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Callan A, Jha S, Valdez L, Tsin A. Cellular and Molecular Mechanisms of Neuronal Degeneration in Early-Stage Diabetic Retinopathy. Curr Vasc Pharmacol 2024; 22:301-315. [PMID: 38693745 DOI: 10.2174/0115701611272737240426050930] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2023] [Revised: 03/12/2024] [Accepted: 03/13/2024] [Indexed: 05/03/2024]
Abstract
BACKGROUND Studies on the early retinal changes in Diabetic Retinopathy (DR) have demonstrated that neurodegeneration precedes vascular abnormalities like microaneurysms or intraretinal hemorrhages. Therefore, there is a growing field of study to analyze the cellular and molecular pathways involved to allow for the development of novel therapeutics to prevent the onset or delay the progression of DR. Molecular Mechanisms: Oxidative stress and mitochondrial dysfunction contribute to neurodegeneration through pathways involving polyol, hexosamine, advanced glycation end products, and protein kinase C. Potential interventions targeting these pathways include aldose reductase inhibitors and protein kinase C inhibitors. Neurotrophic factor imbalances, notably brain-derived neurotrophic factor and nerve growth factor, also play a role in early neurodegeneration, and supplementation of these neurotrophic factors show promise in mitigating neurodegeneration. Cellular Mechanisms: Major cellular mechanisms of neurodegeneration include caspase-mediated apoptosis, glial cell reactivity, and glutamate excitotoxicity. Therefore, inhibitors of these pathways are potential therapeutic avenues. Vascular Component: The nitric oxide pathway, critical for neurovascular coupling, is disrupted in DR due to increased reactive oxygen species. Vascular Endothelial Growth Factor (VEGF), a long-known angiogenic factor, has demonstrated both damaging and neuroprotective effects, prompting a careful consideration of long-term anti-VEGF therapy. CONCLUSION Current DR treatments primarily address vascular symptoms but fall short of preventing or halting the disease. Insights into the mechanisms of retinal neurodegeneration in the setting of diabetes mellitus not only enhance our understanding of DR but also pave the way for future therapeutic interventions aimed at preventing disease progression and preserving vision.
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Affiliation(s)
- Andrew Callan
- Department of Neuroscience, School of Medicine, University of Texas Rio Grande Valley, USA
| | - Sonal Jha
- Department of Neuroscience, School of Medicine, University of Texas Rio Grande Valley, USA
| | - Laura Valdez
- Department of Neuroscience, School of Medicine, University of Texas Rio Grande Valley, USA
| | - Andrew Tsin
- Department of Neuroscience, School of Medicine, University of Texas Rio Grande Valley, USA
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Alkholifi FK, Aodah AH, Foudah AI, Alam A. Exploring the Therapeutic Potential of Berberine and Tocopherol in Managing Diabetic Neuropathy: A Comprehensive Approach towards Alleviating Chronic Neuropathic Pain. Biomedicines 2023; 11:1726. [PMID: 37371821 DOI: 10.3390/biomedicines11061726] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2023] [Revised: 06/12/2023] [Accepted: 06/13/2023] [Indexed: 06/29/2023] Open
Abstract
Diabetic neuropathy (DN) causes sensory dysfunction, such as numbness, tingling, or burning sensations. Traditional medication may not ease pain and discomfort, but natural remedies such as Berberine (BR) and vitamin E or Tocopherol (TOC) have therapeutic potential to reduce inflammation while improving nerve function. Novel substances offer a more potent alternative method for managing severe chronic neuropathic pain that does not react to standard drug therapy by targeting various pathways that regulate it. Rats with diabetic control received oral doses of BR + TOC that showed significant changes in serum insulin levels compared to DN controls after 90 days, suggesting a decrease in sensitivity to painful stimuli partly by modulating the oxidative stress of the inflammatory pathway such as TNF-α suppression or stimulation of TNF-α depending on the amount of dose consumed by them. NF-kB also played its role here. Administering doses of BR and TOC reduced heightened levels of NF-kB and AGEs, effectively counteracting inflammation-targeted key factors in diabetes, promising possibilities for the benefits of these molecules revealed through in vivo investigation. In summary, treating neuropathy pain with a more comprehensive and organic approach can involve harnessing the powerful capabilities of BR and TOC. These compounds have been found to not only considerably decrease inflammation but also provide effective nerve protection while enhancing overall nerve function. With their multifunctional impacts on various neuropathic pain pathways in the body, these naturally occurring substances offer an exciting possibility for those who encounter high levels of neuropathic distress that do not respond well to conventional medication-centred therapies.
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Affiliation(s)
- Faisal K Alkholifi
- Department of Pharmacology & Toxicology, College of Pharmacy, Prince Sattam bin Abdulaziz University, Al-Kharj 11942, Saudi Arabia
| | - Alhussain H Aodah
- Department of Pharmaceutics, College of Pharmacy, Prince Sattam bin Abdulaziz University, Al-Kharj 11942, Saudi Arabia
| | - Ahmed I Foudah
- Department of Pharmacognosy, College of Pharmacy, Prince Sattam bin Abdulaziz University, Al-Kharj 11942, Saudi Arabia
| | - Aftab Alam
- Department of Pharmacognosy, College of Pharmacy, Prince Sattam bin Abdulaziz University, Al-Kharj 11942, Saudi Arabia
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Jiang F, Zhou L, Zhang C, Jiang H, Xu Z. Malondialdehyde levels in diabetic retinopathy patients: a systematic review and meta-analysis. Chin Med J (Engl) 2023; 136:1311-1321. [PMID: 37101358 PMCID: PMC10309507 DOI: 10.1097/cm9.0000000000002620] [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: 08/17/2022] [Indexed: 04/28/2023] Open
Abstract
BACKGROUND It remains unclear whether circulating malondialdehyde (MDA) levels change in people with diabetic retinopathy (DR). This systematic review compared circulating MDA levels in diabetic people with and without DR. METHODS PubMed, Medline (Ovid), Embase (Ovid), and Web of Science were searched for case-control studies conducted before May 2022 in English that compared circulating MDA levels in people with and without DR. The following MeSH search terms were used: ("malondialdehyde" or "thiobarbituric acid reactive substances [TBARS]" or "lipid peroxidation" or "oxidative stress") and "diabetic retinopathy." Newcastle-Ottawa Quality Assessment Scale was used to evaluate the quality of the included studies. Random-effects pairwise meta-analysis pooled the effect size with standardized mean difference (SMD) and 95% confidence intervals (CIs). RESULTS This meta-analysis included 29 case-control studies with 1680 people with DR and 1799 people with diabetes but not DR. Compared to people without DR, the circulating MDA levels were higher in those with DR (SMD, 0.897; 95% CI, 0.631 to 1.162; P < 0.001). The study did not identify credible subgroup effects or publication bias and the sensitivity analysis confirmed the robustness of the study. CONCLUSIONS Circulating MDA levels are higher in people with DR compared to those without. Future comparative studies that use more specific methods are required to draw firm conclusions. REGISTRATION PROSPERO; https://www.crd.york.ac.uk/PROSPERO/ ; No. CRD42022352640.
