethyl-1-piperidinyloxy had the same anti-apoptosis effects on podocytes as did RSV. Finally, we found that 5' adenosine monophosphate-activated protein kinase (AMPK) was activated by RSV in db/db mice and podocytes exposed to high glucose. The protective effects of RSV on podocytes were suppressed by Compound C, a pharmacological inhibitor of AMPK. Together, our results indicate that RSV effectively attenuated renal damage by suppressing oxidative stress-mediated apoptosis of podocytes, which was dependent on AMPK activation. This study revealed a possible mechanism to protect podocytes against apoptosis in DN.
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Affiliation(s)
- Fang Wang
- Department of Endocrinology, The First Affiliated Hospital of Zhengzhou University, China
| | - Ran Li
- Department of Cardiology, The First Affiliated Hospital of Zhengzhou University, China
| | - Linlin Zhao
- Department of Endocrinology, The First Affiliated Hospital of Zhengzhou University, China
| | - Shuang Ma
- The Nephrology Center of the First Affiliated Hospital of Zhengzhou University, China
| | - Guijun Qin
- Department of Endocrinology, The First Affiliated Hospital of Zhengzhou University, China.
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24
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Adki KM, Kulkarni YA. Potential Biomarkers in Diabetic Retinopathy. Curr Diabetes Rev 2020; 16:971-983. [PMID: 32065092 DOI: 10.2174/1573399816666200217092022] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/10/2019] [Revised: 11/28/2019] [Accepted: 01/09/2020] [Indexed: 12/13/2022]
Abstract
BACKGROUND Diabetic retinopathy is one of the important complications of diabetes. In major cases, diabetic retinopathy is unnoticed until the irreversible damage to eye occurs and leads to blurred vision and, eventually, blindness. OBJECTIVE The pathogenesis and diagnosis of diabetic retinopathy are very complex and not fully understood. Currently, well-established laser techniques and medications are available, but these treatment options have their own shortcomings on biological systems. Biomarkers can help to overcome this problem due to easy, fast and economical options for diagnosis of diabetic retinopathy. METHODS The search terms used were "Diabetic retinopathy", "Biomarkers in diabetic retinopathy", "Novel biomarkers in diabetic retinopathy" and "Potential biomarkers of diabetic retinopathy" by using different scientific resources and databases like EBSCO, ProQuest, PubMed and Scopus. Eligibility criteria included biomarkers involved in diabetic retinopathy in the detectable range. Exclusion criteria included the repetition and duplication of the biomarker in diabetic retinopathy. RESULTS Current review and literature study revealed that biomarkers of diabetic retinopathy can be categorized as inflammatory: tumor necrosis factor-α, monocyte chemoattractant protein-1, transforming growth factor- β; antioxidant: nicotinamide adenine dinucleotide phosphate oxidase; nucleic acid: poly ADP ribose polymerase- α, Apelin, Oncofetal; enzyme: ceruloplasmin, protein kinase C; and miscellaneous: erythropoietin. These biomarkers have a great potential in the progression of diabetic retinopathy hence can be used in the diagnosis and management of this debilitating disease. CONCLUSION Above mentioned biomarkers play a key role in the pathogenesis of diabetic retinopathy; hence they can also be considered as potential targets for new drug development.
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Affiliation(s)
- Kaveri M Adki
- Shobhaben Pratapbhai Patel School of Pharmacy & Technology Management, SVKM'S NMIMS, V.L. Mehta Road, Vile Parle (West), Mumbai-400056, India
| | - Yogesh A Kulkarni
- Shobhaben Pratapbhai Patel School of Pharmacy & Technology Management, SVKM'S NMIMS, V.L. Mehta Road, Vile Parle (West), Mumbai-400056, India
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25
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Cantó A, Olivar T, Romero FJ, Miranda M. Nitrosative Stress in Retinal Pathologies: Review. Antioxidants (Basel) 2019; 8:antiox8110543. [PMID: 31717957 PMCID: PMC6912788 DOI: 10.3390/antiox8110543] [Citation(s) in RCA: 27] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2019] [Revised: 10/30/2019] [Accepted: 11/06/2019] [Indexed: 12/20/2022] Open
Abstract
Nitric oxide (NO) is a gas molecule with diverse physiological and cellular functions. In the eye, NO is used to maintain normal visual function as it is involved in photoreceptor light transduction. In addition, NO acts as a rapid vascular endothelial relaxant, is involved in the control of retinal blood flow under basal conditions and mediates the vasodilator responses of different substances such as acetylcholine, bradykinin, histamine, substance P or insulin. However, the retina is rich in polyunsaturated lipid membranes and is sensitive to the action of reactive oxygen and nitrogen species. Products generated from NO (i.e., dinitrogen trioxide (N2O3) and peroxynitrite) have great oxidative damaging effects. Oxygen and nitrogen species can react with biomolecules (lipids, proteins and DNA), potentially leading to cell death, and this is particularly important in the retina. This review focuses on the role of NO in several ocular diseases, including diabetic retinopathy, retinitis pigmentosa, glaucoma or age-related macular degeneration (AMD).
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Affiliation(s)
- Antolin Cantó
- Departamento Ciencias Biomédicas, Facultad de Ciencias de la Salud, Universidad Cardenal Herrera-CEU, CEU Universities, 64315 Valencia, Spain; (A.C.); (T.O.)
| | - Teresa Olivar
- Departamento Ciencias Biomédicas, Facultad de Ciencias de la Salud, Universidad Cardenal Herrera-CEU, CEU Universities, 64315 Valencia, Spain; (A.C.); (T.O.)
| | - Francisco Javier Romero
- Departamento de Ciencias Biomédicas, Universidad Europea de Valencia, 46010 Valencia, Spain;
| | - María Miranda
- Departamento Ciencias Biomédicas, Facultad de Ciencias de la Salud, Universidad Cardenal Herrera-CEU, CEU Universities, 64315 Valencia, Spain; (A.C.); (T.O.)
- Correspondence: ; Tel.: +34-961369000
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Narayanan SP, Shosha E, D Palani C. Spermine oxidase: A promising therapeutic target for neurodegeneration in diabetic retinopathy. Pharmacol Res 2019; 147:104299. [PMID: 31207342 PMCID: PMC7011157 DOI: 10.1016/j.phrs.2019.104299] [Citation(s) in RCA: 36] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/31/2018] [Revised: 04/23/2019] [Accepted: 06/05/2019] [Indexed: 12/20/2022]
Abstract
Diabetic Retinopathy (DR), is a significant public health issue and the leading cause of blindness in working-aged adults worldwide. The vision loss associated with DR affects patients' quality of life and has negative social and psychological effects. In the past, diabetic retinopathy was considered as a vascular disease; however, it is now recognized to be a neuro-vascular disease of the retina. Current therapies for DR, such as laser photocoagulation and anti-VEGF therapy, treat advanced stages of the disease, particularly the vasculopathy and have adverse side effects. Unavailability of effective treatments to prevent the incidence or progression of DR is a major clinical problem. There is a great need for therapeutic interventions capable of preventing retinal damage in DR patients. A growing body of evidence shows that neurodegeneration is an early event in DR pathogenesis. Therefore, studies of the underlying mechanisms that lead to neurodegeneration are essential for identifying new therapeutic targets in the early stages of DR. Deregulation of the polyamine metabolism is implicated in various neurodegenerative diseases, cancer, renal failure, and diabetes. Spermine Oxidase (SMOX) is a highly inducible enzyme, and its dysregulation can alter polyamine homeostasis. The oxidative products of polyamine metabolism are capable of inducing cell damage and death. The current review provides insight into the SMOX-regulated molecular mechanisms of cellular damage and dysfunction, and its potential as a therapeutic target for diabetic retinopathy. Structural and functional changes in the diabetic retina and the mechanisms leading to neuronal damage (excitotoxicity, loss of neurotrophic factors, oxidative stress, mitochondrial dysfunction etc.) are also summarized in this review. Furthermore, existing therapies and new approaches to neuroprotection are discussed.
