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Zuo Z, Li N, Zhang Q, Liu Q, Qin H, Yao K. The Role of Non-coding RNAs in Diabetic Retinopathy: Mechanistic Insights and Therapeutic Potential. Mol Neurobiol 2025:10.1007/s12035-025-04863-z. [PMID: 40164888 DOI: 10.1007/s12035-025-04863-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2024] [Accepted: 03/17/2025] [Indexed: 04/02/2025]
Abstract
Diabetic retinopathy (DR) is the most common ocular complication in diabetic patients, accounting for a significant proportion of diabetes-related eye diseases. Approximately one-third of diabetic patients worldwide are affected by DR. Microvascular diseases, which can lead to severe visual impairment or even blindness, pose a significant threat to the quality of life and visual function of patients. However, the underlying cellular mechanisms of DR remain unclear. Recent studies have discovered that, apart from traditional pathological mechanisms, epigenetic mechanisms may alter key biological processes through gene expression dysregulation, thereby promoting the onset and progression of DR. Non-coding RNAs (ncRNAs), including microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs), play crucial roles in gene regulation and disease pathways. Taking this into account, exploring innovative therapies and developing effective management strategies is crucial. This review focuses on the latest research on ncRNAs in DR, emphasizing their regulatory functions in cell proliferation, apoptosis, and inflammatory responses, and discusses the potential mechanisms by which ncRNAs accelerate disease progression. Additionally, the article highlights the potential role of exosome-associated ncRNAs in DR, proposing their use as early diagnostic markers and targeted therapeutic tools. By integrating current research, this review aims to provide guidance for future studies and promote the advancement of precision diagnostics and therapeutic efficacy in DR.
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Affiliation(s)
- Zhuan Zuo
- Institute of Visual Neuroscience and Stem Cell Engineering, Wuhan University of Science and Technology, Wuhan, 430065, China
- College of Life Sciences and Health, Wuhan University of Science and Technology, Wuhan, 430065, China
| | - Ni Li
- Institute of Visual Neuroscience and Stem Cell Engineering, Wuhan University of Science and Technology, Wuhan, 430065, China
- College of Life Sciences and Health, Wuhan University of Science and Technology, Wuhan, 430065, China
| | - Qian Zhang
- Institute of Visual Neuroscience and Stem Cell Engineering, Wuhan University of Science and Technology, Wuhan, 430065, China
- College of Life Sciences and Health, Wuhan University of Science and Technology, Wuhan, 430065, China
| | - Qin Liu
- Institute of Visual Neuroscience and Stem Cell Engineering, Wuhan University of Science and Technology, Wuhan, 430065, China
- College of Life Sciences and Health, Wuhan University of Science and Technology, Wuhan, 430065, China
| | - Huan Qin
- Institute of Visual Neuroscience and Stem Cell Engineering, Wuhan University of Science and Technology, Wuhan, 430065, China.
- College of Life Sciences and Health, Wuhan University of Science and Technology, Wuhan, 430065, China.
| | - Kai Yao
- Institute of Visual Neuroscience and Stem Cell Engineering, Wuhan University of Science and Technology, Wuhan, 430065, China.
- College of Life Sciences and Health, Wuhan University of Science and Technology, Wuhan, 430065, China.
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Liu J, Zhang F, Shi X. The role of metal nanocarriers, liposomes and chitosan-based nanoparticles in diabetic retinopathy treatment: A review study. Int J Biol Macromol 2025; 291:139017. [PMID: 39708854 DOI: 10.1016/j.ijbiomac.2024.139017] [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: 10/04/2024] [Revised: 12/04/2024] [Accepted: 12/18/2024] [Indexed: 12/23/2024]
Abstract
Diabetic Retinopathy (DR) is a significant and progressive eye complication associated with diabetes mellitus, leading to potential vision loss. The pathophysiology of DR involves complex neurovascular changes due to prolonged hyperglycemia, resulting in microangiopathy and neurodegeneration. Current treatment modalities come with limitations such as low bioavailability of therapeutic agents, risk of side effects, and surgical complications. Consequently, the prevention and management of DR, particularly in its advanced stages, present ongoing challenges. This review investigates recent advancements in nanotechnology as a novel approach to enhance the treatment of DR. A comprehensive literature review of recent studies focusing on nanocarriers for drug delivery in DR treatment and an analysis of their efficacy compared to traditional methods was conducted for this study. The findings indicate that nanotechnology can significantly enhance the bioavailability of therapeutic agents while minimizing systemic exposure and associated side effects. The novelty of this study lies in its focus on the intersection of nanotechnology and ophthalmology, exploring innovative solutions that extend beyond existing literature on DR treatments. By highlighting recent advancements in this field, the study paves the way for future research aimed at developing more effective therapeutic strategies for managing DR.
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Affiliation(s)
- Junling Liu
- Linqu Zhengda Guangming Eye Hospital, Zhengda Guangming Eye Group, Weifang 262600, Shandong, China
| | - Feng Zhang
- Linqu Zhengda Guangming Eye Hospital, Zhengda Guangming Eye Group, Weifang 262600, Shandong, China.
| | - Xiaolong Shi
- Linqu Zhengda Guangming Eye Hospital, Zhengda Guangming Eye Group, Weifang 262600, Shandong, China
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Zhang Y, Qian B, Yang Y, Niu F, Lin C, Yuan H, Wang J, Wu T, Shao Y, Shao S, Liu A, Wu J, Sun P, Chang X, Bi Y, Tang W, Zhu Y, Chen F, Su D, Han X. Visceral Adipocyte-Derived Extracellular Vesicle miR-27a-5p Elicits Glucose Intolerance by Inhibiting Pancreatic β-Cell Insulin Secretion. Diabetes 2024; 73:1832-1847. [PMID: 39186314 PMCID: PMC11493764 DOI: 10.2337/db24-0177] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/03/2024] [Accepted: 08/09/2024] [Indexed: 08/27/2024]
Abstract
Pancreatic β-cell dysfunction caused by obesity can be associated with alterations in the levels of miRNAs. However, the role of miRNAs in such processes remains elusive. Here, we show that pancreatic islet miR-27a-5p, which is markedly increased in obese mice and impairs insulin secretion, is mainly delivered by visceral adipocyte-derived extracellular vesicles (EVs). Depleting miR-27a-5p significantly improved insulin secretion and glucose intolerance in db/db mice. Supporting the function of EV miR-27a-5p as a key pathogenic factor, intravenous injection of miR-27a-5p-containing EVs showed their distribution in mouse pancreatic islets. Tracing the injected adeno-associated virus (AAV)-miR-27a-5p (AAV-miR-27a) or AAV-FABP4-miR-27a-5p (AAV-FABP4-miR-27a) in visceral fat resulted in upregulating miR-27a-5p in EVs and serum and elicited mouse pancreatic β-cell dysfunction. Mechanistically, miR-27a-5p directly targeted L-type Ca2+ channel subtype CaV1.2 (Cacna1c) and reduced insulin secretion in β-cells. Overexpressing mouse CaV1.2 largely abolished the insulin secretion injury induced by miR-27a-5p. These findings reveal a causative role of EV miR-27a-5p in visceral adipocyte-mediated pancreatic β-cell dysfunction in obesity-associated type 2 diabetes mellitus. ARTICLE HIGHLIGHTS
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Affiliation(s)
- Yaqin Zhang
- Key Laboratory of Human Functional Genomics of Jiangsu Province, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Bin Qian
- Key Laboratory of Human Functional Genomics of Jiangsu Province, Nanjing Medical University, Nanjing, Jiangsu, China
- School of Life Science and Technology, China Pharmaceutical University, Nanjing, Jiangsu, China
| | - Yang Yang
- Key Laboratory of Human Functional Genomics of Jiangsu Province, Nanjing Medical University, Nanjing, Jiangsu, China
- Key Laboratory for Regenerative Medicine of Ministry of Education, Institute of Hematology, School of Medicine, Jinan University, Guangzhou, Guangdong, China
| | - Fandi Niu
- Key Laboratory of Human Functional Genomics of Jiangsu Province, Nanjing Medical University, Nanjing, Jiangsu, China
- Department of Cardiology, Xijing Hospital, Air Force Military Medical University, Xi’an, Shanxi, China
| | - Changsong Lin
- Department of Bioinformatics, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Honglei Yuan
- Key Laboratory of Human Functional Genomics of Jiangsu Province, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Jianan Wang
- Key Laboratory of Human Functional Genomics of Jiangsu Province, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Tijun Wu
- Key Laboratory of Human Functional Genomics of Jiangsu Province, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Yixue Shao
- Key Laboratory of Human Functional Genomics of Jiangsu Province, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Shulin Shao
- Department of Laboratory, Nanjing Pukou Hospital of Traditional Chinese Medicine, Nanjing, Jiangsu, China
| | - Aiming Liu
- The First Clinical School of Nanjing Medical University, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Jingwen Wu
- The First Clinical School of Nanjing Medical University, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Peng Sun
- Key Laboratory of Human Functional Genomics of Jiangsu Province, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Xiaoai Chang
- Key Laboratory of Human Functional Genomics of Jiangsu Province, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Yan Bi
- Department of Endocrinology, Drum Tower Hospital affiliated to Nanjing University Medical School, Branch of National Clinical Research Centre for Metabolic Diseases, Nanjing, Jiangsu, China
| | - Wei Tang
- Department of Endocrinology, Islet Cell Senescence and Function Research Laboratory, Jiangsu Province Geriatric Institute, Nanjing, Jiangsu, China
| | - Yunxia Zhu
- Key Laboratory of Human Functional Genomics of Jiangsu Province, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Fang Chen
- Key Laboratory of Human Functional Genomics of Jiangsu Province, Nanjing Medical University, Nanjing, Jiangsu, China
- Department of Cardiovascular Surgery, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
| | - Dongming Su
- Department of Pathology, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Xiao Han
- Key Laboratory of Human Functional Genomics of Jiangsu Province, Nanjing Medical University, Nanjing, Jiangsu, China
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Gao J, Wang C, Zhang J, Shawuti Z, Wang S, Ma C, Wang J. CircZNF609 inhibits miR-150-5p to promote high glucose-induced damage to retinal microvascular endothelial cells. Mol Cell Endocrinol 2024; 590:112261. [PMID: 38679361 DOI: 10.1016/j.mce.2024.112261] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/24/2023] [Revised: 04/18/2024] [Accepted: 04/25/2024] [Indexed: 05/01/2024]
Abstract
Hyperglycemia is a key contributor to diabetic macrovascular and ocular complications. It triggers a cascade of cellular damage, particularly in the retinal microvascular endothelial cells (RMECs). However, the underlying molecular mechanisms remain only partially understood. This study hypothesizes that CircZNF609 plays a pivotal role in mediating high glucose-induced damage in RMECs by modulating miR-150-5p and its downstream target genes, thereby affecting cellular survival, apoptosis, and oxidative stress. Gene expression datasets (GSE193974 and GSE160308) and clinical samples were used to investigate the expression levels of CircZNF609 and its interaction with miR-150-5p in the context of diabetic retinopathy (DR). Our results demonstrate that CircZNF609 is upregulated in both peripheral blood stem cells from DR patients and high glucose-stimulated hRMECs. Functional experiments reveal that silencing CircZNF609 improves cell viability, reduces apoptosis, inhibits tube formation, and modulates oxidative stress markers, whereas CircZNF609 overexpression exacerbates these effects. Moreover, miR-150-5p, a microRNA, was found to be negatively regulated by CircZNF609 and downregulated in DR. Its overexpression mitigates high glucose-induced cell injury. Our findings suggest a novel mechanism whereby CircZNF609 exacerbates high glucose-induced endothelial cell damage by sponging miR-150-5p, implicating the CircZNF609/miR-150-5p axis as a potential therapeutic target in diabetic retinopathy.