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Affiliation(s)
- Fanwen Jiang
- Department of Ophthalmology, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China
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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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Lektemur Alpan A, Çalışır M. The Effect of Two Different Doses of Astaxanthin on Alveolar Bone Loss in an Experimental Model of Periodontitis in Diabetic Rats. J Vet Dent 2022; 39:224-233. [PMID: 35422169 DOI: 10.1177/08987564221093736] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2024]
Abstract
This study evaluated the effects of astaxanthin (ASX) on alveolar bone loss, receptor activator of nuclear factor-κB ligand (RANKL), and osteoprotegerin (OPG) activity in ligature-induced periodontitis in diabetic rats. Diabetes mellitus (DM) was induced with 50 mg/kg intraperitoneal streptozotocin in 40 male Wistar rats. The Wistar rats were divided into six experimental groups: non-ligated (NL; n = 6); ligature only (L; n = 6); DM only (D; n = 6); DM + ligature (DP; n = 6); DM + ligature + 1 mg/kg/day ASX (ASX 1 group; n = 8); and DM + ligature + astaxanthin 5 mg/kg/day ASX (ASX 5 group; n = 8). Silk ligatures were placed along the gingival margin of the left mandibular first molar tooth. The study duration was 11 days, after which the animals were euthanised. Changes in alveolar bone levels were clinically measured, and RANKL and OPG activities were immunohistochemically examined. Alveolar bone loss was the most significant in the DP group (p < 0.05). Decreased alveolar bone loss was observed in the ASX 5 group (p < 0.05). Although RANKL activity was highest in the DP group, it was observed at lower levels in the groups to which ASX was administered. OPG activity did not differ between groups (p > 0.05). The results of this study suggested that 1 and 5 mg/kg ASX administration reduced RANKL activity and alveolar bone loss in rats with experimentally induced periodontitis.
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Affiliation(s)
- Aysan Lektemur Alpan
- Faculty of Dentistry Department of Periodontology, 52990Pamukkale University, Kınıklı Kampusu, Denizli, Turkey
| | - Metin Çalışır
- Faculty of Dentistry Department of Periodontology, 162296Adıyaman University, Adıyaman, Turkey
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Cincotta AH, Cersosimo E, Alatrach M, Ezrokhi M, Agyin C, Adams J, Chilton R, Triplitt C, Chamarthi B, Cominos N, DeFronzo RA. Bromocriptine-QR Therapy Reduces Sympathetic Tone and Ameliorates a Pro-Oxidative/Pro-Inflammatory Phenotype in Peripheral Blood Mononuclear Cells and Plasma of Type 2 Diabetes Subjects. Int J Mol Sci 2022; 23:ijms23168851. [PMID: 36012132 PMCID: PMC9407769 DOI: 10.3390/ijms23168851] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2022] [Revised: 08/01/2022] [Accepted: 08/03/2022] [Indexed: 11/16/2022] Open
Abstract
Bromocriptine-QR is a sympatholytic dopamine D2 agonist for the treatment of type 2 diabetes that has demonstrated rapid (within 1 year) substantial reductions in adverse cardiovascular events in this population by as yet incompletely delineated mechanisms. However, a chronic state of elevated sympathetic nervous system activity and central hypodopaminergic function has been demonstrated to potentiate an immune system pro-oxidative/pro-inflammatory condition and this immune phenotype is known to contribute significantly to the advancement of cardiovascular disease (CVD). Therefore, the possibility exists that bromocriptine-QR therapy may reduce adverse cardiovascular events in type 2 diabetes subjects via attenuation of this underlying chronic pro-oxidative/pro-inflammatory state. The present study was undertaken to assess the impact of bromocriptine-QR on a wide range of immune pro-oxidative/pro-inflammatory biochemical pathways and genes known to be operative in the genesis and progression of CVD. Inflammatory peripheral blood mononuclear cell biology is both a significant contributor to cardiovascular disease and also a marker of the body’s systemic pro-inflammatory status. Therefore, this study investigated the effects of 4-month circadian-timed (within 2 h of waking in the morning) bromocriptine-QR therapy (3.2 mg/day) in type 2 diabetes subjects whose glycemia was not optimally controlled on the glucagon-like peptide 1 receptor agonist on (i) gene expression status (via qPCR) of a wide array of mononuclear cell pro-oxidative/pro-inflammatory genes known to participate in the genesis and progression of CVD (OXR1, NRF2, NQO1, SOD1, SOD2, CAT, GSR, GPX1, GPX4, GCH1, HMOX1, BiP, EIF2α, ATF4, PERK, XBP1, ATF6, CHOP, GSK3β, NFkB, TXNIP, PIN1, BECN1, TLR2, TLR4, TLR10, MAPK8, NLRP3, CCR2, GCR, L-selectin, VCAM1, ICAM1) and (ii) humoral measures of sympathetic tone (norepinephrine and normetanephrine), whole-body oxidative stress (nitrotyrosine, TBARS), and pro-inflammatory factors (IL-1β, IL-6, IL-18, MCP-1, prolactin, C-reactive protein [CRP]). Relative to pre-treatment status, 4 months of bromocriptine-QR therapy resulted in significant reductions of mRNA levels in PBMC endoplasmic reticulum stress-unfolded protein response effectors [GRP78/BiP (34%), EIF2α (32%), ATF4 (29%), XBP1 (25%), PIN1 (14%), BECN1 (23%)], oxidative stress response proteins [OXR1 (31%), NRF2 (32%), NQO1 (39%), SOD1 (52%), CAT (26%), GPX1 (33%), GPX4 (31%), GCH1 (30%), HMOX1 (40%)], mRNA levels of TLR pro-inflammatory pathway proteins [TLR2 (46%), TLR4 (20%), GSK3β (19%), NFkB (33%), TXNIP (18%), NLRP3 (32%), CCR2 (24%), GCR (28%)], mRNA levels of pro-inflammatory cellular receptor proteins CCR2 and GCR by 24% and 28%, and adhesion molecule proteins L-selectin (35%) and VCAM1 (24%). Relative to baseline, bromocriptine-QR therapy also significantly reduced plasma levels of norepinephrine and normetanephrine by 33% and 22%, respectively, plasma pro-oxidative markers nitrotyrosine and TBARS by 13% and 10%, respectively, and pro-inflammatory factors IL-18, MCP1, IL-1β, prolactin, and CRP by 21%,13%, 12%, 42%, and 45%, respectively. These findings suggest a unique role for circadian-timed bromocriptine-QR sympatholytic dopamine agonist therapy in reducing systemic low-grade sterile inflammation to thereby reduce cardiovascular disease risk.
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Affiliation(s)
- Anthony H. Cincotta
- VeroScience LLC, Tiverton, RI 02878, USA
- Correspondence: ; Tel.: +1-401-816-0525
| | - Eugenio Cersosimo
- Texas Diabetes Institute, University Health System, San Antonio, TX 78207, USA
- Division of Diabetes, Department of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA
| | - Mariam Alatrach
- Texas Diabetes Institute, University Health System, San Antonio, TX 78207, USA
- Division of Diabetes, Department of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA
| | | | - Christina Agyin
- Texas Diabetes Institute, University Health System, San Antonio, TX 78207, USA
- Division of Diabetes, Department of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA
| | - John Adams
- Texas Diabetes Institute, University Health System, San Antonio, TX 78207, USA
- Division of Diabetes, Department of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA
| | - Robert Chilton
- Texas Diabetes Institute, University Health System, San Antonio, TX 78207, USA
- Division of Diabetes, Department of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA
| | - Curtis Triplitt
- Texas Diabetes Institute, University Health System, San Antonio, TX 78207, USA
- Division of Diabetes, Department of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA
| | | | | | - Ralph A. DeFronzo
- Texas Diabetes Institute, University Health System, San Antonio, TX 78207, USA
- Division of Diabetes, Department of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA
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Wang XL, Cai FR, Gao YX, Zhang J, Zhang M. Changes and significance of retinal blood oxygen saturation and oxidative stress indexes in patients with diabetic retinopathy. World J Diabetes 2022; 13:408-416. [PMID: 35664547 PMCID: PMC9134027 DOI: 10.4239/wjd.v13.i5.408] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/13/2021] [Revised: 01/28/2022] [Accepted: 04/28/2022] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Diabetic retinopathy (DR) is a diabetic complication that can severely affect the patients’ vision, eventually leading to blindness. DR is the most important manifestation of diabetic micro-vasculopathy and is mainly related to the course of diabetes and the degree of blood glucose control, while the age of diabetes onset, sex, and type of diabetes have little influence on it.