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Affiliation(s)
- S Priya Narayanan
- Clinical and Experimental Therapeutics, College of Pharmacy, University of Georgia, Augusta, GA, United States; Augusta University Culver Vision Discovery Institute, Augusta, GA, United States; Vascular Biology Center, Augusta University, Augusta, GA, United States; VA Medical Center, Augusta, GA, United States.
| | - Esraa Shosha
- Augusta University Culver Vision Discovery Institute, Augusta, GA, United States; Vascular Biology Center, Augusta University, Augusta, GA, United States; Clinical Pharmacy Department, Faculty of Pharmacy, Cairo University, Cairo, Egypt
| | - Chithra D Palani
- Clinical and Experimental Therapeutics, College of Pharmacy, University of Georgia, Augusta, GA, United States; Augusta University Culver Vision Discovery Institute, Augusta, GA, United States; Vascular Biology Center, Augusta University, Augusta, GA, United States
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27
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Neelofar K, Arif Z, Arafat MY, Alam K, Ahmad J. A study on correlation between oxidative stress parameters and inflammatory markers in type 2 diabetic patients with kidney dysfunction in north Indian population. J Cell Biochem 2018; 120:4892-4902. [PMID: 30260031 DOI: 10.1002/jcb.27763] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2018] [Accepted: 09/06/2018] [Indexed: 02/02/2023]
Abstract
BACKGROUND Research reports support the statement that oxidative stress and inflammation are well-known risk factors for chronic kidney disease (CKD) in patients with diabetes. This study was designed to ascertain the associated role of oxidative stress parameters and inflammatory markers in diabetes and related CKD among the north Indian population. METHODS The study was divided into three groups as healthy subjects (group 1), patients with diabetes without complication (group 2), and with CKD (group 3). Serum levels of malondialdehyde (MDA) and nitric oxide (NO), superoxide dismutase (SOD), catalase (CAT), and glutathione reductase (GR) content were estimated in all individuals. Inflammatory cytokines interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α)-α were determined by enzyme-linked immuno-sorbent assay. RESULTS MDA, protein carbonyl, and NO were significantly elevated in patients with type 2 diabetes as compared with healthy subjects (P ≤ 0.05). Total thiols content were found to be significantly decreased in patients with diabetes with CKD. The activity of antioxidant enzymes SOD, CAT, and GR showed a significant suppression in patients with type 2 diabetes with or without CKD as compared with healthy subjects. Nevertheless, the levels of proinflammatory cytokines IL-6 and TNF-α were significantly upregulated ( P ≤ 0.05) as compared with healthy subjects. CONCLUSION Determination of antioxidant defense parameters and inflammatory markers contributes to understand the relationship between oxidative stress and inflammation on the development and prevention of chronic kidney disease in Indian patients with diabetes.
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Affiliation(s)
- Km Neelofar
- Department of Biochemistry, J. N. Medical College, Aligarh Muslim University, Aligarh, India
| | - Zarina Arif
- Department of Biochemistry, J. N. Medical College, Aligarh Muslim University, Aligarh, India
| | - Mir Yasir Arafat
- Center for Vascular & Inflammatory Disease, University of Maryland School of Medicine, Baltimore, Maryland
| | - Khursheed Alam
- Department of Biochemistry, J. N. Medical College, Aligarh Muslim University, Aligarh, India
| | - Jamal Ahmad
- Rajiv Gandhi Centre for Diabetes and Endocrinology, J. N. Medical College, Aligarh Muslim University, Aligarh, India
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Opatrilova R, Kubatka P, Caprnda M, Büsselberg D, Krasnik V, Vesely P, Saxena S, Ruia S, Mozos I, Rodrigo L, Kruzliak P, dos Santos KG. Nitric oxide in the pathophysiology of retinopathy: evidences from preclinical and clinical researches. Acta Ophthalmol 2018; 96:222-231. [PMID: 28391624 DOI: 10.1111/aos.13384] [Citation(s) in RCA: 50] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2016] [Accepted: 12/12/2016] [Indexed: 12/11/2022]
Abstract
Retinopathy is the leading cause of blindness and visual disability in working-aged people. The pathogenesis of retinopathy is an actual and still open query. Alterations contributing to oxidative and nitrosative stress, including elevated nitric oxide and superoxide production, changes in the expression of different isoforms of nitric oxide synthase or endogenous antioxidant system, have been implicated in the mechanisms how this ocular disease develops. In addition, it was documented that renin-angiotensin system has been implicated in the progression of retinopathy. Based on comprehensive preclinical and clinical researches in this area, the role of above-mentioned factors in the pathogenesis of diabetic retinopathy, hypertensive retinopathy and ischaemic proliferative retinopathy is reviewed in this study. Moreover, the genetic susceptibility factors involved in the development of the retinopathy and possible strategies that utilize antioxidants as additive therapy are also highlighted here.
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Affiliation(s)
- Radka Opatrilova
- Department of Chemical Drugs; Faculty of Pharmacy; University of Veterinary and Pharmaceutical Sciences; Brno Czech Republic
| | - Peter Kubatka
- Department of Medical Biology; Jessenius Faculty of Medicine; Comenius University in Bratislava; Martin Slovak Republic
- Division of Oncology; Biomedical Center Martin; Jessenius Faculty of Medicine; Comenius University in Bratislava; Martin Slovak Republic
| | - Martin Caprnda
- 2nd Department of Internal Medicine; Faculty of Pharmacy; Comenius University; Bratislava Slovakia
| | | | - Vladimir Krasnik
- Department of Ophthalmology; Faculty of Medicine; Comenius University; Bratislava Slovakia
| | | | - Sandeep Saxena
- Retina Service; Department of Ophthalmology; King George's Medical University; Lucknow India
| | - Surabhi Ruia
- Retina Service; Department of Ophthalmology; King George's Medical University; Lucknow India
| | - Ioana Mozos
- Department of Functional Sciences; “Victor Babes” University of Medicine and Pharmacy; Timisoara Romania
| | - Luis Rodrigo
- Faculty of Medicine; University of Oviedo; Central University Hospital of Asturias (HUCA); Oviedo Spain
| | - Peter Kruzliak
- Department of Chemical Drugs; Faculty of Pharmacy; University of Veterinary and Pharmaceutical Sciences; Brno Czech Republic
| | - Katia Goncalves dos Santos
- Laboratory of Human Molecular Genetics; Universidade Luterana do Brasil; Canoas Brazil
- Experimental and Molecular Cardiovascular Laboratory; Hospital de Clínicas de Porto Alegre; Porto Alegre Brazil
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Broadgate S, Kiire C, Halford S, Chong V. Diabetic macular oedema: under-represented in the genetic analysis of diabetic retinopathy. Acta Ophthalmol 2018; 96 Suppl A111:1-51. [PMID: 29682912 DOI: 10.1111/aos.13678] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2017] [Accepted: 11/21/2017] [Indexed: 12/15/2022]
Abstract
Diabetic retinopathy, a complication of both type 1 and type 2 diabetes, is a complex disease and is one of the leading causes of blindness in adults worldwide. It can be divided into distinct subclasses, one of which is diabetic macular oedema. Diabetic macular oedema can occur at any time in diabetic retinopathy and is the most common cause of vision loss in patients with type 2 diabetes. The purpose of this review is to summarize the large number of genetic association studies that have been performed in cohorts of patients with type 2 diabetes and published in English-language journals up to February 2017. Many of these studies have produced positive associations with gene polymorphisms and diabetic retinopathy. However, this review highlights that within this large body of work, studies specifically addressing a genetic association with diabetic macular oedema, although present, are vastly under-represented. We also highlight that many of the studies have small patient numbers and that meta-analyses often inappropriately combine patient data sets. We conclude that there will continue to be conflicting results and no meaningful findings will be achieved if the historical approach of combining all diabetic retinopathy disease states within patient cohorts continues in future studies. This review also identifies several genes that would be interesting to analyse in large, well-defined cohorts of patients with diabetic macular oedema in future candidate gene association studies.