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Affiliation(s)
- Jing Gao
- Department of Endocrinology, Fifth Affiliated Hospital of Xinjiang Medical University, State Key Laboratory of Pathogenesis, Prevention and Treatment of High Incidence Diseases in Central Asia, Xinjiang Medical University, Urumqi 830054, China
| | - Chenfei Wang
- Department of Endocrinology, Fifth Affiliated Hospital of Xinjiang Medical University, State Key Laboratory of Pathogenesis, Prevention and Treatment of High Incidence Diseases in Central Asia, Xinjiang Medical University, Urumqi 830054, China
| | - Jie Zhang
- Department of Endocrinology, Fifth Affiliated Hospital of Xinjiang Medical University, Urumqi 830011, China
| | - Zulifeiya Shawuti
- Department of Endocrinology, Fifth Affiliated Hospital of Xinjiang Medical University, Urumqi 830011, China
| | - Siyao Wang
- Department of Endocrinology, Fifth Affiliated Hospital of Xinjiang Medical University, Urumqi 830011, China
| | - Cunhua Ma
- Department of Endocrinology, Fifth Affiliated Hospital of Xinjiang Medical University, Urumqi 830011, China
| | - Juan Wang
- Department of Cardiology, Fifth Affiliated Hospital of Xinjiang Medical University, Urumqi 830011, China.
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Nayak SS, Kuriyakose D, Polisetty LD, Patil AA, Ameen D, Bonu R, Shetty SP, Biswas P, Ulrich MT, Letafatkar N, Habibi A, Keivanlou MH, Nobakht S, Alotaibi A, Hassanipour S, Amini-Salehi E. Diagnostic and prognostic value of triglyceride glucose index: a comprehensive evaluation of meta-analysis. Cardiovasc Diabetol 2024; 23:310. [PMID: 39180024 PMCID: PMC11344391 DOI: 10.1186/s12933-024-02392-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/11/2024] [Accepted: 08/05/2024] [Indexed: 08/26/2024] Open
Abstract
OBJECTIVE The present umbrella review aims to collate and summarize the findings from previous meta-analyses on the Triglyceride and Glucose (TyG) Index, providing insights to clinicians, researchers, and policymakers regarding the usefulness of this biomarker in various clinical settings. METHODS A comprehensive search was conducted in PubMed, Scopus, and Web of Science up to April 14, 2024, without language restrictions. The AMSTAR2 checklist assessed the methodological quality of the included meta-analyses. Statistical analyses were performed using Comprehensive Meta-Analysis (CMA) software. RESULTS A total of 32 studies were finally included. The results revealed significant associations between the TyG index and various health outcomes. For kidney outcomes, a high TyG index was significantly associated with an increased risk of contrast-induced nephropathy (CIN) (OR = 2.24, 95% CI: 1.82-2.77) and chronic kidney disease (CKD) (RR = 1.46, 95% CI: 1.32-1.63). High TyG index was significantly associated with an increased risk of type 2 diabetes mellitus (T2DM) (RR = 3.53, 95% CI: 2.74-4.54), gestational diabetes mellitus (GDM) (OR = 2.41, 95% CI: 1.48-3.91), and diabetic retinopathy (DR) (OR = 2.34, 95% CI: 1.31-4.19). Regarding metabolic diseases, the TyG index was significantly higher in patients with obstructive sleep apnea (OSA) (SMD = 0.86, 95% CI: 0.57-1.15), metabolic syndrome (MD = 0.83, 95% CI: 0.74-0.93), and non-alcoholic fatty liver disease (NAFLD) (OR = 2.36, 95% CI: 1.88-2.97) compared to those without these conditions. In cerebrovascular diseases, a higher TyG index was significantly associated with an increased risk of dementia (OR = 1.14, 95% CI: 1.12-1.16), cognitive impairment (OR = 2.31, 95% CI: 1.38-3.86), and ischemic stroke (OR = 1.37, 95% CI: 1.22-1.54). For cardiovascular outcomes, the TyG index showed significant associations with an increased risk of heart failure (HF) (HR = 1.21, 95% CI: 1.12-1.30), atrial fibrillation (AF) (SMD = 1.22, 95% CI: 0.57-1.87), and hypertension (HTN) (RR = 1.52, 95% CI: 1.25-1.85). CONCLUSION The TyG index is a promising biomarker for screening and predicting various medical conditions, particularly those related to insulin resistance and metabolic disorders. However, the heterogeneity and methodological quality of the included studies suggest the need for further high-quality research to confirm these findings and refine the clinical utility of the TyG index.
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Affiliation(s)
- Sandeep Samethadka Nayak
- Division of Hospital Medicine, Department of Internal Medicine, Bridgeport Hospital, Yale New Heaven, Bridgeport, CT, USA
| | - Dona Kuriyakose
- St. Joseph's Mission Hospital, Kollam District, Anchal, Kerala, India
| | - Lakshmi D Polisetty
- Division of Hospital Medicine, Department of Internal Medicine, Bridgeport Hospital, Yale New Heaven, Bridgeport, CT, USA
- Division of Pulmonary, Critical Care and Sleep Medicine, Department of Internal Medicine, John Dempsey Hospital, University of Connecticut, Bridgeport, CT, USA
| | - Anjali Avinash Patil
- Rajarshee Chhatrapati Shahu Maharaj Government Medical College Kolhapur Shenda park, Kolhapur, Maharashtra, India
| | - Daniyal Ameen
- Division of Hospital Medicine, Department of Internal Medicine, Bridgeport Hospital, Yale New Heaven, Bridgeport, CT, USA
| | - Rakshita Bonu
- Vydehi Institute of Medical Sciences and Research Centre, Bengaluru. 82, Nallurahalli Main Road, Whitefield, Bengaluru, Karnataka, India
| | - Samatha P Shetty
- Director of Capacity Management, NYC Health Hospitals, Elmhurst, USA
| | - Pubali Biswas
- Vydehi Institute of Medical Sciences and Research Centre, Bengaluru. 82, Nallurahalli Main Road, Whitefield, Bengaluru, Karnataka, India
| | - Micheal T Ulrich
- Riverside University Health System Medical Center, Moreno Valley, CA, USA
| | | | - Arman Habibi
- Guilan University of Medical Sciences, Rasht, Iran
| | | | - Sara Nobakht
- Guilan University of Medical Sciences, Rasht, Iran
| | | | - Soheil Hassanipour
- Gastrointestinal and Liver Diseases Research Center, Guilan University of Medical Sciences, P.O. Box: 41448-95655, Rasht, Iran
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Lazzara F, Conti F, Sasmal PK, Alikunju S, Rossi S, Drago F, Platania CBM, Bucolo C. Anti-angiogenic and antioxidant effects of axitinib in human retinal endothelial cells: implications in diabetic retinopathy. Front Pharmacol 2024; 15:1415846. [PMID: 38953109 PMCID: PMC11215076 DOI: 10.3389/fphar.2024.1415846] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2024] [Accepted: 05/17/2024] [Indexed: 07/03/2024] Open
Abstract
Diabetic retinopathy is a secondary microvascular complication of diabetes mellitus. This disease progresses from two stages, non-proliferative and proliferative diabetic retinopathy, the latter characterized by retinal abnormal angiogenesis. Pharmacological management of retinal angiogenesis employs expensive and invasive intravitreal injections of biologic drugs (anti-vascular endothelial growth factor agents). To search small molecules able to act as anti-angiogenic agents, we focused our study on axitinib, which is a tyrosine kinase inhibitor and represents the second line treatment for renal cell carcinoma. Axitinib is an inhibitor of vascular endothelial growth factor receptors, and among the others tyrosine kinase inhibitors (sunitinib and sorafenib) is the most selective towards vascular endothelial growth factor receptors 1 and 2. Besides the well-known anti-angiogenic and immune-modulatory functions, we hereby explored the polypharmacological profile of axitinib, through a bioinformatic/molecular modeling approach and in vitro models of diabetic retinopathy. We showed the anti-angiogenic activity of axitinib in two different in vitro models of diabetic retinopathy, by challenging retinal endothelial cells with high glucose concentration (fluctuating and non-fluctuating). We found that axitinib, along with inhibition of vascular endothelial growth factor receptors 1 (1.82 ± 0.10; 0.54 ± 0.13, phosphorylated protein levels in fluctuating high glucose vs . axitinib 1 µM, respectively) and vascular endothelial growth factor receptors 2 (2.38 ± 0.21; 0.98 ± 0.20, phosphorylated protein levels in fluctuating high glucose vs . axitinib 1 µM, respectively), was able to significantly reduce (p < 0.05) the expression of Nrf2 (1.43 ± 0.04; 0.85 ± 0.01, protein levels in fluctuating high glucose vs . axitinib 1 µM, respectively) in retinal endothelial cells exposed to high glucose, through predicted Keap1 interaction and activation of melanocortin receptor 1. Furthermore, axitinib treatment significantly (p < 0.05) decreased reactive oxygen species production (0.90 ± 0.10; 0.44 ± 0.06, fluorescence units in high glucose vs . axitinib 1 µM, respectively) and inhibited ERK pathway (1.64 ± 0.09; 0.73 ± 0.06, phosphorylated protein levels in fluctuating high glucose vs . axitinib 1 µM, respectively) in HRECs exposed to high glucose. The obtained results about the emerging polypharmacological profile support the hypothesis that axitinib could be a valid candidate to handle diabetic retinopathy, with ancillary mechanisms of action.
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Affiliation(s)
- Francesca Lazzara
- Department of Biomedical and Biotechnological Sciences, School of Medicine, University of Catania, Catania, Italy
| | - Federica Conti
- Department of Biomedical and Biotechnological Sciences, School of Medicine, University of Catania, Catania, Italy
| | | | | | - Settimio Rossi
- Eye Clinic, Multidisciplinary Department of Medical, Surgical and Dental Sciences, University of Campania “Luigi Vanvitelli”, Napoli, Italy
| | - Filippo Drago
- Department of Biomedical and Biotechnological Sciences, School of Medicine, University of Catania, Catania, Italy
- Center for Research in Ocular Pharmacology-CERFO, University of Catania, Catania, Italy
| | - Chiara Bianca Maria Platania
- Department of Biomedical and Biotechnological Sciences, School of Medicine, University of Catania, Catania, Italy
- Center for Research in Ocular Pharmacology-CERFO, University of Catania, Catania, Italy
| | - Claudio Bucolo
- Department of Biomedical and Biotechnological Sciences, School of Medicine, University of Catania, Catania, Italy
- Center for Research in Ocular Pharmacology-CERFO, University of Catania, Catania, Italy
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Li C, Fu J, Ye Y, Li J, He Y, Fang T. The impact of vitamin D on the etiopathogenesis and the progression of type 1 and type 2 diabetes in children and adults. Front Endocrinol (Lausanne) 2024; 15:1360525. [PMID: 38650715 PMCID: PMC11033370 DOI: 10.3389/fendo.2024.1360525] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/23/2023] [Accepted: 03/25/2024] [Indexed: 04/25/2024] Open
Abstract
Diabetes is a common chronic metabolic disease with complex causes and pathogenesis. As an immunomodulator, vitamin D has recently become a research hotspot in the occurrence and development of diabetes and its complications. Many studies have shown that vitamin D can reduce the occurrence of diabetes and delay the progression of diabetes complications, and vitamin D can reduce oxidative stress, inhibit iron apoptosis, promote Ca2+ influx, promote insulin secretion, and reduce insulin resistance. Therefore, the prevention and correction of vitamin D deficiency is very necessary for diabetic patients, but further research is needed to confirm what serum levels of vitamin D3 are maintained in the body. This article provides a brief review of the relationship between vitamin D and diabetes, including its acute and chronic complications.