AIM To explore the changes in blood oxygen saturation and oxidative stress indices of retinal vessels in patients with DR.
METHODS In total, 94 patients (94 eyes) with DR (DR group) diagnosed at Jianyang people’s Hospital between March 2019 and June 2020, and 100 volunteers (100 eyes) (control group) without eye diseases, were included in this study. Arterial and venous blood oxygen saturation, retinal arteriovenous vessel diameter, and serum oxidative stress indicators in the two groups were compared. Based on the stage of the disease, the DR group was divided into the simple DR and proliferative DR groups for stratified analysis.
RESULTS The oxygen saturation of the retinal vessels in the DR group was significantly higher than that in the control group (P < 0.05). The retinal vessel diameters between the DR and control groups were not significantly different. The serum malondialdehyde (MDA) and 8-hydroxydehydroguanosine (8-OHdG) levels in the DR group were significantly higher than those in the control group (P < 0.05). The serum superoxide dismutase (SOD) and reduced glutathione (GSH) levels in the DR group were significantly lower than those in the control group (P < 0.05). The oxygen saturation of the retinal vessels in the patients with proliferative DR was significantly higher than that in the patients with simple DR (P < 0.05). The retinal vessel diameter in patients with proliferative DR was not significantly different from that of patients with simple DR (P > 0.05). Serum MDA and 8-OHdG levels in patients with proliferative DR were significantly higher than those in patients with simple DR (P < 0.05). Serum SOD and GSH levels in patients with proliferative DR were significantly lower than those in patients with simple DR (P < 0.05).
CONCLUSION Increased blood oxygen saturation of retinal arteries and veins and increased oxidative stress damage in patients with DR may be associated with decreased retinal capillary permeability and arterial oxygen dispersion, possibly reflecting the patient’s condition.
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Affiliation(s)
- Xiao-Li Wang
- Department of Ophthalmology, Jianyang People’s Hospital of Sichuan Province, Jianyang 641400, Sichuan Province, China
| | - Fang-Rong Cai
- Department of Ophthalmology, Jianyang People’s Hospital of Sichuan Province, Jianyang 641400, Sichuan Province, China
| | - Yun-Xia Gao
- Department of Ophthalmology, West China Hospital of Sichuan University, Chengdu 610000, Sichuan Province, China
| | - Jian Zhang
- Department of Ophthalmology, Jianyang People’s Hospital of Sichuan Province, Jianyang 641400, Sichuan Province, China
| | - Ming Zhang
- Department of Ophthalmology, West China Hospital of Sichuan University, Chengdu 610000, Sichuan Province, China
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Ahmed SA, Ghoneim DF, Morsy ME, Hassan AA, Mahmoud ARH. Low-Level Laser Therapy with 670 nm Alleviates Diabetic Retinopathy in an Experimental Model. J Curr Ophthalmol 2021; 33:143-151. [PMID: 34409224 PMCID: PMC8365584 DOI: 10.4103/joco.joco_29_20] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2020] [Revised: 01/01/2021] [Accepted: 02/19/2021] [Indexed: 01/24/2023] Open
Abstract
Purpose: To evaluate the effects of low-level laser therapy (LLLT) on the retina with diabetic retinopathy (DR). Methods: Eight Wistar rats were used as a control group, and 64 rats were injected intraperitoneally with 55 mg/kg of streptozotocin to induce diabetes and served as a diabetic group. After the establishment of the DR, the rats were separated into (a) 32 rats with DR; did not receive any treatment, (b) 32 rats with DR were exposed to 670 nm LLLT for 6 successive weeks (2 sessions/week). The retinal protein was analyzed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis, total antioxidant capacity (TAC), hydrogen peroxide (H2O2), and histological examination. Results: LLLT improved retinal proteins such as neurofilament (NF) proteins (200 KDa, 160 KDa, and 86 KDa), neuron-specific enolase (NSE) (46 KDa). Moreover, the percentage changes in TAC were 46.8% (P < 0.001), 14.5% (P < 0.01), 4.8% and 1.6% (P > 0.05), and in H2O2, they were 30% (P < 0.001), 25% (P < 0.001), 20% (P < 0.01), and 5% (P > 0.05) after 1, 2, 4, and 6 weeks, compared with the control. DR displayed swelling and disorganization in the retinal ganglion cells (RGCs) and photoreceptors, congestion of the capillaries in the nerve fiber layer, thickening of the endothelial cells’ capillaries, and edema of the outer segment of the photoreceptors layer. The improvement of the retinal structure was achieved after LLLT. Conclusion: LLLT could modulate retinal proteins such as NSE and NFs, improve the RGCs, photoreceptors, and reduce the oxidative stress that originated in the retina from diabetes-induced DR.
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Affiliation(s)
- Salwa Abdelkawi Ahmed
- Department of Vision Science, Biophysics and Laser Science Unit, Research Institute of Ophthalmology, Giza, Egypt
| | - Dina Fouad Ghoneim
- Department of Medical Application of Laser, Ophthalmic Unit, National Institute of Laser Enhanced Science, Cairo University, Giza, Egypt
| | - Mona Ebrahim Morsy
- Department of Medical Application of Laser, Photobiology Unit, National Institute of Laser Enhanced Science, Cairo University, Giza, Egypt
| | - Aziza Ahmed Hassan
- Department of Medical Application of Laser, Ophthalmic Unit, National Institute of Laser Enhanced Science, Cairo University, Giza, Egypt
| | - Abdel Rahman Hassan Mahmoud
- Department of Medical Application of Laser, Ophthalmic Unit, National Institute of Laser Enhanced Science, Cairo University, Giza, Egypt
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Chen H, Zhang X, Liao N, Ji Y, Mi L, Gan Y, Su Y, Wen F. Identification of NLRP3 Inflammation-Related Gene Promoter Hypomethylation in Diabetic Retinopathy. Invest Ophthalmol Vis Sci 2020; 61:12. [PMID: 33156339 PMCID: PMC7671867 DOI: 10.1167/iovs.61.13.12] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/15/2023] Open
Abstract
Purpose To identify and validate key genes that could provide a new perspective for genetic marker screening of diabetic retinopathy (DR). Methods The gene expression and DNA methylation profiles were obtained from the Gene Expression Omnibus. Differential expression analysis was conducted using the limma package, and then the functions of the differentially expressed genes (DEGs) were analyzed using the DAVID database, followed by protein–protein interaction (PPI) networks using Cytoscape software. We employed the Sequenom MassARRAY system to detect the promoter methylation levels of the candidate genes in peripheral blood mononuclear cells from 32 healthy individuals and 94 patients with type 2 diabetes mellitus (T2D; 64 with DR and 30 without DR) and in fibrovascular membranes (FVMs) from three proliferative DR patients and three controls with idiopathic epiretinal membranes. The mRNA levels of candidate genes were further confirmed via real-time polymerase chain reaction. Results A significant enrichment of 5906 DEGs was found in immune and inflammatory responses. TGFB1, CCL2, and TNFSF2 were identified as the top three core genes associated with NLRP3 inflammation in PPI networks. These genes have relatively low levels of promoter methylation, which have been validated in peripheral blood mononuclear cells and FVMs from DR patients, and the methylation levels were found to be negative correlated with the mRNA levels and HbA1c levels in T2D patients. Conclusions Overall, these data indicate that promoter hypomethylation of NLRP3, TGFB1, CCL2, and TNFSF2 may increase the risk of DR in the Chinese Han population, indicating that these genes might serve as potential targets for the detection and treatment of DR.