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Affiliation(s)
- Suzanne Broadgate
- Nuffield Laboratory of Ophthalmology; Nuffield Department of Clinical Neurosciences; University of Oxford; Oxford UK
| | - Christine Kiire
- Nuffield Laboratory of Ophthalmology; Nuffield Department of Clinical Neurosciences; University of Oxford; Oxford UK
- Oxford Eye Hospital; John Radcliffe Hospital; Oxford University NHS Foundation Trust; Oxford UK
| | - Stephanie Halford
- Nuffield Laboratory of Ophthalmology; Nuffield Department of Clinical Neurosciences; University of Oxford; Oxford UK
| | - Victor Chong
- Nuffield Laboratory of Ophthalmology; Nuffield Department of Clinical Neurosciences; University of Oxford; Oxford UK
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Cheng Y, Du Y, Liu H, Tang J, Veenstra A, Kern TS. Photobiomodulation Inhibits Long-term Structural and Functional Lesions of Diabetic Retinopathy. Diabetes 2018; 67:291-298. [PMID: 29167189 PMCID: PMC5780063 DOI: 10.2337/db17-0803] [Citation(s) in RCA: 51] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/07/2017] [Accepted: 11/08/2017] [Indexed: 12/11/2022]
Abstract
Previous studies demonstrated that brief (3 to 4 min) daily application of light at 670 nm to diabetic rodents inhibited molecular and pathophysiologic processes implicated in the pathogenesis of diabetic retinopathy (DR) and reversed diabetic macular edema in small numbers of patients studied. Whether or not this therapy would inhibit the neural and vascular lesions that characterize the early stages of the retinopathy was unknown. We administered photobiomodulation (PBM) therapy daily for 8 months to streptozotocin-diabetic mice and assessed effects of PBM on visual function, retinal capillary permeability, and capillary degeneration using published methods. Vitamin D receptor and Cyp24a1 transcripts were quantified by quantitative real-time PCR, and the abundance of c-Kit+ stem cells in blood and retina were assessed. Long-term daily administration of PBM significantly inhibited the diabetes-induced leakage and degeneration of retinal capillaries and also significantly inhibited the diabetes-induced reduction in visual function. PBM also inhibited diabetes-induced reductions in retinal Cyp24a1 mRNA levels and numbers of circulating stem cells (CD45-/c-Kit+), but these effects may not account for the beneficial effects of PBM on the retinopathy. PBM significantly inhibits the functional and histopathologic features of early DR, and these effects likely are mediated via multiple mechanisms.
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Affiliation(s)
- Yan Cheng
- Department of Medicine, Case Western Reserve University, Cleveland, OH
- Department of Ophthalmology, Second Hospital of Jilin University, Changchun, Jilin, China
| | - Yunpeng Du
- Department of Medicine, Case Western Reserve University, Cleveland, OH
| | - Haitao Liu
- Department of Medicine, Case Western Reserve University, Cleveland, OH
| | - Jie Tang
- Department of Medicine, Case Western Reserve University, Cleveland, OH
| | - Alex Veenstra
- Department of Medicine, Case Western Reserve University, Cleveland, OH
| | - Timothy S Kern
- Department of Medicine, Case Western Reserve University, Cleveland, OH
- Louis Stokes Cleveland VA Medical Center Research Service 151, Cleveland, OH
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Amato R, Dal Monte M, Lulli M, Raffa V, Casini G. Nanoparticle-Mediated Delivery of Neuroprotective Substances for the Treatment of Diabetic Retinopathy. Curr Neuropharmacol 2018; 16:993-1003. [PMID: 28714394 PMCID: PMC6120116 DOI: 10.2174/1570159x15666170717115654] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2017] [Revised: 05/04/2017] [Accepted: 07/14/2017] [Indexed: 01/20/2023] Open
Abstract
BACKGROUND Diabetic retinopathy (DR) is a major complication of diabetes, characterized by extensive vascular pathology leading to vision loss. Neuronal suffering and death are also present in the diabetic retina as a result of different molecular mechanisms that are compromised or modified in response to high glucose. The aim of this paper is to highlight recent data indicating that neurodegeneration is likely to play a primary role in the development of DR and that strategies based on nanomedicine may be exploited to deliver neuroprotection to the retina. METHODS An extensive analysis of the publications dealing with the role of neuroprotection in DR and with nanoparticle-mediated drug delivery to the retina has been conducted using PubMed, with particular attention to the most recent papers. RESULTS There are important limitations related to possible systemic side effects of neuroprotective substances and to drug bioavailability in the retina such as, for instance, the amount of drug reaching the retina, the need of keeping to a minimum the number of administrations (especially, for example, in the case of intraocular injections) and the need of assuring a long-lasting, graded intraocular drug delivery. In recent years, a variety of investigations have been aimed at the exploitation of approaches of nanomedicine to enhance the pharmacokinetics and pharmacodynamic activity of intraocularly delivered drugs. In particular, we provide some preliminary results that we have obtained about the feasibility of delivering magnetic nanoparticles functionalized with a neuroprotectant to mouse eyes through intraocular injections. CONCLUSION We propose that nanoparticles functionalized with neuroprotective substances may be used to protect the diabetic retina, thus causing an impact in the design of future pharmacologic treatments for DR.
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Affiliation(s)
| | | | | | | | - Giovanni Casini
- Address correspondence to this author at the Department of Biology, University of Pisa, via S. Zeno 31, I-56127 Pisa, Italy; Tel: ++39-050-2211423; E-mail:
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Tugcu B, Nacaroglu SA, Gedikbasi A, Uhri M, Acar N, Ozdemir H. Protective effect of pomegranate juice on retinal oxidative stress in streptozotocin-induced diabetic rats. Int J Ophthalmol 2017; 10:1662-1668. [PMID: 29181308 DOI: 10.18240/ijo.2017.11.05] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2017] [Accepted: 08/02/2017] [Indexed: 12/28/2022] Open
Abstract
AIM To investigate the effect of pomegranate juice (PJ) intake on overall oxidation status in retinas of diabetic rats. METHODS Twenty-seven rats were divided into four groups as control (CO), diabetic (DM), control treated with PJ (CO-PJ), and diabetic treated with PJ (DM-PJ).The retina tissues were used to determine 8-hydroxy-2'-deoxyguanosine (8OHdG), malondialdehyde (MDA), reduced glutathione (GSH) levels, and the enzyme activities of superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px). RESULTS The levels of 8OHdG and MDA were significantly increased in the retina of DM group compared to CO group (P=0.001, P<0.001 respectively). Both 8OHdG and MDA levels were decreased in PJ-DM group compared to DM group (P=0.004, P<0.001 respectively). The activities of antioxidant enzymes GSH, SOD, and GDH-Px were significantly decreased in the retina of DM group compared to CO group (P≤0.01). GSH and GSH-Px activities were higher in PJ-DM group compared with DM group (P=0.010, P=0.042, respectively) but SOD activity was not statistically different (P=0.938). CONCLUSION PJ intake is found to be effective in decreasing oxidative end products, and in increasing the activities of antioxidant enzymes in diabetic retinas of rats, which suggests it may be effective against oxidative stress in diabetic retinas.