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Affiliation(s)
- Candong Li
- Department of Endocrine, Hainan General Hospital, Hainan Affiliated Hospital of Hainan Medical University, Haikou, Hainan, China
| | - Jiaowen Fu
- Department of Endocrine, Hainan General Hospital, Hainan Affiliated Hospital of Hainan Medical University, Haikou, Hainan, China
| | - Yipeng Ye
- Department of Endocrine, Hainan General Hospital, Hainan Affiliated Hospital of Hainan Medical University, Haikou, Hainan, China
| | - Junsen Li
- Department of Endocrine, Hainan General Hospital, Hainan Affiliated Hospital of Hainan Medical University, Haikou, Hainan, China
| | - Yangli He
- Department of Health Care Centre, Hainan General Hospital, Hainan Affiliated Hospital of Hainan Medical University, Haikou, China
| | - Tuanyu Fang
- Department of Endocrine, Hainan General Hospital, Hainan Affiliated Hospital of Hainan Medical University, Haikou, Hainan, China
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Yu HS, Hong EH, Kang JH, Lee YW, Lee WJ, Kang MH, Cho H, Shin YU, Seong M. Expression of microRNAs related to apoptosis in the aqueous humor and lens capsule of patients with glaucoma. Front Med (Lausanne) 2024; 11:1288854. [PMID: 38449883 PMCID: PMC10917207 DOI: 10.3389/fmed.2024.1288854] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2023] [Accepted: 01/25/2024] [Indexed: 03/08/2024] Open
Abstract
Background The aim of this study is to investigate the expression profiles of microRNAs (miRNAs) related to apoptosis in the aqueous humor (AH) and lens capsule (LC) of patients with glaucoma. Methods AH and LC samples were collected from patients with open-angle glaucoma and control participants who were scheduled for cataract surgery. A miRNA PCR array comprising 84 miRNAs was used to analyze the AH (glaucoma, n = 3; control, n = 3) and LC samples (glaucoma, n = 3; control, n = 4). Additionally, the AH and LC samples (glaucoma, n = 3; control, n = 4) were subjected to quantitative real-time PCR to validate the differentially expressed miRNAs determined using the PCR array. Bioinformatics analysis was performed to identify the interactions between miRNAs and diseases. Additionally, the differential expression of these miRNAs and the target gene was validated through in vitro experiments using a retinal ganglion cell (RGC) model. Results Expression levels of 19 and 3 miRNAs were significantly upregulated in the AH and LC samples of the glaucoma group, respectively (p < 0.05). Of these, the expression levels of hsa-miR-193a-5p and hsa-miR-222-3p showed significant differences in both AH and LC samples. Bioinformatics analysis showed experimentally validated 8 miRNA:gene pairs. Among them, PTEN was selected to analyze the expression level in AH and LC from separate cohort (glaucoma, n = 5; control, n = 4). The result showed downregulation of PTEN concurrent with upregulation of the two miRNAs in LC samples of glaucoma group. In vitro experiments validated that the expression levels of hsa-miR-193a-5p and hsa-miR-222-3p were significantly upregulated, and that of PTEN was significantly downregulated in the H2O2-treated RGC, while the level of PTEN was recovered through co-treatment with miR-193a inhibitor or miR-222 inhibitor. Conclusion This is the first study to investigate the differential expression of apoptosis-related miRNAs in the AH and LC of patients with glaucoma. Hsa-miR-193a-5p and hsa-miR-222-3p, which were upregulated in both AH and LC, may be considered potential biomarkers for glaucoma.
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Affiliation(s)
- Hyo Seon Yu
- Department of Ophthalmology, Hanyang University College of Medicine, Seoul, Republic of Korea
| | - Eun Hee Hong
- Department of Ophthalmology, Hanyang University College of Medicine, Seoul, Republic of Korea
- Department of Ophthalmology, Hanyang University Guri Hospital, Guri, Gyeonggi-do, Republic of Korea
- Hanyang Institute of Bioscience and Biotechnology, Hanyang University, Seoul, Republic of Korea
| | - Ji Hye Kang
- Department of Ophthalmology, Hanyang University College of Medicine, Seoul, Republic of Korea
- Graduate School of Biomedical Science & Engineering, Hanyang University, Seoul, Republic of Korea
| | - Yong Woo Lee
- Department of Ophthalmology, Kangwon National University Graduate School of Medicine, Kangwon National University Hospital, Chuncheon, Republic of Korea
| | - Won June Lee
- Department of Ophthalmology, Hanyang University College of Medicine, Seoul, Republic of Korea
- Hanyang Institute of Bioscience and Biotechnology, Hanyang University, Seoul, Republic of Korea
- Department of Ophthalmology, Hanyang University Hospital, Hanyang University College of Medicine, Seoul, Republic of Korea
| | - Min Ho Kang
- Department of Ophthalmology, Hanyang University College of Medicine, Seoul, Republic of Korea
- Department of Ophthalmology, Hanyang University Guri Hospital, Guri, Gyeonggi-do, Republic of Korea
| | - Heeyoon Cho
- Department of Ophthalmology, Hanyang University College of Medicine, Seoul, Republic of Korea
- Department of Ophthalmology, Hanyang University Guri Hospital, Guri, Gyeonggi-do, Republic of Korea
- NOON Eye Clinic, Guri, Gyeonggi-do, Republic of Korea
| | - Yong Un Shin
- Department of Ophthalmology, Hanyang University College of Medicine, Seoul, Republic of Korea
- Department of Ophthalmology, Hanyang University Guri Hospital, Guri, Gyeonggi-do, Republic of Korea
- Hanyang Institute of Bioscience and Biotechnology, Hanyang University, Seoul, Republic of Korea
| | - Mincheol Seong
- Department of Ophthalmology, Hanyang University College of Medicine, Seoul, Republic of Korea
- Department of Ophthalmology, Hanyang University Guri Hospital, Guri, Gyeonggi-do, Republic of Korea
- NOON Eye Clinic, Guri, Gyeonggi-do, Republic of Korea
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Luo Y, Li C. Advances in Research Related to MicroRNA for Diabetic Retinopathy. J Diabetes Res 2024; 2024:8520489. [PMID: 38375094 PMCID: PMC10876316 DOI: 10.1155/2024/8520489] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/31/2023] [Revised: 08/21/2023] [Accepted: 01/27/2024] [Indexed: 02/21/2024] Open
Abstract
Diabetic retinopathy (DR) is a severe microvascular complication of diabetes and is one of the primary causes of blindness in the working-age population in Europe and the United States. At present, no cure is available for DR, but early detection and timely intervention can prevent the rapid progression of the disease. Several treatments for DR are known, primarily ophthalmic treatment based on glycemia, blood pressure, and lipid control, which includes laser photocoagulation, glucocorticoids, vitrectomy, and antivascular endothelial growth factor (anti-VEGF) medications. Despite the clinical efficacy of the aforementioned therapies, none of them can entirely shorten the clinical course of DR or reverse retinopathy. MicroRNAs (miRNAs) are vital regulators of gene expression and participate in cell growth, differentiation, development, and apoptosis. MicroRNAs have been shown to play a significant role in DR, particularly in the molecular mechanisms of inflammation, oxidative stress, and neurodegeneration. The aim of this review is to systematically summarize the signaling pathways and molecular mechanisms of miRNAs involved in the occurrence and development of DR, mainly from the pathogenesis of oxidative stress, inflammation, and neovascularization. Meanwhile, this article also discusses the research progress and application of miRNA-specific therapies for DR.
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Affiliation(s)
- Yahan Luo
- Shanghai TCM-Integrated Hospital, Shanghai University of TCM, Shanghai, China
- Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Chunxia Li
- Shanghai TCM-Integrated Hospital, Shanghai University of TCM, Shanghai, China
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10
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Zhou J, Zhu L, Li Y. Association between the triglyceride glucose index and diabetic retinopathy in type 2 diabetes: a meta-analysis. Front Endocrinol (Lausanne) 2023; 14:1302127. [PMID: 38130393 PMCID: PMC10733479 DOI: 10.3389/fendo.2023.1302127] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/26/2023] [Accepted: 10/25/2023] [Indexed: 12/23/2023] Open
Abstract
The triglyceride-glucose (TyG) index is an accessible and reliable surrogate indicator of insulin resistance and is strongly associated with diabetes. However, its relationship with diabetic retinopathy (DR) remains controversial. This meta-analysis aimed to assess the relationship between the TyG index and the prevalence of DR. Initial studies were searched from PubMed, Embase, Web of Science, and China National Knowledge Infrastructure (CNKI) electronic databases. The retrieval time range was from the establishment of the database to June 2023. Pooled estimates were derived using a random-effects model and reported as odds ratio (OR) with 95% confidence intervals (CIs). Two researchers independently assessed the methodological quality of the included studies. The Newcastle-Ottawa Quality Scale (NOS) was utilized to assess cohort studies or case-control studies. The Agency for Healthcare Research and Quality (AHRQ) methodology checklist was applied to assess cross-sectional studies. Ten observational studies encompassing 13716 patients with type 2 diabetes were included in the meta-analysis. The results showed that a higher TyG index increased the risk of DR compared with a low TyG index (OR: 2.34, 95% CI: 1.31-4.19, P < 0.05). When the index was analyzed as a continuous variable, consistent results were observed (OR: 1.48, 95% CI: 1.12-1.97, P < 0.005). There was no significant effect on the results of the sensitivity analyses excluding one study at a time (P all < 0.05). A higher TyG index may be associated with an increased prevalence of DR in patients with type 2 diabetes. However, high-quality cohort or case-control studies are needed to further substantiate this evidence. Systematic review registration https://www.crd.york.ac.uk/PROSPERO/, identifier CRD42023432747.