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Affiliation(s)
- Hui Chen
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, China
| | - Xiongze Zhang
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, China
| | - Nanying Liao
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, China
| | - Yuying Ji
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, China
| | - Lan Mi
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, China
| | - Yuhong Gan
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, China
| | - Yongyue Su
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, China
| | - Feng Wen
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, China
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Association of Oxidative Stress on Pregnancy. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2020; 2020:6398520. [PMID: 33014274 PMCID: PMC7512072 DOI: 10.1155/2020/6398520] [Citation(s) in RCA: 43] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/15/2020] [Revised: 08/19/2020] [Accepted: 09/01/2020] [Indexed: 02/02/2023]
Abstract
The pathophysiological mechanism underlying pregnancy complications such as congenital malformations, miscarriage, preeclampsia, or fetal growth restriction is not entirely known. However, the negative impact of the mother's body oxidative imbalance on the fetus and the course of gestation is increasingly discussed. This article is an integrative review of some original studies and review papers on the effects of oxidative stress on the adverse pregnancy outcomes mainly birth defects in fetuses. A systematic search for English language articles published from 2010 until 2020 was made, using MEDLINE data. Additionally, we analyzed the Cochrane and Scopus databases, discussions with experts, and a review of bibliography of articles from scientifically relevant and valuable sources. The main purposes are to assess the contribution of the existing literature of associations of oxidative stress on the etiology of the abovementioned conditions and to identify relevant information and outline existing knowledge. Furthermore, the authors aim to find any gaps in the research, thereby providing grounds for our own research. The key search terms were "oxidative stress in pregnancy," "oxidative stress and congenital malformations," and "oxidative stress and adverse pregnancy outcomes." Studies have confirmed that oxidative stress has a significant impact on pregnancy and is involved in the pathomechanism of adverse pregnancy outcomes.
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Kalyani RS, Raghunath V. Assessment of serum and salivary adiponectin levels in newly diagnosed Type II diabetes mellitus patients. J Oral Maxillofac Pathol 2020; 24:245-250. [PMID: 33456232 PMCID: PMC7802862 DOI: 10.4103/jomfp.jomfp_87_18] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2018] [Accepted: 05/13/2019] [Indexed: 01/23/2023] Open
Abstract
Background Adiponectin, an adipocytokine, plays an important role in the development of Type 2 Diabetes Mellitus (T2DM) in obese and cardiovascular disease patients, with few studies having observed low plasma concentrations. Persistent low-grade inflammation, an important feature in T2DM and obesity, bears an indirect influence on insulin resistance and insulin secretion and is reflected by increased plasma levels of C-reactive protein (CRP). Thus, low levels of anti-inflammatory cytokine, adiponectin, depicts that inflammation could be the link between T2DM, obesity and adiponectin. Since these factors need to be explored to prevent or adequately treat T2DM, especially among Indian diabetics, this study was undertaken. Also of interest was to assess its salivary concentrations. Aim This study aimed to assess serum and salivary adiponectin levels in newly diagnosed T2DM individuals along with postprandial blood sugar (PPBS) and glycosylated hemoglobin (HbA1C) and high-sensitivity-CRP (hs-CRP). Materials and Methods Serum and salivary levels of adiponectin, PPBS, HbA1c and hs-CRP were assessed in 30 newly diagnosed T2DM (Group I) individuals and compared with 30 healthy individuals (Group II, healthy control). Glucose oxidase peroxidase, automatic analyzer, turbidimetric immunoassay and ELISA methods were adopted for PPBS, HbA1c, hs-CRP and adiponectin estimation. Results Statistically significant decrease in mean serum (16.93 ± 3.86) and salivary (24.96 ± 8.21) adiponectin levels, were observed in Group I compared to Group II individuals with a p value of 0.00 and 0.04 respectively. In Group I individuals a significant p value of 0.02 was noted only between salivary adiponectin and PPBS. None of the other parameters correlated significantly with serum adiponectin levels. Conclusion Decreased serum and salivary adiponectin levels in T2DM furthered the importance of its role in Indian T2DM. Decreased salivary adiponectin levels probably reflected salivary hypofunction. This being the preliminary study in saliva, more studies are required to emphasize its role both as a diagnostic marker and as an anti-inflammatory cytokine in T2DM.
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Affiliation(s)
- R Suma Kalyani
- Department of Oral Pathology, Narayana Dental College and Hospital, Nellore, Andhra Pradesh, India
| | - Vandana Raghunath
- Department of Oral Pathology, Narayana Dental College and Hospital, Nellore, Andhra Pradesh, India
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Assessment of neuron-specific enolase, S100B and malondialdehyde levels in serum and vitreous of patients with proliferative diabetic retinopathy. Int Ophthalmol 2019; 40:227-234. [PMID: 31571092 DOI: 10.1007/s10792-019-01175-9] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2019] [Accepted: 09/19/2019] [Indexed: 01/17/2023]
Abstract
PURPOSE To assess the vitreous and serum levels of neuron-specific enolase (NSE), S100B and malondialdehyde (MDA) in proliferative diabetic retinopathy (PDR) cases and investigate the correlation between preoperative and postoperative anatomical and clinical features. MATERIALS AND METHODS The study group included patients who had pars plana vitrectomy (PPV) for PDR. The control group included non-diabetic individuals who underwent PPV surgery for vitreoretinal interface disorders. Samples of serum were taken from all participants preoperatively, while vitreous samples were taken during the PPV. Vitreous and serum levels of NSE, S100B and MDA were measured, and comparisons were made between the groups. RESULTS The study group consisted of 56 eyes of 56 cases with PDR. The control group consisted of 20 eyes of 20 cases. The concentrations of vitreous NSE, S100B and MDA were significantly higher than the control group (p < 0.0001, p < 0.05, p < 0.001, respectively). Serum levels were statistically different for NSE and S100B (p < 0.05). CONCLUSION Our results clearly show that vitreous levels of S100B, NSE and MDA and serum concentrations of NSE and S100B increased significantly in patients with PDR. The findings may possibly indicate neurodegeneration and oxidative stress; therefore, these markers may have a diagnostic value in patients with PDR.
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Suzuki Y, Yao T, Okumura K, Seko Y, Kitano S. Elevation of the vitreous body concentrations of oxidative stress-responsive apoptosis-inducing protein (ORAIP) in proliferative diabetic retinopathy. Graefes Arch Clin Exp Ophthalmol 2019; 257:1519-1525. [PMID: 31062144 DOI: 10.1007/s00417-019-04343-w] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2019] [Revised: 04/18/2019] [Accepted: 04/25/2019] [Indexed: 12/18/2022] Open
Abstract
PURPOSE Oxidative stress has been implicated in the pathogenesis of various disorders, including diabetic retinopathy (DR). Oxidative stress-responsive apoptosis-inducing protein (ORAIP; a tyrosine-sulfated secreted form of eukaryotic translation initiation factor 5A [eIF5A]) is a recently discovered pro-apoptotic ligand that is secreted from cells in response to oxidative stress and induces apoptosis in an autocrine fashion. This study aimed to determine if ORAIP plays a role in DR. METHODS To investigate the role of ORAIP in DR, we analyzed the levels of ORAIP in the vitreous body and their relationship with the extent of proliferative diabetic retinopathy (PDR). Enzyme-linked immunosorbent assay was used to quantify the levels of ORAIP, vascular endothelial growth factor (VEGF), C-C motif chemokine ligand 2 (CCL2), interleukin-6 (IL-6), and IL-8 in the vitreous body of 40 eyes from 28 patients with PDR and 11 patients with non-PDR (NPDR). We also analyzed the expression of ORAIP in insoluble proliferative tissues from vitreous body samples by immunofluorescent staining. RESULTS The vitreous body concentration of ORAIP was significantly (P = 0.0433) higher in the PDR group (52.26 ± 8.68 [mean ± SE] ng/mL, n = 29) than in the NPDR group (28.21 ± 7.30 ng/mL, n = 11). However, there were no significant correlations between the concentration of ORAIP and those of VEGF, IL-6, CCL2, or IL-8. ORAIP expression was observed in the insoluble proliferative tissues in vitreous body samples of most patients in the PDR group, whereas almost no expression of ORAIP was observed in patients in the NPDR group. CONCLUSIONS Our findings strongly suggest that ORAIP plays a role in oxidative stress-induced retinal injury and may be a sensitive diagnostic marker and a promising therapeutic target for oxidative stress-induced cytotoxicity.