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Affiliation(s)
- Betul Tugcu
- Department of Ophthalmology, Faculty of Medicine, Bezmialem University, Istanbul 34093, Turkey
| | - Senay Asik Nacaroglu
- Department of Ophthalmology, Bagcilar Training and Research Hospital, Istanbul 34200, Turkey
| | - Asuman Gedikbasi
- Department of Biochemistry, Bakirkoy Dr. Sadi Konuk Training and Research Hospital, Istanbul 34147, Turkey
| | - Mehmet Uhri
- Department of Pathology, Kanuni Sultan Suleyman Training and Research Hospital, Istanbul 34303, Turkey
| | - Nur Acar
- Department of Ophthalmology, Acibadem University, School of Medicine, Istanbul 34457, Turkey
| | - Hakan Ozdemir
- Department of Ophthalmology, Faculty of Medicine, Bezmialem University, Istanbul 34093, Turkey
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Al Jameil N, Tabassum H, Fatima S, Naiman Ali M, Rizwana H, Aziz Khan F. Ameliorating Effect of Vitamin C Against Potassium Dichromate Induced Oxidative Stress and Inflammatory Response in Rats. INT J PHARMACOL 2017. [DOI: 10.3923/ijp.2017.990.999] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2023]
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Zhang J, Liu R, Kuang HY, Gao XY, Liu HL. Protective treatments and their target retinal ganglion cells in diabetic retinopathy. Brain Res Bull 2017; 132:53-60. [DOI: 10.1016/j.brainresbull.2017.05.007] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2017] [Accepted: 05/10/2017] [Indexed: 12/19/2022]
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Liu H, Tang J, Du Y, Saadane A, Tonade D, Samuels I, Veenstra A, Palczewski K, Kern TS. Photoreceptor Cells Influence Retinal Vascular Degeneration in Mouse Models of Retinal Degeneration and Diabetes. Invest Ophthalmol Vis Sci 2017; 57:4272-81. [PMID: 27548901 PMCID: PMC5015983 DOI: 10.1167/iovs.16-19415] [Citation(s) in RCA: 48] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022] Open
Abstract
Purpose Loss of photoreceptor cells is associated with retinal vascular degeneration in retinitis pigmentosa, whereas the presence of photoreceptor cells is implicated in vascular degeneration in diabetic retinopathy. To investigate how both the absence and presence of photoreceptors could damage the retinal vasculature, we compared two mouse models of photoreceptor degeneration (opsin−/− and RhoP23H/P23H ) and control C57Bl/5J mice, each with and without diabetes. Methods Retinal thickness, superoxide, expression of inflammatory proteins, ERG and optokinetic responses, leukocyte cytotoxicity, and capillary degeneration were evaluated at 1 to 10 months of age using published methods. Results Retinal photoreceptor cells degenerated completely in the opsin mutants by 2 to 4 months of age, and visual function subsided correspondingly. Retinal capillary degeneration was substantial while photoreceptors were still present, but slowed after the photoreceptors degenerated. Diabetes did not further exacerbate capillary degeneration in these models of photoreceptor degeneration, but did cause capillary degeneration in wild-type animals. Photoreceptor cells, however, did not degenerate in wild-type diabetic mice, presumably because the stress responses in these cells were less than in the opsin mutants. Retinal superoxide and leukocyte damage to retinal endothelium contributed to the degeneration of retinal capillaries in diabetes, and leukocyte-mediated damage was increased in both opsin mutants during photoreceptor cell degeneration. Conclusions Photoreceptor cells affect the integrity of the retinal microvasculature. Deterioration of retinal capillaries in opsin mutants was appreciable while photoreceptor cells were present and stressed, but was less after photoreceptors degenerated. This finding proves relevant to diabetes, where persistent stress in photoreceptors likewise contributes to capillary degeneration.
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Affiliation(s)
- Haitao Liu
- Department of Medicine Case Western Reserve University, Cleveland, Ohio, United States
| | - Jie Tang
- Department of Medicine Case Western Reserve University, Cleveland, Ohio, United States
| | - Yunpeng Du
- Department of Medicine Case Western Reserve University, Cleveland, Ohio, United States
| | - Aicha Saadane
- Department of Ophthalmology and Visual Science, Case Western Reserve University, Cleveland, Ohio, United States
| | - Deoye Tonade
- Department of Pharmacology and Cleveland Center for Membrane and Structural Biology, Case Western Reserve University, Cleveland, Ohio, United States
| | - Ivy Samuels
- Veterans Administration Medical Center Research Service 151, Cleveland, Ohio, United States
| | - Alex Veenstra
- Veterans Administration Medical Center Research Service 151, Cleveland, Ohio, United States
| | - Krzysztof Palczewski
- Department of Pharmacology and Cleveland Center for Membrane and Structural Biology, Case Western Reserve University, Cleveland, Ohio, United States
| | - Timothy S Kern
- Department of Medicine Case Western Reserve University, Cleveland, Ohio, United States 2Department of Ophthalmology and Visual Science, Case Western Reserve University, Cleveland, Ohio, United States 3Department of Pharmacology and Cleveland Center for Membrane and Structural Biology, Case Western Reserve University, Cleveland, Ohio, United States 4Veterans Administration Medical Center Research Service 151, Cleveland, Ohio, United States
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Tonade D, Liu H, Kern TS. Photoreceptor Cells Produce Inflammatory Mediators That Contribute to Endothelial Cell Death in Diabetes. Invest Ophthalmol Vis Sci 2017; 57:4264-71. [PMID: 27548900 PMCID: PMC5015981 DOI: 10.1167/iovs.16-19859] [Citation(s) in RCA: 56] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
Abstract
PURPOSE Recent studies suggest that photoreceptor cells regulate local inflammation in the retina in diabetes. The purpose of this study was to determine if photoreceptor cells themselves produce inflammatory proteins in diabetes and if soluble factors released by photoreceptors in elevated glucose induce inflammatory changes in nearby cells. METHODS Laser capture microdissection was used to isolate the outer retina (photoreceptors) from the inner retina in nondiabetic and diabetic mice. Diabetes-induced changes in the expression of inflammatory targets were assessed by reverse transcription polymerase chain reaction and immunohistochemistry. Cell culture experiments were carried out to determine if photoreceptors in vitro and ex vivo release soluble mediators that can stimulate nearby cells. Photoreceptor contribution to leukocyte-mediated endothelial cell death was tested using coculture models. RESULTS Messenger ribonucleic acid and protein expression levels for inflammatory proteins intercellular adhesion molecule 1 (ICAM1), inducible nitric oxide synthase (iNOS), and cyclooxygenase 2 (COX2) were increased in photoreceptors cells in diabetes. In vitro and ex vivo studies show that photoreceptor cells in elevated glucose release mediators that can induce tumor necrosis factor-α in leukocytes and endothelial cells, but not in glia. The soluble mediators released by photoreceptor cells in elevated glucose are regulated by transforming growth factor β-activated kinase 1 and nicotinamide adenine dinucleotide phosphate oxidase (NADPH oxidase) signaling. In contrast to enhanced leukocyte-mediated killing of endothelial cells by leukocytes from wild-type diabetic mice, leukocytes from diabetic mice lacking photoreceptor cells (opsin-/-) did not kill endothelial cells. CONCLUSIONS These data indicate that photoreceptor cells are a source of inflammatory proteins in diabetes, and their release of soluble mediators can contribute to the death of retinal capillaries in diabetes.