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Affiliation(s)
- Jianlong Zhou
- Department of Traditional Chinese Medicine, People’s Hospital of Deyang City, Deyang, China
| | - Lv Zhu
- Department of Integrative Medicine, West China Hospital, Sichuan University, Chengdu, China
| | - Yadi Li
- Department of Traditional Chinese Medicine, People’s Hospital of Deyang City, Deyang, China
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11
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Mohammad HMF, Eladl MA, Abdelmaogood AKK, Elshaer RE, Ghanam W, Elaskary A, Saleh MAK, Eltrawy AH, Ali SK, Moursi SMM, Bilasy SE, Zaitone SA, Alzlaiq WA, Atteya H. Protective Effect of Topiramate against Diabetic Retinopathy and Computational Approach Recognizing the Role of NLRP3/IL-1β/TNF-α Signaling. Biomedicines 2023; 11:3202. [PMID: 38137423 PMCID: PMC10741203 DOI: 10.3390/biomedicines11123202] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2023] [Revised: 10/27/2023] [Accepted: 11/07/2023] [Indexed: 12/24/2023] Open
Abstract
The possible impact of topiramate against diabetic retinopathy (DREN) and its molecular mechanisms in relation to the nod-like receptor family pyrin domain containing 3 (NLRP3) inflammasome has not been studied before. Thus, in the present study, we aimed to utilize a computational approach to investigate the possible protective effect of topiramate on experimental DREN and explore its impact on NLRP3/interlukin-1β signaling and brain-derived neurotrophic factor (BDNF) expression. Male albino mice were distributed to four experimental groups and assigned the following categorizations: (i) saline, (ii) diabetic, (iii) diabetic + topiramate 10 mg/kg and (iv) diabetic + topiramate 30 mg/kg. We observed shrinkage of total retinal thickness and elevation in retinal glutamate, malondialdehyde, NLRP3 and interlukin-1β but decreased glutathione (GSH) levels in the diabetic mice. Additionally, retinal ultra-structures in the diabetic group showed abnormalities and vacuolations in the pigmented epithelium, the photoreceptor segment, the outer nuclear layer, the inner nuclear layer and the ganglion cell layer (GCL). Mice treated with topiramate 10 or 30 mg/kg showed downregulation in retinal malondialdehyde, NLRP3 and interlukin-1β levels; improvements in the retinal pathologies; enhanced immunostaining for BDNF and improved ultra-structures in different retinal layers. Overall, the current results suggest topiramate as a neuroprotective agent for DREN, and future studies are warranted to further elucidate the mechanism of its protective action.
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Affiliation(s)
- Hala M. F. Mohammad
- Department of Clinical Pharmacology, Faculty of Medicine, Suez Canal University, Ismailia 41522, Egypt
- Center of Excellence in Molecular and Cellular Medicine (CEMCM), Faculty of Medicine, Suez Canal University, Ismailia 41522, Egypt
| | - Mohamed Ahmed Eladl
- Department of Basic Medical Sciences, College of Medicine, University of Sharjah, Sharjah 27272, United Arab Emirates
| | - Asmaa K. K. Abdelmaogood
- Department of Clinical and Chemical Pathology, Faculty of Medicine, Suez Canal University, Ismailia 41522, Egypt
| | - Rabie E. Elshaer
- Pathology Department, Faculty of Medicine (Boys), Al-Azhar University, Cairo 11884, Egypt
| | - Walaa Ghanam
- Department of Pathology, Faculty of Medicine, Suez University, Suez 43533, Egypt
| | - Abdelhakeem Elaskary
- Ophthalmology Department, Al-Azher Asyut Faculty of Medicine for Men, Asyut 71524, Egypt (M.A.K.S.)
| | - Mohamed A. K. Saleh
- Ophthalmology Department, Al-Azher Asyut Faculty of Medicine for Men, Asyut 71524, Egypt (M.A.K.S.)
| | - Amira H. Eltrawy
- Department of Anatomy and Embryology, Faculty of Medicine, Alexandria University, Alexandria 21526, Egypt
- Department of Anatomy, Faculty of Medicine, University of Tabuk, Tabuk 71451, Saudi Arabia
| | - Sahar K. Ali
- Department of Clinical Pharmacology, Faculty of Medicine, Zagazig University, Zagazig 44519, Egypt
| | - Suzan M. M. Moursi
- Medical Physiology Department, Faculty of Medicine, Zagazig University, Zagazig 44519, Egypt
| | - Shymaa E. Bilasy
- College of Dental Medicine, California Northstate University, 9700 Taron Dr., Elk Grove, CA 95757, USA
- Department of Biochemistry, Faculty of Pharmacy, Suez Canal University, Ismailia 41522, Egypt
| | - Sawsan A. Zaitone
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, University of Tabuk, Tabuk 71451, Saudi Arabia
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Suez Canal University, Ismailia 41522, Egypt
| | - Wafa Ali Alzlaiq
- Department of Clinical Pharmacy, College of Pharmacy, Imam Abdulrahman Bin Faisal University, Dammam 31441, Saudi Arabia
| | - Hayam Atteya
- Department of Pharmacy Practice and Clinical Pharmacy, Faculty of Pharmacy, Future University in Egypt, Cairo 11835, Egypt
- Department of Medical Pharmacology, Faculty of Medicine, Cairo University, Giza 12613, Egypt
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12
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Rák T, Kovács-Valasek A, Pöstyéni E, Csutak A, Gábriel R. Complementary Approaches to Retinal Health Focusing on Diabetic Retinopathy. Cells 2023; 12:2699. [PMID: 38067127 PMCID: PMC10705724 DOI: 10.3390/cells12232699] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2023] [Revised: 11/20/2023] [Accepted: 11/20/2023] [Indexed: 12/18/2023] Open
Abstract
Diabetes mellitus affects carbohydrate homeostasis but also influences fat and protein metabolism. Due to ophthalmic complications, it is a leading cause of blindness worldwide. The molecular pathology reveals that nuclear factor kappa B (NFκB) has a central role in the progression of diabetic retinopathy, sharing this signaling pathway with another major retinal disorder, glaucoma. Therefore, new therapeutic approaches can be elaborated to decelerate the ever-emerging "epidemics" of diabetic retinopathy and glaucoma targeting this critical node. In our review, we emphasize the role of an improvement of lifestyle in its prevention as well as the use of phytomedicals associated with evidence-based protocols. A balanced personalized therapy requires an integrative approach to be more successful for prevention and early treatment.
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Affiliation(s)
- Tibor Rák
- Department of Ophthalmology, Clinical Centre, Medical School, University of Pécs, Rákóczi út 2., 7623 Pécs, Hungary; (T.R.)
| | - Andrea Kovács-Valasek
- Department of Neurobiology, University of Pécs, Ifjúság útja 6, 7624 Pécs, Hungary
- János Szentágothai Research Centre, University of Pécs, Ifjúság útja 20, 7624 Pécs, Hungary
| | - Etelka Pöstyéni
- Department of Neurobiology, University of Pécs, Ifjúság útja 6, 7624 Pécs, Hungary
| | - Adrienne Csutak
- Department of Ophthalmology, Clinical Centre, Medical School, University of Pécs, Rákóczi út 2., 7623 Pécs, Hungary; (T.R.)
| | - Róbert Gábriel
- Department of Neurobiology, University of Pécs, Ifjúság útja 6, 7624 Pécs, Hungary
- János Szentágothai Research Centre, University of Pécs, Ifjúság útja 20, 7624 Pécs, Hungary
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13
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Li P, Wang L, Liu Q, Du ZJ. Bioinformatics and in vitro study reveal the roles of microRNA-346 in high glucose-induced human retinal pigment epithelial cell damage. Int J Ophthalmol 2023; 16:1756-1765. [PMID: 38028527 PMCID: PMC10626347 DOI: 10.18240/ijo.2023.11.04] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2023] [Accepted: 07/05/2023] [Indexed: 12/01/2023] Open
Abstract
AIM To study microRNAs (miRNAs) and their potential effects in high glucose-induced human retinal pigment epithelial cell damage. METHODS We screened the GSE52233 miRNA expression dataset for differentially expressed miRNAs (DEMs). The target genes of the top 10 DEMs were predicted using miRWalk 2.0 database, followed by function enrichment and protein-protein interaction analysis. miRNA expression was determined in the human retinal pigment epithelial cell line ARPE-19 treated with high glucose (HG) by quantitative reverse transcription-polymerase chain reaction (qRT-PCR). Cell proliferation was determined using cell counting kit (CCK)-8 assay. Cell cycle, apoptosis, and reactive oxygen species (ROS) levels were determined by flow cytometry. The direct interaction between miRNA and targets was validated using dual-luciferase reporter assay. RESULTS Thirty-nine DEMs were screened, and we predicted 125 miRNA-mRNA pairs for the top 10 DEMs, including 119 target genes of seven DEMs such as miR-346, which was upregulated in diabetic retinopathy (DR). miR-346 target genes were substantially enriched in the regulation of intracellular transport and retinoic acid-inducible gene I (RIG-I)-like receptor signaling pathway. Expression of three upregulated and downregulated miRNAs were verified by qRT-PCR in HG-treated ARPE-19 cells. Expression of miR-346 was elevated in HG treated ARPE-19 cells in a dose-dependent manner. HG inhibited cell proliferation and induced apoptosis, which were partly reversed by transfecting an miR-346 inhibitor, which even decreased the ROS levels elevated due to HG. Argonaute 2 (AGO2) was a target of miR-346. CONCLUSION miR-346 is a key miRNA and plays an important role in HG-induced damage in human retinal pigment epithelial cells.
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Affiliation(s)
- Peng Li
- Department of Ophthalmology, Xijing 986 Hospital Department, Fourth Military Medical University, Xi'an 710054, Shaanxi Province, China
| | - Li Wang
- Ophthalmology Teaching and Research Section of Institute of Medical Technology, Xi'an Medical College, Xi'an 710032, Shaanxi Province, China
| | - Qing Liu
- Department of Ophthalmology, Xijing 986 Hospital Department, Fourth Military Medical University, Xi'an 710054, Shaanxi Province, China
| | - Zhao-Jiang Du
- Department of Ophthalmology, Xi'an Central Hospital, Xi'an 710001, Shaanxi Province, China
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14
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Sun WJ, An XD, Zhang YH, Zhao XF, Sun YT, Yang CQ, Kang XM, Jiang LL, Ji HY, Lian FM. The ideal treatment timing for diabetic retinopathy: the molecular pathological mechanisms underlying early-stage diabetic retinopathy are a matter of concern. Front Endocrinol (Lausanne) 2023; 14:1270145. [PMID: 38027131 PMCID: PMC10680169 DOI: 10.3389/fendo.2023.1270145] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/31/2023] [Accepted: 10/23/2023] [Indexed: 12/01/2023] Open
Abstract
Diabetic retinopathy (DR) is a prevalent complication of diabetes, significantly impacting patients' quality of life due to vision loss. No pharmacological therapies are currently approved for DR, excepted the drugs to treat diabetic macular edema such as the anti-VEGF agents or steroids administered by intraocular route. Advancements in research have highlighted the crucial role of early intervention in DR for halting or delaying disease progression. This holds immense significance in enhancing patients' quality of life and alleviating the societal burden associated with medical care costs. The non-proliferative stage represents the early phase of DR. In comparison to the proliferative stage, pathological changes primarily manifest as microangiomas and hemorrhages, while at the cellular level, there is a loss of pericytes, neuronal cell death, and disruption of components and functionality within the retinal neuronal vascular unit encompassing pericytes and neurons. Both neurodegenerative and microvascular abnormalities manifest in the early stages of DR. Therefore, our focus lies on the non-proliferative stage of DR and we have initially summarized the mechanisms involved in its development, including pathways such as polyols, that revolve around the pathological changes occurring during this early stage. We also integrate cutting-edge mechanisms, including leukocyte adhesion, neutrophil extracellular traps, multiple RNA regulation, microorganisms, cell death (ferroptosis and pyroptosis), and other related mechanisms. The current status of drug therapy for early-stage DR is also discussed to provide insights for the development of pharmaceutical interventions targeting the early treatment of DR.