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Affiliation(s)
- Yuta Suzuki
- Department of Ophthalmology, Diabetes Center, Tokyo Women's Medical University, Tokyo, Japan
| | - Takako Yao
- Division of Cardiovascular Medicine, Institute for Adult Diseases, Asahi Life Foundation, Tokyo, Japan
| | - Ko Okumura
- Department of Biofunctional Microbiota, Graduate School of Medicine, Juntendo University, 2-1-1 Hongo, Bunkyo-ku, Tokyo, 113-8421, Japan
| | - Yoshinori Seko
- Department of Biofunctional Microbiota, Graduate School of Medicine, Juntendo University, 2-1-1 Hongo, Bunkyo-ku, Tokyo, 113-8421, Japan.
| | - Shigehiko Kitano
- Department of Ophthalmology, Diabetes Center, Tokyo Women's Medical University, Tokyo, Japan
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Perturbed Biochemical Pathways and Associated Oxidative Stress Lead to Vascular Dysfunctions in Diabetic Retinopathy. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2019; 2019:8458472. [PMID: 30962865 PMCID: PMC6431380 DOI: 10.1155/2019/8458472] [Citation(s) in RCA: 46] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/07/2018] [Revised: 12/26/2018] [Accepted: 01/27/2019] [Indexed: 02/08/2023]
Abstract
Diabetic retinopathy (DR) is a vascular insult that accompanies the hyperglycemic state. Retinal vasculature holds a pivotal role in maintaining the integrity of the retina, and any alteration to retinal vasculature affects retinal functions. The blood retinal barrier, a prerequisite to vision acuity, is most susceptible to damage during the progression of DR. This is a consequence of impaired biochemical pathways such as the polyol, advanced end glycation products (AGE), hexosamine, protein kinase C (PKC), and tissue renin-angiotensin system (RAS) pathways. Moreover, the role of histone modification and altered miRNA expression is also emerging as a major contributor. Epigenetic changes create a link between altered protein function and redox status of retinal cells, creating a state of metabolic memory. Although various biochemical pathways underlie the etiology of DR, the major insult to the retina is due to oxidative stress, a unifying factor of altered biochemical pathways. This review primarily focuses on the critical biochemical pathways altered in DR leading to vascular dysfunctions and discusses antioxidants as plausible treatment strategies.
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Chittawar S, Dutta D, Qureshi Z, Surana V, Khandare S, Dubey TN. Neutrophil-lymphocyte Ratio is a Novel Reliable Predictor of Nephropathy, Retinopathy, and Coronary Artery Disease in Indians with Type-2 Diabetes. Indian J Endocrinol Metab 2017; 21:864-870. [PMID: 29285450 PMCID: PMC5729675 DOI: 10.4103/ijem.ijem_197_17] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/23/2023] Open
Abstract
BACKGROUND AND AIMS Neutrophil-lymphocyte ratio (NLR) has been suggested to be a predictor of coronary artery disease (CAD), and end-organ damage in type-2 diabetes mellitus (T2DM). Similar data are lacking from Indians with T2DM. Hence, this study aimed to evaluate the role of NLR as a predictor of microvascular complications and CAD in T2DM. SUBJECTS AND METHODS Consecutive T2DM patients attending the outpatient services of 2 different hospitals, who gave consent, underwent clinical, anthropometric evaluation, and evaluation for the occurrence of retinopathy, nephropathy, neuropathy, and CAD. RESULTS A total of 298 patients were screened of which 265 patients' data were analyzed. Occurrence of hypertension, neuropathy, nephropathy, retinopathy, and CAD was 12.8%, 18.5%, 41.5%, 62.3%, and 3.8%, respectively. Patients in higher NLR quartiles had significantly higher diabetes duration, occurrence of nephropathy, albuminuria, retinopathy, CAD and lpwer glomerular filtration rate. Patients with more microvascular complications had significantly longer diabetes duration, blood pressure, NLR, creatinine, and urine albumin excretion. Binary logistic regression revealed NLR followed by body mass index were best predictors of microvascular complications. NLR had areas under the receiver operating characteristic curve (AUC) of 0.888 (95% CI: 0.848-0.929; P < 0.001), 0.708 (95% CI: 0.646-0.771; P < 0.001), and 0.768 (95% CI: 0.599-938; P = 0.004) in predicting albuminuria, retinopathy, and CAD, respectively. NLR of 2.00 had sensitivity and specificity of 86.4% and 69% in predicting albuminuria; sensitivity and specificity of 64.2% and 63% in predicting retinopathy; sensitivity and specificity of 80% and 47.1% in predicting CAD. CONCLUSION NLR is inexpensive, easy to use, reliable predictor of nephropathy, retinopathy, and CAD in Indian T2DM.
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Affiliation(s)
- Sachin Chittawar
- Department of Medicine, Gandhi Medical College, Bhopal, Madhya Pradesh, India
| | - Deep Dutta
- Department of Endocrinology, Diabetology and Metabolic Disorders, Venkateshwar Hospitals, Dwarka, New Delhi, India
| | - Zahran Qureshi
- Department of Pharmacology, Gandhi Medical College, Bhopal, Madhya Pradesh, India
| | - Vineet Surana
- Department of Endocrinology, Yashoda Hospital, Hyderabad, Telangana, India
| | - Sagar Khandare
- Department of Medicine, Gandhi Medical College, Bhopal, Madhya Pradesh, India
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Pietryga M, Dydowicz P, Toboła K, Napierała M, Miechowicz I, Gąsiorowska A, Brązert M, Florek E. Selected oxidative stress biomarkers in antenatal diagnosis as 11-14 gestational weeks. Free Radic Biol Med 2017; 108:517-523. [PMID: 28428000 DOI: 10.1016/j.freeradbiomed.2017.04.020] [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: 12/28/2016] [Revised: 04/03/2017] [Accepted: 04/16/2017] [Indexed: 10/19/2022]
Abstract
The primary objective in modern obstetrics and prenatal diagnosis is to predict risks of congenital abnormalities. The aim of the research was to assess the correlation between selected oxidative stress biomarkers with the risk of foetal chromosomal aberration evaluated at the first trimester screening. A series of studies show that balanced free radical activity and oxidative homeostasis are essential for proper bodily growth and function. Reactive oxygen species (ROS) may be one of the factors associated with disruption of cell cycle and tissue development, thus leading to developmental abnormalities. That's why it's so important to examine connection between level of oxidative stress and congenital abnormalities. Using ultrasonography examinations between 11-13+6d gestational weeks combined with serum levels of pregnancy associated plasma protein A and human chorionic gonadotropin and spectrophotometric analysis of oxidative stress markers such as glutathione (GSH), S-transferase, S-nitrosothiols (RSNO), trolox equivalent antioxidant capacity (TEAC), protein and nitrites we tried to find correlation between birth defects and oxidative stress status. In conclusion, our analysis suggests that elevated maternal serum levels of protein, S-transferase and TEAC as well as decreased maternal serum levels of GSH and protein correlated with the risk of chromosomal aberrations and congenital developmental defects in a foetus.