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Affiliation(s)
- Deoye Tonade
- Department of Pharmacology Case Western Reserve University, Cleveland, Ohio, United States
| | - Haitao Liu
- Department of Medicine, Case Western Reserve University, Cleveland, Ohio, United States
| | - Timothy S Kern
- Department of Pharmacology Case Western Reserve University, Cleveland, Ohio, United States 2Department of Medicine, Case Western Reserve University, Cleveland, Ohio, United States 3Veterans Administration Medical Center Research Service, Cleveland, Ohio, United States
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Do photoreceptor cells cause the development of retinal vascular disease? Vision Res 2017; 139:65-71. [PMID: 28438678 DOI: 10.1016/j.visres.2017.03.011] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2017] [Revised: 03/29/2017] [Accepted: 03/30/2017] [Indexed: 10/19/2022]
Abstract
The retinal vasculature is affected in a number of clinically important retinopathies, including diabetic retinopathy. There has been a considerable amount of research into the pathogenesis of retinal microvascular diseases, but the potential contribution of the most abundant cell population in the retina, photoreceptor cells, has been largely overlooked. This review summarizes ongoing research suggesting that photoreceptor cells play a critical role in the development of retinal vascular disease in diabetic retinopathy and other retinopathies.
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Sinha S, Saxena S, Prasad S, Mahdi AA, Bhasker SK, Das S, Krasnik V, Caprnda M, Opatrilova R, Kruzliak P. Association of serum levels of anti-myeloperoxidase antibody with retinal photoreceptor ellipsoid zone disruption in diabetic retinopathy. J Diabetes Complications 2017; 31:864-868. [PMID: 28279572 DOI: 10.1016/j.jdiacomp.2017.02.011] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/05/2016] [Revised: 11/01/2016] [Accepted: 02/16/2017] [Indexed: 12/31/2022]
Abstract
AIM To study the association of serum levels of anti-myeloperoxidase (MPO) antibody with retinal photoreceptor ellipsoid zone (EZ) disruption in diabetic retinopathy. METHODS Consecutive patients with type 2 DM [diabetes mellitus with no retinopathy (NODR; n=20); non-proliferative diabetic retinopathy (NPDR; n=18); proliferative diabetic retinopathy (PDR; n=16)] and healthy controls (n=20) between the ages of 40 and 65years were included. Disruption of EZ was graded by spectral domain optical coherence tomography as no disruption of EZ and disrupted EZ. The serum levels of anti-MPO antibody was analyzed using standard protocol. Association between the variables was evaluated using multiple regression analysis. RESULTS A significant difference was found between the serum levels of anti-MPO antibody in various study groups (p<0.001). A positive association was found between EZ disruption and levels of anti-MPO antibody [adjusted odd's ratio (AOR)=1.079, CI 1.010-1.124, p=0.04]. A significant positive correlation was found between logMAR visual acuity and grade of disruption (AOR=1.008, CI 1.006-5.688, p=0.04). CONCLUSIONS An increased serum anti-MPO antibody levels is associated with retinal photoreceptor EZ disruption and decreased visual acuity in diabetic retinopathy.
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Affiliation(s)
- Shivani Sinha
- Retina service, Department of Ophthalmology, King George's Medical University, Lucknow, India
| | - Sandeep Saxena
- Retina service, Department of Ophthalmology, King George's Medical University, Lucknow, India.
| | - Senthamizh Prasad
- Department of Preventive and Social Medicine, King George's Medical University, Lucknow, India
| | - Abbas Ali Mahdi
- Department of Biochemistry, King George's Medical University, Lucknow, India
| | - Shashi Kumar Bhasker
- Retina service, Department of Ophthalmology, King George's Medical University, Lucknow, India
| | - Siddharth Das
- Department of Rheumatology, King George's Medical University, Lucknow, India
| | - Vladimir Krasnik
- Department of Ophthalmology, Faculty of Medicine, Comenius University and University Hospital, Bratislava, Slovakia
| | - Martin Caprnda
- 2nd Department of Internal Medicine, Faculty of Medicine, Comenius University, Bratislava, Slovakia
| | - Radka Opatrilova
- Department of Chemical Drugs, Faculty of Pharmacy, University of Veterinary and Pharmaceutical Sciences, Brno, Czech Republic
| | - Peter Kruzliak
- Department of Chemical Drugs, Faculty of Pharmacy, University of Veterinary and Pharmaceutical Sciences, Brno, Czech Republic.
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Zhang J, Yang J, Huang T, Shu Y, Chen L. Identification of novel proliferative diabetic retinopathy related genes on protein–protein interaction network. Neurocomputing 2016. [DOI: 10.1016/j.neucom.2015.09.136] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
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Abstract
Diabetes mellitus represents a growing international public health issue with a near quadrupling in its worldwide prevalence since 1980. Though it has many known microvascular complications, vision loss from diabetic retinopathy is one of the most devastating for affected individuals. In addition, there is increasing evidence to suggest that diabetic patients have a greater risk for glaucoma as well. Though the pathophysiology of glaucoma is not completely understood, both diabetes and glaucoma appear to share some common risk factors and pathophysiologic similarities with studies also reporting that the presence of diabetes and elevated fasting glucose levels are associated with elevated intraocular pressure-the primary risk factor for glaucomatous optic neuropathy. While no study has completely addressed the possibility of detection bias, most recent epidemiologic evidence suggests that diabetic populations are likely enriched with glaucoma patients. As the association between diabetes and glaucoma becomes better defined, routine evaluation for glaucoma in diabetic patients, particularly in the telemedicine setting, may become a reasonable consideration to reduce the risk of vision loss in these patients.
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Affiliation(s)
- Brian J Song
- Massachusetts Eye and Ear Infirmary, Department of Ophthalmology, Harvard Medical School, 243 Charles Street, Boston, MA, 02114, USA.
| | - Lloyd Paul Aiello
- Beetham Eye Institute, Joslin Diabetes Center, Harvard Medical School, 1 Joslin Place, Boston, MA, 02115, USA
| | - Louis R Pasquale
- Massachusetts Eye and Ear Infirmary, Department of Ophthalmology, Harvard Medical School, 243 Charles Street, Boston, MA, 02114, USA
- Channing Division of Network Medicine, Brigham and Women's Hospital, 181 Longwood Avenue, Boston, MA, 02215, USA
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Winges A, Garcia TB, Prager P, Wiedemann P, Kohen L, Bringmann A, Hollborn M. Osmotic expression of aldose reductase in retinal pigment epithelial cells: involvement of NFAT5. Graefes Arch Clin Exp Ophthalmol 2016; 254:2387-2400. [PMID: 27628063 DOI: 10.1007/s00417-016-3492-x] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2016] [Revised: 08/22/2016] [Accepted: 08/29/2016] [Indexed: 12/29/2022] Open
Abstract
BACKGROUND Diabetic retinopathy is associated with osmotic stress resulting from hyperglycemia and intracellular sorbitol accumulation. Systemic hypertension is a risk factor of diabetic retinopathy. High intake of dietary salt increases extracellular osmolarity resulting in systemic hypertension. We determined the effects of extracellular hyperosmolarity, chemical hypoxia, and oxidative stress on the gene expression of enzymes involved in sorbitol production and conversion in cultured human retinal pigment epithelial (RPE) cells. METHODS Alterations in the expression of aldose reductase (AR) and sorbitol dehydrogenase (SDH) genes were examined with real-time RT-PCR. Protein levels were determined with Western blot analysis. Nuclear factor of activated T cell 5 (NFAT5) was knocked down with siRNA. RESULTS AR gene expression in RPE cells was increased by high (25 mM) extracellular glucose, CoCl2 (150 μM)-induced chemical hypoxia, H2O2 (20 μM)-induced oxidative stress, and extracellular hyperosmolarity induced by addition of NaCl or sucrose. Extracellular hyperosmolarity (but not hypoxia) also increased AR protein level. SDH gene expression was increased by hypoxia and oxidative stress, but not extracellular hyperosmolarity. Hyperosmolarity and hypoxia did not alter the SDH protein level. The hyperosmotic AR gene expression was dependent on activation of metalloproteinases, autocrine/paracrine TGF-β signaling, activation of p38 MAPK, ERK1/2, and PI3K signal transduction pathways, and the transcriptional activity of NFAT5. Knockdown of NAFT5 or inhibition of AR decreased the cell viability under hyperosmotic (but not hypoxic) conditions and aggravated the hyperosmotic inhibition of cell proliferation. CONCLUSIONS The data suggest that sorbitol accumulation in RPE cells occurs under hyperosmotic, but not hypoxic and oxidative stress conditions. NFAT5- and AR-mediated sorbitol accumulation may protect RPE cells under conditions of osmotic stress.