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Affiliation(s)
- Wen-Jie Sun
- Guang’anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
- China Academy of Chinese Medical Sciences, Beijing, China
| | - Xue-Dong An
- Guang’anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
- China Academy of Chinese Medical Sciences, Beijing, China
| | - Yue-Hong Zhang
- Guang’anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
- China Academy of Chinese Medical Sciences, Beijing, China
| | - Xue-Fei Zhao
- Guang’anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
- China Academy of Chinese Medical Sciences, Beijing, China
| | - Yu-Ting Sun
- Guang’anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
- China Academy of Chinese Medical Sciences, Beijing, China
| | - Cun-Qing Yang
- Guang’anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
- China Academy of Chinese Medical Sciences, Beijing, China
| | - Xiao-Min Kang
- Guang’anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
- Beijing University of Chinese Medicine, Beijing, China
| | - Lin-Lin Jiang
- Guang’anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
- Beijing University of Chinese Medicine, Beijing, China
| | - Hang-Yu Ji
- Guang’anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Feng-Mei Lian
- Guang’anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
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15
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Huang Y, Chen X, Zhuang J, Yu K. The Role of Retinal Dysfunction in Myopia Development. Cell Mol Neurobiol 2023; 43:1905-1930. [PMID: 36427109 PMCID: PMC11412200 DOI: 10.1007/s10571-022-01309-1] [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: 04/07/2022] [Accepted: 11/16/2022] [Indexed: 11/27/2022]
Abstract
Myopia is a refractive disorder arising from a mismatch between refractive power and relatively long axial length of the eye. With its dramatically increasing prevalence, myopia has become a pervasive social problem. It is commonly accepted that abnormal visual input acts as an initiating factor of myopia. As the first station to perceive visual signals, the retina plays an important role in myopia etiology. The retina is a fine-layered structure with multitudinous cells, processing intricate visual signals via numerous molecular pathways. Accordingly, dopaminergic mechanisms, contributions of rod and cone photoreceptors, myopic structural changes of retinal pigment epithelium (RPE) and neuro-retinal layers have all suggested a vital role of retinal dysfunction in myopia development. Herein, we separately discuss myopia-related retinal dysfunction and current dilemmas by different levels, from molecules to cells, with the hope that the comprehensive delineation could contribute to a better understanding of myopia etiology, indicate novel therapeutic targets, and inspire future studies.
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Affiliation(s)
- Yuke Huang
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Guang-Dong Provincial Key Laboratory of Ophthalmology and Visual Science, Sun Yat-Sen University, No.7 Jinsui Road, Tianhe District, Guangzhou City, China
| | - Xi Chen
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Guang-Dong Provincial Key Laboratory of Ophthalmology and Visual Science, Sun Yat-Sen University, No.7 Jinsui Road, Tianhe District, Guangzhou City, China
| | - Jing Zhuang
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Guang-Dong Provincial Key Laboratory of Ophthalmology and Visual Science, Sun Yat-Sen University, No.7 Jinsui Road, Tianhe District, Guangzhou City, China
| | - Keming Yu
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Guang-Dong Provincial Key Laboratory of Ophthalmology and Visual Science, Sun Yat-Sen University, No.7 Jinsui Road, Tianhe District, Guangzhou City, China.
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16
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Luo Q, Jiang Z, Jiang J, Wan L, Li Y, Huang Y, Qiu J, Yu K, Zhuang J. Tsp-1 + microglia attenuate retinal neovascularization by maintaining the expression of Smad3 in endothelial cells through exosomes with decreased miR-27a-5p. Theranostics 2023; 13:3689-3706. [PMID: 37441592 PMCID: PMC10334831 DOI: 10.7150/thno.84236] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2023] [Accepted: 06/12/2023] [Indexed: 07/15/2023] Open
Abstract
Rationale: Microglia with a repertoire of functions are critical in pathological regulation of angiogenesis in the retina. However, retinal microglia with beneficial contributions and corresponding mechanisms during pathological neovascularization are poorly understood. Methods: We conducted a bioinformatic comparison of public single-cell RNA transcriptome data between retinal microglia from mice with oxygen-induced retinopathy (OIR) and an antiangiogenic microglial population named MG3 from the spine. The essential beneficial factor thrombospondin-1 (Tsp-1) from microglia was discovered and then validated in the retina of mice with OIR at P17. Exosomes were isolated from Tsp-1-knockout microglia (KO-Exos) and Tsp-1+ microglia (NT-Exos). Human umbilical vein endothelial cells (HUVEC) morphology studies, exosomes' miRNA sequencing, luciferase reporter assay, miRNA loss of function studies, and intravitreal injection were used to explore the mechanism of Tsp-1 and microglia-associated retinal angiogenesis. Results: The bioinformatic analyses of single-cell RNA-seq data indicated that a subtype of retinal microglia named RMG1 shares features with MG3 in regulating wound healing, cell adhesion, and angiogenesis. Remarkably, Tsp-1, an extracellular matrix protein with robust inhibition of angiogenesis, was especially expressed in both MG3 and RMG1. However, the scarcity of Tsp-1+ cells was observed in RMG1, which could be an obstacle to attenuating retinal neovascularization. Subsequently, we found that exosomes derived from Tsp-1+ microglia inhibit the migration and tube formation of HUVEC. Moreover, the knockout of Tsp-1 led to the enrichment of miR-27a-5p in exosomes from microglia and promoted angiogenesis compared to that of NT-Exos in vitro. Furthermore, in the luciferase reporter assay on the transcriptional activity of the promoter, we demonstrated that Tsp-1 negatively regulates miR-27a-5p expression. In addition, SMAD family member 3 (Smad3), a receptor-activated Smad protein that is conducive to vascular homeostasis, was defined as a functional target gene of miR-27a-5p. These data were consistently confirmed in vivo in the retina of mice with OIR. Conclusion: Collectively, the Tsp-1/miR-27a-5p/Smad3 axis is involved in microglia-related and exosome-mediated antiangiogenic regulation of the retina. Therefore, this study reveals a novel mechanism by which retinal microglia maintain vascular homeostasis, thereby providing a new therapeutic target for pathological neovascularization.
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Affiliation(s)
- Qian Luo
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, No.7 Jinsui Road, Tianhe District, Guangzhou, 510060, China
- Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Guangzhou, 510060, China
| | - Zihua Jiang
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, No.7 Jinsui Road, Tianhe District, Guangzhou, 510060, China
- Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Guangzhou, 510060, China
| | - Jingyi Jiang
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, No.7 Jinsui Road, Tianhe District, Guangzhou, 510060, China
- Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Guangzhou, 510060, China
| | - Linxi Wan
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, No.7 Jinsui Road, Tianhe District, Guangzhou, 510060, China
- Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Guangzhou, 510060, China
| | - Yan Li
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, No.7 Jinsui Road, Tianhe District, Guangzhou, 510060, China
- Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Guangzhou, 510060, China
| | - Yuke Huang
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, No.7 Jinsui Road, Tianhe District, Guangzhou, 510060, China
- Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Guangzhou, 510060, China
| | - Jin Qiu
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, No.7 Jinsui Road, Tianhe District, Guangzhou, 510060, China
- Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Guangzhou, 510060, China
| | - Keming Yu
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, No.7 Jinsui Road, Tianhe District, Guangzhou, 510060, China
- Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Guangzhou, 510060, China
| | - Jing Zhuang
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, No.7 Jinsui Road, Tianhe District, Guangzhou, 510060, China
- Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Guangzhou, 510060, China
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17
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Habibi A, Zarei-Behjani Z, Falamarzi K, Malekpour M, Ebrahimi F, Soleimani M, Nejabat M, Khosravi A, Moayedfard Z, Pakbaz S, Dehdari Ebrahimi N, Azarpira N. Extracellular vesicles as a new horizon in the diagnosis and treatment of inflammatory eye diseases: A narrative review of the literature. Front Immunol 2023; 14:1097456. [PMID: 36969177 PMCID: PMC10033955 DOI: 10.3389/fimmu.2023.1097456] [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: 11/13/2022] [Accepted: 02/14/2023] [Indexed: 03/11/2023] Open
Abstract
Extracellular vesicles include exosomes, microvesicles, and apoptotic bodies. Their cargos contain a diverse variety of lipids, proteins, and nucleic acids that are involved in both normal physiology and pathology of the ocular system. Thus, studying extracellular vesicles may lead to a more comprehensive understanding of the pathogenesis, diagnosis, and even potential treatments for various diseases. The roles of extracellular vesicles in inflammatory eye disorders have been widely investigated in recent years. The term "inflammatory eye diseases" refers to a variety of eye conditions such as inflammation-related diseases, degenerative conditions with remarkable inflammatory components, neuropathy, and tumors. This study presents an overview of extracellular vesicles' and exosomes' pathogenic, diagnostic, and therapeutic values in inflammatory eye diseases, as well as existing and potential challenges.
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Affiliation(s)
- Azam Habibi
- Department of Tissue Engineering and Cell Therapy, School of Advanced Technologies in Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Zeinab Zarei-Behjani
- Department of Tissue Engineering and Cell Therapy, School of Advanced Technologies in Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Kimia Falamarzi
- Student Research Committee, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Mahdi Malekpour
- Student Research Committee, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Fatemeh Ebrahimi
- Student Research Committee, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Masood Soleimani
- Department of Tissue Engineering and Applied Cell Science, School of Advanced Technologies in Medicine, Shaheed Beheshti University of Medical Sciences, Tehran, Iran
| | - Mahmood Nejabat
- Department of Ophthalmology School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Amir Khosravi
- Department of Ophthalmology School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Zahra Moayedfard
- Department of Tissue Engineering and Cell Therapy, School of Advanced Technologies in Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Sara Pakbaz
- Department of Pathology, University of Toronto, Toronto, ON, Canada
| | | | - Negar Azarpira
- Transplant Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
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18
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Cao H, Xu X, Wang K, Li C. Down-Regulation of circCOL1A2 Suppresses the Dysfunction of Diabetes-Related Retinal Microvascular Endothelial Cells via miR-646/FGF7 Axis. Curr Eye Res 2022; 47:1525-1533. [PMID: 35924466 DOI: 10.1080/02713683.2022.2110264] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/27/2023]
Abstract
PURPOSE Diabetic retinopathy (DR), the major complication of diabetes, is the leading cause of vision loss and blindness globally. Altered circular RNAs (circRNAs) expression has been found to be involved in DR process. Hence, this work aimed to explore the role and mechanism of circCOL1A2 in DR. METHODS Human retinal microvascular endothelial cells (RMECs) treated with high glucose (HG) were used for functional analysis. Levels of genes and proteins were detected using quantitative real-time polymerase chain reaction and western blotting. In vitro experiments were conducted by transwell, tube formation, CCK-8 assays and ELISA, respectively. The binding interaction between miR-646 and circCOL1A2 or FGF7 (Fibroblast Growth Factor 7) was confirmed using dual-luciferase reporter and RNA immunoprecipitation assays. RESULTS CircCOL1A2 was highly expressed in retinal tissues of DR patients and HG-induced RMECs. Then RMECs were exposed to HG treatment to mimic the diabetic conditions in vitro. Functionally, circCOL1A2 knockdown attenuated HG-evoked RMEC migration, proliferation, angiogenesis, blood-retina barrier (BRB) injury and inflammation. Mechanistically, circCOL1A2 functioned as a sponge for miR-646, and miR-646 directly targeted FGF7. Further rescue experiments showed that miR-646 inhibition abated the protective effects of circCOL1A2 knockdown on RMEC function under HG treatment. Besides that, miR-646 was decreased in HG-induced RMECs, re-expression of miR-646 reversed HG-evoked RMEC dysfunction, which was rescued by FGF7 overexpression. CONCLUSION CircCOL1A2 silencing can suppress HG-induced migration, proliferation, angiogenesis, BRB injury and inflammation in RMECs through miR-646/FGF7 axis, suggesting the potential involvement of circCOL1A2 in DR process.