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Affiliation(s)
- Marek Pietryga
- Ultrasound and Prenatal Diagnostic Laboratory, Gynaecology and Obstetrics Hospital K. Marcinkowski Poznań University of Medical Sciences, Poland; Department of Obstetrics and Female Health, Chair of Gynaecology, Obstetrics and Gynaecological Oncology, K. Marcinkowski Poznań University of Medical Sciences, Poland.
| | - Piotr Dydowicz
- Ultrasound and Prenatal Diagnostic Laboratory, Gynaecology and Obstetrics Hospital K. Marcinkowski Poznań University of Medical Sciences, Poland; Department of Gynaecology and Obstetrics, Chair of Medical Education, Faculty of Health Sciences, K. Marcinkowski Poznań University of Medical Sciences, Poland.
| | - Kinga Toboła
- Ultrasound and Prenatal Diagnostic Laboratory, Gynaecology and Obstetrics Hospital K. Marcinkowski Poznań University of Medical Sciences, Poland; Department of Obstetrics and Female Health, Chair of Gynaecology, Obstetrics and Gynaecological Oncology, K. Marcinkowski Poznań University of Medical Sciences, Poland.
| | - Marta Napierała
- Laboratory of Environmental Research, Department of Toxicology, K. Marcinkowski Poznań University of Medical Sciences, Poland.
| | - Izabela Miechowicz
- Department of Computer Science and Statistics, K. Marcinkowski Poznań University of Medical Sciences, Poland.
| | - Anna Gąsiorowska
- Gynaecology and Obstetrics Ward, Podhalański Specialist Hospital in Nowy Targ, Poland.
| | - Maciej Brązert
- Department of Reproductive Medicine, Chair of Gynaecology, Obstetrics and Gynaecological Oncology, K. Marcinkowski Poznań University of Medical Sciences, Poland.
| | - Ewa Florek
- Laboratory of Environmental Research, Department of Toxicology, K. Marcinkowski Poznań University of Medical Sciences, Poland.
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Chatziralli IP, Theodossiadis G, Dimitriadis P, Charalambidis M, Agorastos A, Migkos Z, Platogiannis N, Moschos MM, Theodossiadis P, Keryttopoulos P. The Effect of Vitamin E on Oxidative Stress Indicated by Serum Malondialdehyde in Insulin-dependent Type 2 Diabetes Mellitus Patients with Retinopathy. Open Ophthalmol J 2017; 11:51-58. [PMID: 28567166 PMCID: PMC5420190 DOI: 10.2174/1874364101711010051] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2016] [Revised: 02/16/2017] [Accepted: 03/03/2017] [Indexed: 12/14/2022] Open
Abstract
Background: Several studies have focused on oxidative stress on diabetes mellitus (DM). Our purpose was to investigate the impact of oxidative stress on progression of diabetic retinopathy (DR) in insulin-dependent type 2 DM patients, measuring serum malondialdehyde (MDA), as well as to examine the effect of vitamin E on DR progression in the above-mentioned patients. Methods: Participants in the study were 282 insulin-dependent type 2 DM patients with DR. All participants underwent a thorough ophthalmological examination, so as to grade DR, along with serum MDA measurement. All participants received 300mg vitamin E daily for 3 months and were examined again. Serum MDA pre- and post-intake of Vitamin E was the main outcome. Results: Serum MDA was positively associated with DR stage, while there was a statistically significant difference pre- and post-intake of vitamin E in all DR stages. In a subgroup analysis of patients with proliferative DR, there was a significant difference at baseline between patients who have received prior laser photocoagulation and the treatment naïve patients, while after intake of vitamin E, no statistically significant difference was noticed. Conclusion: Oxidative stress has been found to play significant role in the pathogenesis and progression of DR, while vitamin E seems to reduce MDA levels and subsequent oxidative stress, suggesting that it might have protective role in DR progression.
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Affiliation(s)
| | | | | | | | - Antonios Agorastos
- Department of Internal Medicine, General Hospital of Veroia, Veroia, Greece
| | - Zisis Migkos
- Department of Internal Medicine, General Hospital of Veroia, Veroia, Greece
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Kadłubowska J, Malaguarnera L, Wąż P, Zorena K. Neurodegeneration and Neuroinflammation in Diabetic Retinopathy: Potential Approaches to Delay Neuronal Loss. Curr Neuropharmacol 2017; 14:831-839. [PMID: 27306035 PMCID: PMC5333588 DOI: 10.2174/1570159x14666160614095559] [Citation(s) in RCA: 56] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/01/1970] [Revised: 08/11/2015] [Accepted: 01/01/1970] [Indexed: 02/06/2023] Open
Abstract
In spite of the extensive research the complex pathogenesis of diabetic retinopathy (DR) has not been fully elucidated. For many years it has been thought that diabetic retinopathy manifests only with microangiopathic lesions, which are totally responsible for the loss of vision in diabetic patients. In view of the current knowledge on the microangiopathic changes in the fundus of the eye, diabetic retinopathy is perceived as a neurodegenerative disease. Several clinical tools are available to detect neuronal dysfunction at early stages of diabetes. Many functional changes in the retina can be identified before vascular pathology develops, suggesting that they result from a direct effect of diabetes on the neural retina. In the course of diabetes there is a chronic loss of retinal neurons due to increased frequency of apoptosis. The neuronal apoptosis begins very early in the course of diabetes. This observation has led to suggestions that precautions against DR should be implemented immediately after diabetes is diagnosed. Neurodegeneration cannot be reversed; therefore treatments preventing neuronal cell loss in the retina need to be developed to protect diabetic patients. This review is an attempt to summarize what is currently known about the mechanisms of neuronal apoptosis in the context of diabetic retinopathy and vascular degeneration as well as about potential treatments of DR
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Affiliation(s)
| | | | | | - Katarzyna Zorena
- Department of Immunobiology and Environment Microbiology, Medical University of Gdańsk, Dębinki 7, 80-211 Gdańsk, Poland
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Restaino RM, Deo SH, Parrish AR, Fadel PJ, Padilla J. Increased monocyte-derived reactive oxygen species in type 2 diabetes: role of endoplasmic reticulum stress. Exp Physiol 2017; 102:139-153. [PMID: 27859785 DOI: 10.1113/ep085794] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2016] [Accepted: 11/16/2016] [Indexed: 12/14/2022]
Abstract
NEW FINDINGS What is the central question of this study? Patients with type 2 diabetes exhibit increased oxidative stress in peripheral blood mononuclear cells, including monocytes; however, the mechanisms remain unknown. What is the main finding and its importance? The main finding of this study is that factors contained within the plasma of patients with type 2 diabetes can contribute to increased oxidative stress in monocytes, making them more adherent to endothelial cells. We show that these effects are largely mediated by the interaction between endoplasmic reticulum stress and NADPH oxidase activity. Recent evidence suggests that exposure of human monocytes to glucolipotoxic media to mimic the composition of plasma of patients with type 2 diabetes (T2D) results in the induction of endoplasmic reticulum (ER) stress markers and formation of reactive oxygen species (ROS). The extent to which these findings translate to patients with T2D remains unclear. Thus, we first measured ROS (dihydroethidium fluorescence) in peripheral blood mononuclear cells (PBMCs) from whole blood of T2D patients (n = 8) and compared the values with age-matched healthy control subjects (n = 8). The T2D patients exhibited greater basal intracellular ROS (mean ± SD, +3.4 ± 1.4-fold; P < 0.05) compared with control subjects. Next, the increase in ROS in PBMCs isolated from T2D patients was partly recapitulated in cultured human monocytes (THP-1 cells) exposed to plasma from T2D patients for 36 h (+1.3 ± 0.08-fold versus plasma from control subjects; P < 0.05). In addition, we found that increased ROS formation in THP-1 cells treated with T2D plasma was NADPH oxidase derived and led to increased endothelial cell adhesion (+1.8 ± 0.5-fold; P < 0.05) and lipid uptake (+1.3 ± 0.3-fold; P < 0.05). Notably, we found that T2D plasma-induced monocyte ROS and downstream functional effects were abolished by treating cells with tauroursodeoxycholic acid, a chemical chaperone known to inhibit ER stress. Collectively, these data indicate that monocyte ROS production with T2D can be attributed, in part, to signals from the circulating environment. Furthermore, an interplay between ER stress and NADPH oxidase activity contributes to ROS production and may be a mechanism mediating endothelial cell adhesion and foam cell formation in T2D.