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Affiliation(s)
- Anica Winges
- Department of Ophthalmology and Eye Hospital, Faculty of Medicine, University of Leipzig, Liebigstrasse 10-14, D-04103, Leipzig, Germany
| | - Tarcyane Barata Garcia
- Department of Ophthalmology and Eye Hospital, Faculty of Medicine, University of Leipzig, Liebigstrasse 10-14, D-04103, Leipzig, Germany
| | - Philipp Prager
- Department of Ophthalmology and Eye Hospital, Faculty of Medicine, University of Leipzig, Liebigstrasse 10-14, D-04103, Leipzig, Germany
| | - Peter Wiedemann
- Department of Ophthalmology and Eye Hospital, Faculty of Medicine, University of Leipzig, Liebigstrasse 10-14, D-04103, Leipzig, Germany
| | - Leon Kohen
- Department of Ophthalmology and Eye Hospital, Faculty of Medicine, University of Leipzig, Liebigstrasse 10-14, D-04103, Leipzig, Germany
- Helios Klinikum Aue, Aue, Germany
| | - Andreas Bringmann
- Department of Ophthalmology and Eye Hospital, Faculty of Medicine, University of Leipzig, Liebigstrasse 10-14, D-04103, Leipzig, Germany
| | - Margrit Hollborn
- Department of Ophthalmology and Eye Hospital, Faculty of Medicine, University of Leipzig, Liebigstrasse 10-14, D-04103, Leipzig, Germany.
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Nita M, Grzybowski A. The Role of the Reactive Oxygen Species and Oxidative Stress in the Pathomechanism of the Age-Related Ocular Diseases and Other Pathologies of the Anterior and Posterior Eye Segments in Adults. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2016; 2016:3164734. [PMID: 26881021 PMCID: PMC4736974 DOI: 10.1155/2016/3164734] [Citation(s) in RCA: 893] [Impact Index Per Article: 99.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/29/2015] [Revised: 11/16/2015] [Accepted: 11/17/2015] [Indexed: 12/18/2022]
Abstract
The reactive oxygen species (ROS) form under normal physiological conditions and may have both beneficial and harmful role. We search the literature and current knowledge in the aspect of ROS participation in the pathogenesis of anterior and posterior eye segment diseases in adults. ROS take part in the pathogenesis of keratoconus, Fuchs endothelial corneal dystrophy, and granular corneal dystrophy type 2, stimulating apoptosis of corneal cells. ROS play a role in the pathogenesis of glaucoma stimulating apoptotic and inflammatory pathways on the level of the trabecular meshwork and promoting retinal ganglion cells apoptosis and glial dysfunction in the posterior eye segment. ROS play a role in the pathogenesis of Leber's hereditary optic neuropathy and traumatic optic neuropathy. ROS induce apoptosis of human lens epithelial cells. ROS promote apoptosis of vascular and neuronal cells and stimulate inflammation and pathological angiogenesis in the course of diabetic retinopathy. ROS are associated with the pathophysiological parainflammation and autophagy process in the course of the age-related macular degeneration.
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Affiliation(s)
- Małgorzata Nita
- Domestic and Specialized Medicine Centre “Dilmed”, Ulica Bohaterów Monte Cassino 3, 40-231 Katowice, Poland
| | - Andrzej Grzybowski
- Department of Ophthalmology, Poznan City Hospital, Ulica Szwajcarska 3, 61-285 Poznań, Poland
- Chair of Ophthalmology, Medical Faculty, University of Warmia and Mazury, Ulica Żołnierska 14 C, 10-719 Olsztyn, Poland
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Hernández C, Dal Monte M, Simó R, Casini G. Neuroprotection as a Therapeutic Target for Diabetic Retinopathy. J Diabetes Res 2016; 2016:9508541. [PMID: 27123463 PMCID: PMC4830713 DOI: 10.1155/2016/9508541] [Citation(s) in RCA: 58] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/22/2015] [Revised: 02/29/2016] [Accepted: 03/16/2016] [Indexed: 02/07/2023] Open
Abstract
Diabetic retinopathy (DR) is a multifactorial progressive disease of the retina and a leading cause of vision loss. DR has long been regarded as a vascular disorder, although neuronal death and visual impairment appear before vascular lesions, suggesting an important role played by neurodegeneration in DR and the appropriateness of neuroprotective strategies. Upregulation of vascular endothelial growth factor (VEGF), the main target of current therapies, is likely to be one of the first responses to retinal hyperglycemic stress and VEGF may represent an important survival factor in early phases of DR. Of central importance for clinical trials is the detection of retinal neurodegeneration in the clinical setting, and spectral domain optical coherence tomography seems the most indicated technique. Many substances have been tested in animal studies for their neuroprotective properties and for possible use in humans. Perhaps, the most intriguing perspective is the use of endogenous neuroprotective substances or nutraceuticals. Together, the data point to the central role of neurodegeneration in the pathogenesis of DR and indicate neuroprotection as an effective strategy for treating this disease. However, clinical trials to determine not only the effectiveness and safety but also the compliance of a noninvasive route of drug administration are needed.
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Affiliation(s)
- Cristina Hernández
- CIBERDEM (CIBER de Diabetes y Enfermedades Metabolicas Asociadas) and Diabetes and Metabolism Research Unit, Vall d'Hebron Institut de Recerca (VHIR), Universitat Autonoma de Barcelona, Passeig Vall d'Hebron 119-129, 08035 Barcelona, Spain
- *Cristina Hernández: and
| | - Massimo Dal Monte
- Department of Biology, University of Pisa, Via San Zeno 31, 56127 Pisa, Italy
- Interdepartmental Research Center Nutrafood “Nutraceuticals and Food for Health”, University of Pisa, Via del Borghetto 80, 56124 Pisa, Italy
| | - Rafael Simó
- CIBERDEM (CIBER de Diabetes y Enfermedades Metabolicas Asociadas) and Diabetes and Metabolism Research Unit, Vall d'Hebron Institut de Recerca (VHIR), Universitat Autonoma de Barcelona, Passeig Vall d'Hebron 119-129, 08035 Barcelona, Spain
| | - Giovanni Casini
- Department of Biology, University of Pisa, Via San Zeno 31, 56127 Pisa, Italy
- Interdepartmental Research Center Nutrafood “Nutraceuticals and Food for Health”, University of Pisa, Via del Borghetto 80, 56124 Pisa, Italy
- *Giovanni Casini:
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Chen WP, Wang YD, Ma Y, Zhang ZY, Hu LY, Lin JL, Lin BQ. Danhong Huayu Koufuye combined with metformin attenuated diabetic retinopathy in Zucker diabetic fatty rats. Int J Ophthalmol 2015; 8:1094-100. [PMID: 26682154 DOI: 10.3980/j.issn.2222-3959.2015.06.03] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2015] [Accepted: 04/13/2015] [Indexed: 12/21/2022] Open
Abstract
AIM To evaluate effects of Danhong Huayu Koufuye (DHK, a Chinese medicinal formulae) alone or combined with metformin on diabetic retinopathy (DR) in Zucker diabetic fatty (ZDF) rats, an animal model of obese type-2 diabetes, and then to investigate the mechanisms. METHODS ZDF (fa/fa) rats were administered with vehicle (distilled water), metformin, DHK, and DHK plus metformin. Electrophysiological and histological analysis were applied to evaluated effects of DHK alone or combined with metformin on DR. The levels of fasting blood glucose (FBG) and glycosylated hemoglobin (HbA1c) in blood were measured to evaluate the antihyperglycemic activity of DHK. Furthermore, levels of nitric oxide (NO), malondialdehyde (MDA) and activities of superoxide dismutase (SOD), glutathione peroxidase (GSH-Px) in serum were measured to study effects of DHK on oxidative stress in ZDF rats. In addition, body weight, lipidic indexes and insulin level were also assessed. RESULTS DHK combined with metformin significantly reversed the prolongation of latency times of flash electroretinogram (FERG) and oscillatory potentials (OPs) in diabetic rats. Furthermore, DHK alone or combined with metformin showed a remarkable suppression of retinal neovascularization and amelioration of retinal internal limiting membrane morphology. Moreover, DHK alone or plus metformin reduced FBG (P<0.05), HbA1c (P<0.01) and MDA (P<0.01) levels in diabetic rats. In addition, reductions in levels of triglycerides (TG) (P<0.01) and low density lipoprotein cholesterol (LDL-c) (P<0.01 and P<0.05, respectively) were also observed in diabetic rats treated with DHK alone or plus metformin. CONCLUSION DHK in combination with metformin had a preventive and therapeutic effect on DR in type-2 diabetic rats, and the possible mechanisms may be alleviating hyperglycemia, reducing oxidative stress and improving lipid metabolism.