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Affiliation(s)
- Haijing Cao
- Department of Ophthalmology, The Affiliated Huaian No.1 People's Hospital of Nanjing Medical University, Huai'an, China
| | - Xinhuai Xu
- Department of Ophthalmology, The Affiliated Huaian No.1 People's Hospital of Nanjing Medical University, Huai'an, China
| | - Kai Wang
- Department of Chronic Disease Prevention and Control, Huaian City Center for Disease Control and Prevention, Huai'an, China
| | - Chaopeng Li
- Department of Ophthalmology, The Affiliated Huaian No.1 People's Hospital of Nanjing Medical University, Huai'an, China
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19
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Gharbia S, Nazarie SR, Dinescu S, Balta C, Herman H, Peteu VE, Gherghiceanu M, Hermenean A, Costache M. Adipose-Derived Stem Cells (ADSCs) Supplemented with Hepatocyte Growth Factor (HGF) Attenuate Hepatic Stellate Cell Activation and Liver Fibrosis by Inhibiting the TGF-β/Smad Signaling Pathway in Chemical-Induced Liver Fibrosis Associated with Diabetes. Cells 2022; 11:3338. [PMID: 36359733 PMCID: PMC9653841 DOI: 10.3390/cells11213338] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2022] [Revised: 10/17/2022] [Accepted: 10/19/2022] [Indexed: 10/20/2023] Open
Abstract
Liver fibrosis can develop on the background of hyperglycemia in diabetes mellitus. However, xenobiotic-related factors may accelerate diabetes-associated liver fibrosis. In this study, we aimed to assess the antfibrotic effect of ADSC and HGF therapy and to establish the cellular and molecular mechanisms through in vitro and in vivo experiments. In vitro, TGF-β1-activated hepatic stellate cells (HSCs) were cocultured with ADSCs or HGF, and the expression of several fibrosis markers was investigated. The antifibrotic effect of the ADSCs, HGF, and ADSCs supplemented with HGF was further assessed in vivo on diabetic mice with liver fibrosis experimentally induced. In vitro results showed the inhibition of HSC proliferation and decrease in fibrogenesis markers. Coadministration of ADSCs and HGF on diabetic mice with liver fibrosis enhanced antifibrotic effects confirmed by the downregulation of Col I, α-SMA, TGF-β1, and Smad2, while Smad7 was upregulated. Moreover, stem cell therapy supplemented with HGF considerably attenuated inflammation and microvesicular steatosis, decreased collagen deposits, and alleviated liver fibrosis. In conclusion, the HGF-based ADSC therapy might be of interest for the treatment of liver fibrosis in diabetic patients, consecutive aggression exerts by different environmental factors.
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Affiliation(s)
- Sami Gharbia
- Department of Biochemistry and Molecular Biology, University of Bucharest, 050663 Bucharest, Romania
- “Aurel Ardelean” Institute of Life Sciences, “Vasile Goldis” Western University of Arad, 310025 Arad, Romania
| | - Simona-Rebeca Nazarie
- Department of Biochemistry and Molecular Biology, University of Bucharest, 050663 Bucharest, Romania
| | - Sorina Dinescu
- Department of Biochemistry and Molecular Biology, University of Bucharest, 050663 Bucharest, Romania
- The Research Institute of the University of Bucharest (ICUB), University of Bucharest, 050663 Bucharest, Romania
| | - Cornel Balta
- “Aurel Ardelean” Institute of Life Sciences, “Vasile Goldis” Western University of Arad, 310025 Arad, Romania
| | - Hildegard Herman
- “Aurel Ardelean” Institute of Life Sciences, “Vasile Goldis” Western University of Arad, 310025 Arad, Romania
| | | | - Mihaela Gherghiceanu
- Victor Babes National Institute of Pathology, 050096 Bucharest, Romania
- Department of Cell Biology, Faculty of Medicine, “Carol Davila” University of Medicine and Pharmacy, 050474 Bucharest, Romania
| | - Anca Hermenean
- “Aurel Ardelean” Institute of Life Sciences, “Vasile Goldis” Western University of Arad, 310025 Arad, Romania
- Department of Histology, Faculty of Medicine, Vasile Goldis Western University of Arad, 310414 Arad, Romania
| | - Marieta Costache
- Department of Biochemistry and Molecular Biology, University of Bucharest, 050663 Bucharest, Romania
- The Research Institute of the University of Bucharest (ICUB), University of Bucharest, 050663 Bucharest, Romania
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20
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Malakoti F, Mohammadi E, Akbari Oryani M, Shanebandi D, Yousefi B, Salehi A, Asemi Z. Polyphenols target miRNAs as a therapeutic strategy for diabetic complications. Crit Rev Food Sci Nutr 2022; 64:1865-1881. [PMID: 36069329 DOI: 10.1080/10408398.2022.2119364] [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] [Indexed: 11/03/2022]
Abstract
MiRNAs are a large group of non-coding RNAs which participate in different cellular pathways like inflammation and oxidation through transcriptional, post-transcriptional, and epigenetic regulation. In the post-transcriptional regulation, miRNA interacts with the 3'-UTR of mRNAs and prevents their translation. This prevention or dysregulation can be a cause of pathological conditions like diabetic complications. A huge number of studies have revealed the association between miRNAs and diabetic complications, including diabetic nephropathy, cardiomyopathy, neuropathy, retinopathy, and delayed wound healing. To address this issue, recent studies have focused on the use of polyphenols as selective and safe drugs in the treatment of diabetes complications. In this article, we will review the involvement of miRNAs in diabetic complications' occurrence or development. Finally, we will review the latest findings on targeting miRNAs by polyphenols like curcumin, resveratrol, and quercetin for diabetic complications therapy.
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Affiliation(s)
- Faezeh Malakoti
- Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Erfan Mohammadi
- Molecular Medicine Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Mahsa Akbari Oryani
- Department of Pathology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Darioush Shanebandi
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Bahman Yousefi
- Research Center for Integrative Medicine in Aging, Aging Research Institute, Tabriz University of Medical Sciences, Tabriz, Iran
- Department of Biochemistry, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Azadeh Salehi
- Faculty of Pharmacy, Islamic Azad University of Tehran Branch, Tehran, Iran
| | - Zatollah Asemi
- Research Center for Biochemistry and Nutrition in Metabolic Diseases, Institute for Basic Sciences, Kashan University of Medical Sciences, Kashan, I.R. Iran
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21
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Systemic Beta-Hydroxybutyrate Affects BDNF and Autophagy into the Retina of Diabetic Mice. Int J Mol Sci 2022; 23:ijms231710184. [PMID: 36077579 PMCID: PMC9455989 DOI: 10.3390/ijms231710184] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2022] [Revised: 09/02/2022] [Accepted: 09/03/2022] [Indexed: 11/17/2022] Open
Abstract
Background: Diabetic retinopathy (DR) is a neurovascular disease, characterized by a deficiency of brain-derived neurotrophic factor (BDNF), a regulator of autophagy. Beta-hydroxybutyrate (BHB), previously reported as a protective agent in DR, has been associated with BDNF promotion. Here, we investigated whether systemic BHB affects the retinal levels of BDNF and local autophagy in diabetic mice with retinopathy; Methods: C57BL/6J mice were administered with intraperitoneal (i.p.) streptozotocin (STZ) (75 mg/kg) injection to develop diabetes. After 2 weeks, they received i.p. injections of BHB (25−50−100 mg/kg) twice a week for 10 weeks. Retinal samples were collected in order to perform immunofluorescence, Western blotting, and ELISA analysis; Results: BHB 50 mg/kg and 100 mg/kg significantly improved retinal BDNF levels (p < 0.01) in diabetic mice. This improvement was negatively associated with autophagosome−lysosome formations (marked by LC3B and ATG14) and to higher levels of connexin 43 (p < 0.01), a marker of cell integrity. Moreover, BHB administration significantly reduced M1 microglial activation and autophagy (p < 0.01); Conclusions: The systemic administration of BHB in mice with DR improves the retinal levels of BDNF, with the consequent reduction of the abnormal microglial autophagy. This leads to retinal cell safety through connexin 43 restoration.
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22
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Fahmideh F, Marchesi N, Campagnoli LIM, Landini L, Caramella C, Barbieri A, Govoni S, Pascale A. Effect of troxerutin in counteracting hyperglycemia-induced VEGF upregulation in endothelial cells: a new option to target early stages of diabetic retinopathy? Front Pharmacol 2022; 13:951833. [PMID: 36046820 PMCID: PMC9420903 DOI: 10.3389/fphar.2022.951833] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2022] [Accepted: 07/25/2022] [Indexed: 12/21/2022] Open
Abstract
Diabetic retinopathy (DR), one of the most common complications of diabetes mellitus, is characterized by degeneration of retinal neurons and neoangiogenesis. Until today, the pharmacological approaches for DR are limited and focused on counteracting the end-stage of this neurodegenerative disease, therefore efforts should be carried out to discover novel pharmacological targets useful to prevent DR development. Hyperglycemia is a major risk factor for endothelial dysfunction and vascular complication, which subsequently may trigger neurodegeneration. We previously demonstrated that, in the rat retina, hyperglycemia activates a new molecular cascade implicating, up-stream, protein kinase C βII (PKC βII), which in turn leads to a higher expression of vascular endothelial growth factor (VEGF), via the mRNA-binding Hu-antigen R (HuR) protein. VEGF is a pivotal mediator of neovascularization and a well-known vasopermeability factor. Blocking the increase of VEGF via modulation of this cascade can thus represent a new pharmacological option to prevent DR progression. To this aim, proper in vitro models are crucial for drug discovery, as they allow to better identify promising effective molecules. Considering that endothelial cells are key elements in DR and that hyperglycemia triggers the PKCβII/HuR/VEGF pathway, we set up two distinct in vitro models applying two different stimuli. Namely, human umbilical vein endothelial cells were exposed to phorbol 12-myristate 13-acetate, which mimics diacylglycerol whose synthesis is triggered by diabetic hyperglycemia, while human retinal endothelial cells were treated with high glucose for different times. After selecting the optimal experimental conditions able to determine an increased VEGF production, in search of molecules useful to prevent DR development, we investigated the capability of troxerutin, an antioxidant flavonoid, to counteract not only the rise of VEGF but also the activation of the PKCβII/HuR cascade in both in vitro models. The results show the capability of troxerutin to hinder the hyperglycemia-induced increase in VEGF in both models through PKCβII/HuR pathway modulation. Further, these data confirm the key engagement of this cascade as an early event triggered by hyperglycemia to promote VEGF expression. Finally, the present findings also suggest the potential use of troxerutin as a preventive treatment during the early phases of DR.