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Affiliation(s)
- Robert M Restaino
- Department of Medical Pharmacology and Physiology, University of Missouri, Columbia, MO, USA
| | - Shekhar H Deo
- Department of Medical Pharmacology and Physiology, University of Missouri, Columbia, MO, USA
| | - Alan R Parrish
- Department of Medical Pharmacology and Physiology, University of Missouri, Columbia, MO, USA
| | - Paul J Fadel
- Department of Kinesiology, University of Texas-Arlington, Arlington, TX, USA
| | - Jaume Padilla
- Department of Nutrition and Exercise Physiology, University of Missouri, Columbia, MO, USA.,Dalton Cardiovascular Research Center, University of Missouri, Columbia, MO, USA.,Department of Child Health, University of Missouri, Columbia, MO, USA
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Hyperlipidemia-Mediated Increased Advanced Lipoxidation End Products Formation, an Important Factor Associated with Decreased Erythrocyte Glucose-6-Phosphate Dehydrogenase Activity in Mild Nonproliferative Diabetic Retinopathy. Can J Diabetes 2016; 41:82-89. [PMID: 27916496 DOI: 10.1016/j.jcjd.2016.07.007] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/08/2016] [Revised: 06/16/2016] [Accepted: 07/25/2016] [Indexed: 11/22/2022]
Abstract
OBJECTIVES The present study aimed to evaluate the role of hyperlipidemia in increased formation of advanced lipoxidation end products (ALEs) and to evaluate whether there is any relationship between ALEs generation and erythrocyte glucose-6-phosphate dehydrogenase (G6PD) activity in cases of mild nonproliferative diabetic retinopathy (MNPDR). METHODS In this study, we enrolled 100 patients with type 2 diabetes and MNPDR, 100 subjects with type 2 diabetes but without retinopathy (DNR) and 90 normal individuals without diabetes as healthy controls (HCs). Erythrocyte nicotinamide dinucleotide phosphate (NADPH), G6PD activity, serum total cholesterol, low- and high-density lipoprotein (LDL, HDL) and triglyceride levels were determined by photometric assay. Serum malondialdehyde (MDA) protein adduct and hexanoyl-lysine (HEL) were measured by an enzyme-linked immunosorbent assay (ELISA). RESULTS A robust linear relationship was observed between MDA protein adduct and LDL or cholesterol or triglyceride levels, and HEL and LDL or cholesterol or triglyceride levels in subjects with MNPDR (p=0.0001). A significant inverse association was observed between erythrocyte G6PD activity and serum MDA protein adductor HEL levels in subjects with MNPDR (p=0.0001). CONCLUSIONS Hyperlipidemia is an important factor that is associated with increased ALEs formation in persons with MNPDR. Increased ALEs generation was associated with decreased G6PD activity and low NADPH levels in cases of MNPDR, suggesting their detrimental role in the occurrence of early NPDR.
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Das UN. Diabetic macular edema, retinopathy and age-related macular degeneration as inflammatory conditions. Arch Med Sci 2016; 12:1142-1157. [PMID: 27695506 PMCID: PMC5016593 DOI: 10.5114/aoms.2016.61918] [Citation(s) in RCA: 36] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/07/2015] [Accepted: 04/20/2015] [Indexed: 12/15/2022] Open
Abstract
Diabetic macular edema (DME) and diabetic retinopathy (DR) are complications affecting about 25% of all patients with long-standing type 1 and type 2 diabetes mellitus and are a major cause of significant decrease in vision and quality of life. Age-related macular degeneration (AMD) is not uncommon, and diabetes mellitus affects the incidence and progression of AMD through altering hemodynamics, increasing oxidative stress, accumulating advanced glycation end products, etc. Recent studies suggest that DME, DR and AMD are inflammatory conditions characterized by a breakdown of the blood-retinal barrier, inflammatory processes and an increase in vascular permeability. Key factors that seem to have a dominant role in DME, DR and AMD are angiotensin II, prostaglandins and the vascular endothelial growth factor and a deficiency of anti-inflammatory bioactive lipids. The imbalance between pro- and anti-inflammatory eicosanoids and enhanced production of pro-angiogenic factors may initiate the onset and progression of DME, DR and AMD. This implies that bioactive lipids that possess anti-inflammatory actions and suppress the production of angiogenic factors could be employed in the prevention and management of DME, DR and AMD.
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Wert KJ, Mahajan VB, Zhang L, Yan Y, Li Y, Tosi J, Hsu CW, Nagasaki T, Janisch KM, Grant MB, Mahajan M, Bassuk AG, Tsang SH. Neuroretinal hypoxic signaling in a new preclinical murine model for proliferative diabetic retinopathy. Signal Transduct Target Ther 2016; 1. [PMID: 27195131 PMCID: PMC4868361 DOI: 10.1038/sigtrans.2016.5] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022] Open
Abstract
Diabetic retinopathy (DR) affects approximately one-third of diabetic patients and, if left untreated, progresses to proliferative DR (PDR) with associated vitreous hemorrhage, retinal detachment, iris neovascularization, glaucoma and irreversible blindness. In vitreous samples of human patients with PDR, we found elevated levels of hypoxia inducible factor 1 alpha (HIF1α). HIFs are transcription factors that promote hypoxia adaptation and have important functional roles in a wide range of ischemic and inflammatory diseases. To recreate the human PDR phenotype for a preclinical animal model, we generated a mouse with neuroretinal-specific loss of the von Hippel Lindau tumor suppressor protein, a protein that targets HIF1α for ubiquitination. We found that the neuroretinal cells in these mice overexpressed HIF1α and developed severe, irreversible ischemic retinopathy that has features of human PDR. Rapid progression of retinopathy in these mutant mice should facilitate the evaluation of therapeutic agents for ischemic and inflammatory blinding disorders. In addition, this model system can be used to manipulate the modulation of the hypoxia signaling pathways, for the treatment of non-ocular ischemic and inflammatory disorders.