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Affiliation(s)
- Wen-Pei Chen
- School of Chinese Materia Medica, Guangzhou University of Chinese Medicine, Guangzhou 510006, Guangdong Province, China
| | - Yan-Dong Wang
- Zhongshan Ophthalmic Center, Sun Yat-Sen University, Guangzhou 510060, Guangdong Province, China
| | - Yan Ma
- School of Chinese Materia Medica, Guangzhou University of Chinese Medicine, Guangzhou 510006, Guangdong Province, China
| | - Zi-Yang Zhang
- School of Chinese Materia Medica, Guangzhou University of Chinese Medicine, Guangzhou 510006, Guangdong Province, China
| | - Lu-Yun Hu
- School of Chinese Materia Medica, China Pharmaceutical University, Nanjing 210000, Jiangsu Province, China
| | - Jun-Li Lin
- School of Chinese Materia Medica, Guangzhou University of Chinese Medicine, Guangzhou 510006, Guangdong Province, China
| | - Bao-Qin Lin
- School of Chinese Materia Medica, Guangzhou University of Chinese Medicine, Guangzhou 510006, Guangdong Province, China
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Kita T, Clermont AC, Murugesan N, Zhou Q, Fujisawa K, Ishibashi T, Aiello LP, Feener EP. Plasma Kallikrein-Kinin System as a VEGF-Independent Mediator of Diabetic Macular Edema. Diabetes 2015; 64:3588-99. [PMID: 25979073 PMCID: PMC4587649 DOI: 10.2337/db15-0317] [Citation(s) in RCA: 53] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/06/2015] [Accepted: 05/03/2015] [Indexed: 11/13/2022]
Abstract
This study characterizes the kallikrein-kinin system in vitreous from individuals with diabetic macular edema (DME) and examines mechanisms contributing to retinal thickening and retinal vascular permeability (RVP). Plasma prekallikrein (PPK) and plasma kallikrein (PKal) were increased twofold and 11.0-fold (both P < 0.0001), respectively, in vitreous from subjects with DME compared with those with a macular hole (MH). While the vascular endothelial growth factor (VEGF) level was also increased in DME vitreous, PKal and VEGF concentrations do not correlate (r = 0.266, P = 0.112). Using mass spectrometry-based proteomics, we identified 167 vitreous proteins, including 30 that were increased in DME (fourfold or more, P < 0.001 vs. MH). The majority of proteins associated with DME displayed a higher correlation with PPK than with VEGF concentrations. DME vitreous containing relatively high levels of PKal and low VEGF induced RVP when injected into the vitreous of diabetic rats, a response blocked by bradykinin receptor antagonism but not by bevacizumab. Bradykinin-induced retinal thickening in mice was not affected by blockade of VEGF receptor 2. Diabetes-induced RVP was decreased by up to 78% (P < 0.001) in Klkb1 (PPK)-deficient mice compared with wild-type controls. B2- and B1 receptor-induced RVP in diabetic mice was blocked by endothelial nitric oxide synthase (NOS) and inducible NOS deficiency, respectively. These findings implicate the PKal pathway as a VEGF-independent mediator of DME.
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Affiliation(s)
- Takeshi Kita
- Joslin Diabetes Center, Harvard Medical School, Boston, MA
| | | | | | - Qunfang Zhou
- Joslin Diabetes Center, Harvard Medical School, Boston, MA
| | - Kimihiko Fujisawa
- Department of Ophthalmology, Graduate School of Medical Sciences, Kyushu University, Higashi-ku, Fukuoka City, Japan
| | - Tatsuro Ishibashi
- Department of Ophthalmology, Graduate School of Medical Sciences, Kyushu University, Higashi-ku, Fukuoka City, Japan
| | - Lloyd Paul Aiello
- Joslin Diabetes Center, Harvard Medical School, Boston, MA Beetham Eye Institute, Department of Ophthalmology, Harvard Medical School, Boston, MA
| | - Edward P Feener
- Joslin Diabetes Center, Harvard Medical School, Boston, MA Department of Medicine, Harvard Medical School, Boston, MA
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Tetramethylpyrazine Protects Retinal Capillary Endothelial Cells (TR-iBRB2) against IL-1β-Induced Nitrative/Oxidative Stress. Int J Mol Sci 2015; 16:21775-90. [PMID: 26370989 PMCID: PMC4613279 DOI: 10.3390/ijms160921775] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2015] [Revised: 08/19/2015] [Accepted: 08/31/2015] [Indexed: 12/22/2022] Open
Abstract
Blood-retinal barrier (BRB) breakdown is one of the primary causes of diabetic retinopathy (DR). The pro-inflammatory factor interleukin-1β (IL-1β) was reported to be involved in the induction of BRB breakdown during the pathogenesis of DR. In the present study, we investigated the protective effect of tetramethylpyrazine (TMP), a major active component of the traditional herb Ligusticum chuanxiong, on IL-1β-induced cell death of the rat retinal capillary endothelial TR-iBRB2 cells. Our results showed that IL-1β-induced cell dysfunction in TR-iBRB2 cells via inducing nitrative/oxidative stress; however, such effect was attenuated with the pre-treatment of TMP. The cellular protective effect of TMP was likely to be mediated through the inhibition of inducible nitric oxide synthase (iNOS) expression and leukostasis as well as suppression of reactive oxygen species (ROS) generation, mitochondrial dysfunction and MAPKs activation. These findings significantly contribute to a better understanding of the protective effect of TMP in DR and form the basis of the therapeutic development of TMP in treating such disease in the future.
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Elgayar SAM, Eltony SA, Sayed AA, Abdel-Rouf MM. Genistein Treatment Confers Protection against Gliopathy and Vasculopathy of the Diabetic Retina in Rats. Ultrastruct Pathol 2015; 39:385-94. [PMID: 26548435 DOI: 10.3109/01913123.2015.1045664] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
Abstract
Retinopathy remains an important complication of diabetes. This work was carried out to evaluate the protective effects of genistein from diabetic retinopathy in rat. Fifteen adult male albino rats were divided into two groups; Group I: control (n = 5) and Group II: streptozotocin induced diabetic group (n = 10), which is equally divided into two subgroups; IIa (diabetic vehicle control) and IIb (diabetic genistein-treated). Specimens were taken from the retina 12 weeks post induction, processed and examined using light, immunohistochemical, ultrastructural techniques. Blood samples were assayed for the levels of glucose. In comparison with the diabetic non-treated group, the histological changes in macro and microglial glial cells reactivity and retinal blood capillaries were improved in genistein-treated groups. In addition, GFAP and iNOS expressions in the retina and the blood glucose level were reduced. Genistein ameliorates the histological changes of diabetic retinopathy reaching healing features, which resemble that of a normal retina.