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Affiliation(s)
- F. Fahmideh
- Department of Drug Sciences, Pharmacology Section, University of Pavia, Pavia, Italy
| | - N. Marchesi
- Department of Drug Sciences, Pharmacology Section, University of Pavia, Pavia, Italy
- *Correspondence: N. Marchesi, ; A. Pascale,
| | - L. I. M. Campagnoli
- Department of Drug Sciences, Pharmacology Section, University of Pavia, Pavia, Italy
| | - L. Landini
- Bausch & Lomb—Iom S.p.A, Vimodrone (Milan), Italy
| | - C. Caramella
- Department of Drug Sciences, Pharmacology Section, University of Pavia, Pavia, Italy
| | - A. Barbieri
- Department of Drug Sciences, Pharmacology Section, University of Pavia, Pavia, Italy
| | - S. Govoni
- Department of Drug Sciences, Pharmacology Section, University of Pavia, Pavia, Italy
| | - A. Pascale
- Department of Drug Sciences, Pharmacology Section, University of Pavia, Pavia, Italy
- *Correspondence: N. Marchesi, ; A. Pascale,
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23
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Sun S, Wang F, Sun Y, Bai L. miR-146a suppresses the expression of vascular endothelial growth factor and inflammatory responses in diabetic retinopathy. Growth Factors 2022; 40:89-97. [PMID: 35605149 DOI: 10.1080/08977194.2022.2077732] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/04/2022]
Abstract
This study was designed to explore the role of miR-146a in diabetic retinopathy (DR). 30 healthy control (HC), 50 patients with type 2 diabetes mellitus, and 48 DR patients were enrolled. Blood was collected and levels of miR-146a expression, vascular endothelial growth factor (VEGF), and three inflammatory cytokines (NF-κB, IL-1β, and TNF-α) were detected. Moreover, ARPE-19 cells were treated with miR-146a mimic or inhibitor in the presence of high glucose to evaluate its effect in vitro. DR patients had the lowest level of miR-146a and the highest level of VEGF as well as the most severe inflammation among the three groups. In addition, the miR-146a level was negatively correlated with the expression of VEGF and three inflammatory cytokines, respectively in DR patients. Moreover, VEGF expression was positively correlated with these three inflammatory cytokines in DR patients. In summary, miR-146a could inhibit VEGF expression and inflammation in DR.
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Affiliation(s)
- Shichao Sun
- Department of Neurology, The Second Hospital, Hebei Medical University, Shijiazhuang, Hebei, China
| | - Fujun Wang
- Department of Endocrinology, The Fourth Hospital, Hebei Medical University, Shijiazhuang, Hebei, China
| | - Yao Sun
- Department of Radiology, The Hebei Province Hospital of TCM, Shijiazhuang, Hebei, China
| | - Lei Bai
- Department of Endocrinology, The Fourth Hospital, Hebei Medical University, Shijiazhuang, Hebei, China
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24
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C-terminal binding protein 2 promotes high-glucose-triggered cell proliferation, angiogenesis and cellular adhesion of human retinal endothelial cell line. Int Ophthalmol 2022; 42:2975-2985. [PMID: 35353294 DOI: 10.1007/s10792-022-02283-9] [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: 10/21/2021] [Accepted: 03/12/2022] [Indexed: 10/18/2022]
Abstract
PURPOSE The proliferation and angiogenesis of human retinal endothelial cells (HRECs) are critical for the pathophysiology of diabetic retinopathy (DR). C-terminal binding protein 2 (CtBP2) has multiple biologic functions, but its effect on HRECs under high-glucose (HG) conditions is unclear. METHODS The cell viability, angiogenesis, cellular adhesion and CtBP2 expression levels of HRECs were measured following treatment with different concentrations of glucose. Small interfering CtBP2-targeting RNA, wide-type and function mutant plasmid of CtBP2 were constructed and then were transfected into HRECs to evaluate the effects of CtBP2 on cell functions of HRECs. RESULTS The expression of CtBP2 in HRECs was increased after HG treatment. HG treatment significantly increased cell proliferation, angiogenesis, and decreased relative gene expressions in gap junctions, tight junctions and adherens junctions. After CtBP2 was inhibited via siRNA, the changes induced by HG were partially restored. Conversely, only wild-type CtBP2 could increase cell proliferation and angiogenesis under HG condition. Mechanistically, we also found that CtBP2 exerted its functions to effect HG-induced changes via Akt signaling pathway. CONCLUSION This study implicates that CtBP2 promotes HG-induced cell proliferation, angiogenesis and cellular adhesion, and CtBP2 might be a potential target in the prevention of DR.
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25
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Trotta MC, Gesualdo C, Petrillo F, Cavasso G, Corte AD, D'Amico G, Hermenean A, Simonelli F, Rossi S. Serum Iba-1, GLUT5, and TSPO in Patients With Diabetic Retinopathy: New Biomarkers for Early Retinal Neurovascular Alterations? A Pilot Study. Transl Vis Sci Technol 2022; 11:16. [PMID: 35285861 PMCID: PMC8934554 DOI: 10.1167/tvst.11.3.16] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022] Open
Abstract
Purpose This study explored the possibility of highlighting early retinal neurovascular alterations of diabetic retinopathy (DR) by monitoring in DR patients the serum levels of microglial biomarkers ionized calcium-binding adapter molecule 1 (Iba-1), glucose transporter 5 (GLUT5), and translocator protein (TSPO), along with serum changes of the endothelial dysfunction marker arginase-1. Methods Serum markers were determined by enzyme-linked immunosorbent assay in 50 patients: 12 non-diabetic subjects, 14 diabetic patients without DR, 13 patients with non-proliferative DR (NPDR), and 11 patients with proliferative DR (PDR). The results were correlated with hyperreflective retinal spots (HRS), observed with optical coherence tomography (OCT). Results Although HRS were absent in diabetic patients without DR, NPDR patients showed an average of 4 ± 1 HRS, whereas the highest presence was detected in PDR patients, with 8 ± 1 HRS (P < 0.01 vs. NPDR). HRS were positively correlated (P < 0.01) with serum levels of arginase-1 (r = 0.91), Iba-1 (r = 0.96), GLUT5 (r = 0.94), and TSPO (r = 0.88). Moreover, serum proinflammatory cytokines and chemokines showed a positive correlation (P < 0.01) with HRS number and the serum markers analyzed. Conclusions Serum markers of microglial activation positively correlate with retinal HRS in NPDR and PDR patients. Translational Relevance These data corroborate the possibility of highlighting early retinal neurovascular changes due to diabetes by monitoring circulating microglial markers.
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Affiliation(s)
- Maria Consiglia Trotta
- Department of Experimental Medicine, University of Campania "Luigi Vanvitelli," Naples, Italy
| | - Carlo Gesualdo
- Eye Clinic, Multidisciplinary Department of Medical, Surgical and Dental Sciences, University of Campania "Luigi Vanvitelli," Naples, Italy
| | | | - Giancuomo Cavasso
- Eye Clinic, Multidisciplinary Department of Medical, Surgical and Dental Sciences, University of Campania "Luigi Vanvitelli," Naples, Italy
| | - Alberto Della Corte
- Eye Clinic, Multidisciplinary Department of Medical, Surgical and Dental Sciences, University of Campania "Luigi Vanvitelli," Naples, Italy
| | - Giovanbattista D'Amico
- "Aurel Ardelean" Institute of Life Sciences, Vasile Goldis Western University of Arad, Arad, Romania
| | - Anca Hermenean
- "Aurel Ardelean" Institute of Life Sciences, Vasile Goldis Western University of Arad, Arad, Romania
| | - Francesca Simonelli
- Eye Clinic, Multidisciplinary Department of Medical, Surgical and Dental Sciences, University of Campania "Luigi Vanvitelli," Naples, Italy
| | - Settimio Rossi
- Eye Clinic, Multidisciplinary Department of Medical, Surgical and Dental Sciences, University of Campania "Luigi Vanvitelli," Naples, Italy
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26
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Huang XM, Yang BF, Zheng WL, Liu Q, Xiao F, Ouyang PW, Li MJ, Li XY, Meng J, Zhang TT, Cui YH, Pan HW. Cost-effectiveness of artificial intelligence screening for diabetic retinopathy in rural China. BMC Health Serv Res 2022; 22:260. [PMID: 35216586 PMCID: PMC8881835 DOI: 10.1186/s12913-022-07655-6] [Citation(s) in RCA: 39] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2021] [Accepted: 02/16/2022] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Diabetic retinopathy (DR) has become a leading cause of global blindness as a microvascular complication of diabetes. Regular screening of diabetic retinopathy is strongly recommended for people with diabetes so that timely treatment can be provided to reduce the incidence of visual impairment. However, DR screening is not well carried out due to lack of eye care facilities, especially in the rural areas of China. Artificial intelligence (AI) based DR screening has emerged as a novel strategy and show promising diagnostic performance in sensitivity and specificity, relieving the pressure of the shortage of facilities and ophthalmologists because of its quick and accurate diagnosis. In this study, we estimated the cost-effectiveness of AI screening for DR in rural China based on Markov model, providing evidence for extending use of AI screening for DR. METHODS We estimated the cost-effectiveness of AI screening and compared it with ophthalmologist screening in which fundus images are evaluated by ophthalmologists. We developed a Markov model-based hybrid decision tree to analyze the costs, effectiveness and incremental cost-effectiveness ratio (ICER) of AI screening strategies relative to no screening strategies and ophthalmologist screening strategies (dominated) over 35 years (mean life expectancy of diabetes patients in rural China). The analysis was conducted from the health system perspective (included direct medical costs) and societal perspective (included medical and nonmedical costs). Effectiveness was analyzed with quality-adjusted life years (QALYs). The robustness of results was estimated by performing one-way sensitivity analysis and probabilistic analysis. RESULTS From the health system perspective, AI screening and ophthalmologist screening had incremental costs of $180.19 and $215.05 but more quality-adjusted life years (QALYs) compared with no screening. AI screening had an ICER of $1,107.63. From the societal perspective which considers all direct and indirect costs, AI screening had an ICER of $10,347.12 compared with no screening, below the cost-effective threshold (1-3 times per capita GDP of Chinese in 2019). CONCLUSIONS Our analysis demonstrates that AI-based screening is more cost-effective compared with conventional ophthalmologist screening and holds great promise to be an alternative approach for DR screening in the rural area of China.
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Affiliation(s)
- Xiao-Mei Huang
- Department of Ophthalmology, the First Affiliated Hospital, Jinan University, Guangzhou, China.,Institute of Ophthalmology, School of Medicine, Jinan University, Guangzhou, China
| | - Bo-Fan Yang
- Institute of Ophthalmology, School of Medicine, Jinan University, Guangzhou, China
| | - Wen-Lin Zheng
- Institute of Ophthalmology, School of Medicine, Jinan University, Guangzhou, China.,Department of Public Health and Preventive Medicine, School of Medicine, Jinan University, Guangzhou, China
| | - Qun Liu
- Institute of Ophthalmology, School of Medicine, Jinan University, Guangzhou, China
| | - Fan Xiao
- Institute of Ophthalmology, School of Medicine, Jinan University, Guangzhou, China.,Department of Public Health and Preventive Medicine, School of Medicine, Jinan University, Guangzhou, China
| | - Pei-Wen Ouyang
- Department of Ophthalmology, the First Affiliated Hospital, Jinan University, Guangzhou, China.,Institute of Ophthalmology, School of Medicine, Jinan University, Guangzhou, China
| | - Mei-Jun Li
- Department of Ophthalmology, the First Affiliated Hospital, Jinan University, Guangzhou, China.,Institute of Ophthalmology, School of Medicine, Jinan University, Guangzhou, China
| | - Xiu-Yun Li
- Department of Ophthalmology, Affiliated Hospital of Weifang Medical University, Weifang, China
| | - Jing Meng
- Department of Ophthalmology, the First Affiliated Hospital, Jinan University, Guangzhou, China
| | | | - Yu-Hong Cui
- School of Basic Medical Sciences, The Guangzhou Institute of Cardiovascular Disease, The Second Affiliated Hospital, Guangzhou Medical University, Guangzhou, China.,Department of Histology and Embryology, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou, China
| | - Hong-Wei Pan
- Department of Ophthalmology, the First Affiliated Hospital, Jinan University, Guangzhou, China. .,Institute of Ophthalmology, School of Medicine, Jinan University, Guangzhou, China.