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Affiliation(s)
- Katherine J Wert
- Bernard and Shirlee Brown Glaucoma Laboratory and Barbara & Donald Jonas Laboratory of Regenerative Medicine, Columbia University, New York, NY, USA; Edward S. Harkness Eye Institute, Columbia University, New York, NY, USA; Institute of Human Nutrition, Columbia University, New York, NY, USA
| | - Vinit B Mahajan
- Department of Ophthalmology and Visual Sciences, University of Iowa, Iowa City, IA, USA; Omics Laboratory, University of Iowa, Iowa City, IA, USA
| | - Lijuan Zhang
- Bernard and Shirlee Brown Glaucoma Laboratory and Barbara & Donald Jonas Laboratory of Regenerative Medicine, Columbia University, New York, NY, USA; Edward S. Harkness Eye Institute, Columbia University, New York, NY, USA
| | - Yuanqing Yan
- Department of Pharmacology and Therapeutics, University of Florida, Gainesville, FL, USA
| | - Yao Li
- Bernard and Shirlee Brown Glaucoma Laboratory and Barbara & Donald Jonas Laboratory of Regenerative Medicine, Columbia University, New York, NY, USA; Edward S. Harkness Eye Institute, Columbia University, New York, NY, USA
| | - Joaquin Tosi
- Bernard and Shirlee Brown Glaucoma Laboratory and Barbara & Donald Jonas Laboratory of Regenerative Medicine, Columbia University, New York, NY, USA; Edward S. Harkness Eye Institute, Columbia University, New York, NY, USA
| | - Chun Wei Hsu
- Bernard and Shirlee Brown Glaucoma Laboratory and Barbara & Donald Jonas Laboratory of Regenerative Medicine, Columbia University, New York, NY, USA; Edward S. Harkness Eye Institute, Columbia University, New York, NY, USA
| | - Takayuki Nagasaki
- Edward S. Harkness Eye Institute, Columbia University, New York, NY, USA
| | - Kerstin M Janisch
- Bernard and Shirlee Brown Glaucoma Laboratory and Barbara & Donald Jonas Laboratory of Regenerative Medicine, Columbia University, New York, NY, USA; Edward S. Harkness Eye Institute, Columbia University, New York, NY, USA
| | - Maria B Grant
- Eugene and Marilyn Glick Eye Institute, Department of Ophthalmology, Indiana University School of Medicine, Indianapolis, IN, USA
| | - MaryAnn Mahajan
- Department of Ophthalmology and Visual Sciences, University of Iowa, Iowa City, IA, USA; Omics Laboratory, University of Iowa, Iowa City, IA, USA
| | | | - Stephen H Tsang
- Bernard and Shirlee Brown Glaucoma Laboratory and Barbara & Donald Jonas Laboratory of Regenerative Medicine, Columbia University, New York, NY, USA; Edward S. Harkness Eye Institute, Columbia University, New York, NY, USA; Institute of Human Nutrition, Columbia University, New York, NY, USA; New York Presbyterian Hospital/Columbia University Medical Center, New York, NY, USA; Department of Pathology and Cellular Biology, Columbia University, New York, NY, USA
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Chen X, Bakillah A, Zhou L, Pan X, Hoepfner F, Jacob M, Jiang XC, Lazar J, Schlitt A, Hussain MM. Nitrated apolipoprotein AI/apolipoprotein AI ratio is increased in diabetic patients with coronary artery disease. Atherosclerosis 2016; 245:12-21. [PMID: 26687998 PMCID: PMC4738057 DOI: 10.1016/j.atherosclerosis.2015.11.021] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/05/2015] [Revised: 11/13/2015] [Accepted: 11/19/2015] [Indexed: 12/17/2022]
Abstract
AIMS/HYPOTHESIS Recent studies have suggested that determination of HDL function may be more informative than its concentration in predicting its protective role in coronary artery disease (CAD). Apolipoprotein AI (apoAI), the major protein of HDL, is nitrosylated in vivo to nitrated apoAI (NT-apoAI) that might cause dysfunction. We hypothesized that NT-apoAI/apoAI ratio might be associated with diabetes mellitus (DM) in CAD patients. METHODS We measured plasma NT-apoAI and apoAI levels in 777 patients with coronary artery disease (CAD) by ELISA. Further, we measured plasma cholesterol efflux potential in subjects with similar apoAI but different NT-apoAI levels. RESULTS We found that median NT-apoAI/apoAI ratio was significantly higher in diabetes mellitus (DM) (n = 327) versus non-diabetic patients (n = 450). Further analysis indicated that DM, thiobarbituric acid-reactive substances and C-reactive protein levels were independent predictors of higher NT-apoAI/apoAI ratio. There was negative correlation between NT-apoAI/apoAI and use of anti-platelet and lipid lowering drugs. The cholesterol efflux capacity of plasma from 67 individuals with differing NT-apoAI but similar apoAI levels from macrophages in vitro was negatively correlated with NT-apoAI/apoAI ratio. CONCLUSIONS Higher NT-apoAI/apoAI ratio is significantly associated with DM in this relatively large German cohort with CAD and may contribute to associated complications by reducing cholesterol efflux capacity.
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Affiliation(s)
- Xueying Chen
- Department of Cell Biology, SUNY Downstate Medical Center, Brooklyn, NY, USA; Institute of Cardiology, Zhongshan Hospital, Fudan University, Shanghai, PR China
| | - Ahmed Bakillah
- Department of Cell Biology, SUNY Downstate Medical Center, Brooklyn, NY, USA
| | - Liye Zhou
- Department of Cell Biology, SUNY Downstate Medical Center, Brooklyn, NY, USA
| | - Xiaoyue Pan
- Department of Cell Biology, SUNY Downstate Medical Center, Brooklyn, NY, USA
| | | | - Marrit Jacob
- Department of Medicine III, University Clinic Halle, Germany
| | - Xian-Cheng Jiang
- Department of Cell Biology, SUNY Downstate Medical Center, Brooklyn, NY, USA; VA New York Harbor Healthcare System, Brooklyn, NY 11209, USA
| | - Jason Lazar
- Division of Cardiovascular Medicine, SUNY Downstate Medical Center, Brooklyn, NY, USA
| | - Axel Schlitt
- Department of Medicine III, University Clinic Halle, Germany; Paracelsus-Harz-Clinic Bad Suderode, Quedlinburg, Germany
| | - M Mahmood Hussain
- Department of Cell Biology, SUNY Downstate Medical Center, Brooklyn, NY, USA; VA New York Harbor Healthcare System, Brooklyn, NY 11209, USA; Department of Pediatrics, SUNY Downstate Medical Center, Brooklyn, NY, USA.
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24
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Shen J, Bi YL, Das UN. Potential role of polyunsaturated fatty acids in diabetic retinopathy. Arch Med Sci 2014; 10:1167-74. [PMID: 25624855 PMCID: PMC4296072 DOI: 10.5114/aoms.2014.47826] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/28/2014] [Revised: 03/05/2014] [Accepted: 03/12/2014] [Indexed: 12/17/2022] Open
Abstract
Diabetic retinopathy (DR) is a serious complication of long-standing diabetes mellitus. It affects about 25% of all patients with diabetes mellitus and causes a significant decrease in the quality of life. Despite many years of research, the exact pathway that leads to the development and progression of DR is not clear. Recent studies suggest that polyunsaturated fatty acids (PUFAs) and their metabolites could play a significant role in DR. There is evidence to suggest that an imbalance between pro- and anti-inflammatory eicosanoids and enhanced production of pro-angiogenic factors may initiate the onset and progression of DR. This implies that PUFAs and their metabolites that possess anti-inflammatory actions and suppress the production of angiogenic factors could be employed in the prevention and management of DR.
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Affiliation(s)
- Junhui Shen
- Department of Ophthalmology, Tongji Hospital Affiliated to Tongji University School of Medicine, Shanghai, China
| | - Yan-Long Bi
- Department of Ophthalmology, Tongji Hospital Affiliated to Tongji University School of Medicine, Shanghai, China
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