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Affiliation(s)
- Sanaa A M Elgayar
- a Department of Histology, Faculty of Medicine , Assiut University , Assiut , Egypt
| | - Sohair A Eltony
- a Department of Histology, Faculty of Medicine , Assiut University , Assiut , Egypt
| | - Abdelrahman A Sayed
- a Department of Histology, Faculty of Medicine , Assiut University , Assiut , Egypt
| | - Maha M Abdel-Rouf
- a Department of Histology, Faculty of Medicine , Assiut University , Assiut , Egypt
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Wu Y, Chen Y, Wu Q, Jia L, Du X. Minocycline inhibits PARP‑1 expression and decreases apoptosis in diabetic retinopathy. Mol Med Rep 2015; 12:4887-94. [PMID: 26165350 PMCID: PMC4581760 DOI: 10.3892/mmr.2015.4064] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2014] [Accepted: 06/03/2015] [Indexed: 01/30/2023] Open
Abstract
The present study aimed to investigate the mechanism underlying the effects of minocycline on diabetic retinopathy-associated cellular apoptosis. A total of 40 Sprague Dawley (SD) rats were used as a diabetic retinopathy model following injection with streptozotocin. Among the 34 rats in which the diabetes model was successfully established, 24 rats were divided into two experimental groups: I and II (T1 and T2, respectively), and orally administered with various doses of minocycline. The remaining 10 rats served as the diabetic retinopathy control group. An additional group of 10 healthy SD rats with comparable weight served as normal controls. The rats in T1 and T2 groups were treated daily for eight consecutive weeks with minocycline at a dose of 2.5 mg/kg and 5 mg/kg, respectively. The mRNA expression levels of poly (ADP-ribose) polymerase-1 (PARP-1) were subsequently measured by reverse transcription-quantitative polymerase chain reaction, and the protein expression levels of poly-ADP-ribose were measured by western blot analysis and immunohistochemistry. Retinal morphology was observed following hematoxylin and eosin staining, and retinal cell apoptosis was measured by terminal deoxynucleotidyl transferase dUTP nick end labeling and caspase-3 activity assays. The amplitudes of the electroretinogram (ERG) b-wave and oscillary potentials (OPs) were measured using visual electrophysiology, and compared among the four groups. The results of the present study demonstrated that in the diabetic rats, retinal PARP-1 gene expression was markedly upregulated, the number of apoptotic cells and the activity levels of caspase-3 were increased, and the amplitude of the ERG b-wave and the OPs were markedly lower as compared with the normal rats. Following treatment with minocycline, the abnormal expression of PARP-1 in the retina was inhibited, and cellular apoptosis was decreased. In conclusion, the results of the present study suggest that PARP-1 is involved in the development of diabetic retinopathy, and minocycline is able to inhibit PARP-1 expression and decrease cellular apoptosis, suggesting that minocycline may prove to be a promising drug for the treatment of diabetic retinopathy.
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Affiliation(s)
- Ying Wu
- Department of Ultrasound, Shanghai First People's Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai 200080, P.R. China
| | - Yongdong Chen
- Department of Ophthalmology, Shanghai Jiaotong University Affiliated Sixth People's Hospital, Shanghai 200233, P.R. China
| | - Qiang Wu
- Department of Ophthalmology, Shanghai Jiaotong University Affiliated Sixth People's Hospital, Shanghai 200233, P.R. China
| | - Lili Jia
- Department of Ophthalmology, Shanghai Jiaotong University Affiliated Sixth People's Hospital, Shanghai 200233, P.R. China
| | - Xinhua Du
- Department of Ophthalmology, Shanghai Jiaotong University Affiliated Sixth People's Hospital, Shanghai 200233, P.R. China
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Liu H, Tang J, Du Y, Lee CA, Golczak M, Muthusamy A, Antonetti DA, Veenstra AA, Amengual J, von Lintig J, Palczewski K, Kern TS. Retinylamine Benefits Early Diabetic Retinopathy in Mice. J Biol Chem 2015; 290:21568-79. [PMID: 26139608 DOI: 10.1074/jbc.m115.655555] [Citation(s) in RCA: 46] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2015] [Indexed: 12/12/2022] Open
Abstract
Recent evidence suggests an important role for outer retinal cells in the pathogenesis of diabetic retinopathy (DR). Here we investigated the effect of the visual cycle inhibitor retinylamine (Ret-NH2) on the development of early DR lesions. Wild-type (WT) C57BL/6J mice (male, 2 months old when diabetes was induced) were made diabetic with streptozotocin, and some were given Ret-NH2 once per week. Lecithin-retinol acyltransferase (LRAT)-deficient mice and P23H mutant mice were similarly studied. Mice were euthanized after 2 (WT and Lrat(-/-)) and 8 months (WT) of study to assess vascular histopathology, accumulation of albumin, visual function, and biochemical and physiological abnormalities in the retina. Non-retinal effects of Ret-NH2 were examined in leukocytes treated in vivo. Superoxide generation and expression of inflammatory proteins were significantly increased in retinas of mice diabetic for 2 or 8 months, and the number of degenerate retinal capillaries and accumulation of albumin in neural retina were significantly increased in mice diabetic for 8 months compared with nondiabetic controls. Administration of Ret-NH2 once per week inhibited capillary degeneration and accumulation of albumin in the neural retina, significantly reducing diabetes-induced retinal superoxide and expression of inflammatory proteins. Superoxide generation also was suppressed in Lrat(-/-) diabetic mice. Leukocytes isolated from diabetic mice treated with Ret-NH2 caused significantly less cytotoxicity to retinal endothelial cells ex vivo than did leukocytes from control diabetics. Administration of Ret-NH2 once per week significantly inhibited the pathogenesis of lesions characteristic of early DR in diabetic mice. The visual cycle constitutes a novel target for inhibition of DR.
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Affiliation(s)
| | - Jie Tang
- From the Departments of Medicine and
| | | | | | - Marcin Golczak
- Pharmacology, Case Western Reserve University, Cleveland, Ohio 44106
| | - Arivalagan Muthusamy
- Department of Ophthalmology and Visual Sciences, University of Michigan, Ann Arbor, Michigan 48105, and
| | - David A Antonetti
- Department of Ophthalmology and Visual Sciences, University of Michigan, Ann Arbor, Michigan 48105, and
| | | | - Jaume Amengual
- Pharmacology, Case Western Reserve University, Cleveland, Ohio 44106
| | | | | | - Timothy S Kern
- From the Departments of Medicine and Pharmacology, Case Western Reserve University, Cleveland, Ohio 44106, Veterans Affairs Medical Center, Cleveland, Ohio 44106
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Abstract
This is a summary of current and emerging pharmacologic therapies utilized in the treatment of diabetic retinopathy (DR). Current therapies, such as ranibizumab, bevacizumab, triamcinolone acetonide, and fluocinolone acetonide, inhibit angiogenesis and inflammation and may be used alone or in combination with laser treatment. Emerging therapies aim to reduce oxidative stress or inhibit other signal transduction pathways, including the protein kinase C cascade and aldose reductase pathway. Future therapies may target other molecules crucial to the pathogenesis of DR, including hepatocyte growth factors and matrix metalloproteinase 9. Finally, the emergence of novel mechanisms of medication delivery may also be on the horizon.
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Affiliation(s)
- Vaidehi S. Dedania
- Department of Ophthalmology, Albany Medical Center, Lions Eye Institute, Albany, NY 12208, USA
| | - Sophie J. Bakri
- Department of Ophthalmology, Mayo Clinic, Rochester, MN 55905, USA
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