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27
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Qin X, Zou H. The role of lipopolysaccharides in diabetic retinopathy. BMC Ophthalmol 2022; 22:86. [PMID: 35193549 PMCID: PMC8862382 DOI: 10.1186/s12886-022-02296-z] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2021] [Accepted: 02/03/2022] [Indexed: 11/29/2022] Open
Abstract
Diabetes mellitus (DM) is a complex metabolic syndrome characterized by hyperglycemia. Diabetic retinopathy (DR) is the most common complication of DM and the leading cause of blindness in the working-age population of the Western world. Lipopolysaccharides (LPS) is an essential ingredient of the outer membrane of gram-negative bacteria, which induces systemic inflammatory responses and cellular apoptotic changes in the host. High-level serum LPS has been found in diabetic patients at the advanced stages, which is mainly due to gut leakage and dysbiosis. In this light, increasing evidence points to a strong correlation between systemic LPS challenge and the progression of DR. Although the underlying molecular mechanisms have not been fully elucidated yet, LPS-related pathobiological events in the retina may contribute to the exacerbation of vasculopathy and neurodegeneration in DR. In this review, we focus on the involvement of LPS in the progression of DR, with emphasis on the blood-retina barrier dysfunction and dysregulated glial activation. Eventually, we summarize the recent advances in the therapeutic strategies for antagonising LPS activity, which may be introduced to DR treatment with promising clinical value.
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Affiliation(s)
- Xinran Qin
- Department of Ophthalmology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Haidong Zou
- Department of Ophthalmology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China. .,Shanghai Eye Diseases Prevention & Treatment Center, Shanghai Eye Hospital, Shanghai, China. .,Shanghai Engineering Center for Precise Diagnosis and Treatment of Eye Diseases, Shanghai, China. .,National Clinical Research Center for Eye Diseases, Shanghai, China. .,Shanghai Key Laboratory of Fundus Diseases, Shanghai, China.
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28
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Conti F, Lazzara F, Romano GL, Platania CBM, Drago F, Bucolo C. Caffeine Protects Against Retinal Inflammation. Front Pharmacol 2022; 12:824885. [PMID: 35069225 PMCID: PMC8773454 DOI: 10.3389/fphar.2021.824885] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2021] [Accepted: 12/13/2021] [Indexed: 01/28/2023] Open
Abstract
Caffeine, one of the most consumed central nervous system (CNS) stimulants, is an antagonist of A1 and A2A adenosine receptors. In this study, we investigated the potential protective effects of this methylxanthine in the retinal tissue. We tested caffeine by using in vitro and in vivo paradigms of retinal inflammation. Human retinal pigment epithelial cells (ARPE-19) were exposed to lipopolysaccharide (LPS) with or without caffeine. This latter was able to reduce the inflammatory response in ARPE-19 cells exposed to LPS, attenuating the release of IL-1β, IL-6, and TNF-α and the nuclear translocation of p-NFκB. Additionally, caffeine treatment restored the integrity of the ARPE-19 monolayer assessed by transepithelial electrical resistance (TEER) and the sodium fluorescein permeability test. Finally, the ischemia reperfusion (I/R) injury model was used in C57BL/6J mice to induce retinal inflammation and investigate the effects of caffeine treatment. Mouse eyes were treated topically with caffeine, and a pattern electroretinogram (PERG) was used to assess the retinal ganglion cell (RGC) function; furthermore, we evaluated the levels of IL-6 and BDNF in the retina. Retinal BDNF dropped significantly (p < 0.05) in the I/R group compared to the control group (normal mice); on the contrary, caffeine treatment maintained physiological levels of BDNF in the retina of I/R eyes. Caffeine was also able to reduce IL-6 mRNA levels in the retina of I/R eyes. In conclusion, these findings suggest that caffeine is a good candidate to counteract inflammation in retinal diseases.
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Affiliation(s)
- Federica Conti
- Department of Biomedical and Biotechnological Sciences, School of Medicine, University of Catania, Catania, Italy
| | - Francesca Lazzara
- Department of Biomedical and Biotechnological Sciences, School of Medicine, University of Catania, Catania, Italy
| | - Giovanni Luca Romano
- Department of Biomedical and Biotechnological Sciences, School of Medicine, University of Catania, Catania, Italy.,Center for Research in Ocular Pharmacology-CERFO, University of Catania, Catania, Italy
| | - Chiara Bianca Maria Platania
- Department of Biomedical and Biotechnological Sciences, School of Medicine, University of Catania, Catania, Italy
| | - Filippo Drago
- Department of Biomedical and Biotechnological Sciences, School of Medicine, University of Catania, Catania, Italy.,Center for Research in Ocular Pharmacology-CERFO, University of Catania, Catania, Italy
| | - Claudio Bucolo
- Department of Biomedical and Biotechnological Sciences, School of Medicine, University of Catania, Catania, Italy.,Center for Research in Ocular Pharmacology-CERFO, University of Catania, Catania, Italy
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Shi ZH, Han XY, Yao MD, Liu C, Jiang Q, Yan B. Differential MicroRNA Expression Pattern in Endothelial Progenitor Cells During Diabetic Retinopathy. Front Cell Dev Biol 2022; 9:773050. [PMID: 34977023 PMCID: PMC8717624 DOI: 10.3389/fcell.2021.773050] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2021] [Accepted: 10/25/2021] [Indexed: 12/22/2022] Open
Abstract
Endothelial progenitor cells (EPCs) are involved in the pathogenesis of microvascular dysfunction in diabetic retinopathy (DR). MicroRNAs (miRNAs) serve as crucial regulators in many biological process and human diseases. Herein, to investigate the expression profile and possible role of miRNAs in EPCs, small RNA sequencing was conducted to identify EPC dysfunction-related miRNAs in DR. A total of 72 miRNAs were differentially expressed in EPCs following high glucose stress. Based on Gene Ontology (GO) analysis, the target genes of differentially expressed miRNAs were targeted to “protein binding,” “cell differentiation,” and “cytoskeleton.” Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis revealed that cGMP-PKG signaling pathway was tightly associated with miRNA-mediated EPC function. Furthermore, miR-375–3p was verified to be up-regulated in the clinical samples of DR patients. Inhibition of miR-375–3p protected against hyperglycemic stress- or hypoxic stress-induced EPC injury, which increased the viability, proliferation, migration, and tube formation ability of EPCs and retarded the development of apoptosis. Collectively, this study provides a novel insight into the pathogenesis of EPC dysfunction in DR. miR-375–3p is a potential target for the diagnosis or treatment of DR.
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Affiliation(s)
- Ze-Hui Shi
- Eye Institute, Eye & ENT Hospital, Shanghai Medical College, Fudan University, Shanghai, China
| | - Xiao-Yan Han
- Eye Institute, Eye & ENT Hospital, Shanghai Medical College, Fudan University, Shanghai, China
| | - Mu-Di Yao
- The Affiliated Eye Hospital, Nanjing Medical University, Nanjing, China.,The Fourth School of Clinical Medicine, Nanjing Medical University, Nanjing, China
| | - Chang Liu
- The Affiliated Eye Hospital, Nanjing Medical University, Nanjing, China.,The Fourth School of Clinical Medicine, Nanjing Medical University, Nanjing, China
| | - Qin Jiang
- The Affiliated Eye Hospital, Nanjing Medical University, Nanjing, China.,The Fourth School of Clinical Medicine, Nanjing Medical University, Nanjing, China
| | - Biao Yan
- Eye Institute, Eye & ENT Hospital, Shanghai Medical College, Fudan University, Shanghai, China.,NHC Key Laboratory of Myopia (Fudan University), Key Laboratory of Myopia, Chinese Academy of Medical Sciences, Shanghai Key Laboratory of Visual Impairment and Restoration (Fudan University), Shanghai, China
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Zhao H, Kong H, Wang B, Wu S, Chen T, Cui Y. RNA-Binding Proteins and Alternative Splicing Genes Are Coregulated in Human Retinal Endothelial Cells Treated with High Glucose. J Diabetes Res 2022; 2022:7680513. [PMID: 35308095 PMCID: PMC8926481 DOI: 10.1155/2022/7680513] [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] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/16/2021] [Revised: 02/17/2022] [Accepted: 02/21/2022] [Indexed: 01/10/2023] Open
Abstract
To explore the relevant RNA-binding proteins (RBPs) and alternative splicing events (ASEs) in diabetic retinopathy (DR). We devised a comprehensive work to integrate analyses of the differentially expressed genes, including differential RBPs, and variable splicing characteristics related to DR in human retinal endothelial cells induced by low glucose and high glucose in dataset GSE117238. A total of 2320 differentially expressed genes (DEGs) were identified, including 1228 upregulated genes and 1092 downregulated genes. Further analysis screened out 232 RBP genes, and 42 AS genes overlapped DEGs. We selected high expression and consistency six RBP genes (FUS, HNRNPA2B1, CANX, EIF1, CALR, and POLR2A) for coexpression analysis. Through analysis, we found eight RASGs (MDM2, GOLGA2P7, NFE2L1, KDM4A, FAM111A, CIRBP, IDH1, and MCM7) that could be regulated by RBP. The coexpression network was conducted to further elucidate the regulatory and interaction relationship between RBPs and AS. Apoptotic progress, protein phosphorylation, and NF-kappaB cascade revealed by the functional enrichment analysis of RASGs regulated by RBPs were closely related to diabetic retinopathy. Furthermore, the expression of differentially expressed RBPs was validated by qRT-PCR in mouse retinal microvascular endothelial cells and retinas from the streptozotocin mouse model. The results showed that Fus, Hnrnpa2b1, Canx, Calr, and Polr2a were remarkedly difference in high-glucose-treated retinal microvascular endothelial cells and Fus, Hnrnpa2b1, Canx, and Calr were remarkedly difference in retinas from streptozotocin-induced diabetic mice compared to control. The regulatory network between identified RBPs and RASGs suggests the presence of several signaling pathways possibly involved in the pathogenesis of DR. The verified RBPs should be further addressed by future studies investigating associations between RBPs and the downstream of AS, as they could serve as potential biomarkers and targets for DR.
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Affiliation(s)
- Hongran Zhao
- Department of Ophthalmology, Qilu Hospital of Shandong University, Shandong University, Jinan, Shandong Province, China
- School of Medicine, Shandong University, Jinan, Shandong Province, China
| | - Hui Kong
- School of Medicine, Shandong University, Jinan, Shandong Province, China
- Shandong University of Traditional Chinese Medicine, Jinan, Shandong Province, China
| | - Bozhao Wang
- Department of Ophthalmology, Qilu Hospital of Shandong University, Shandong University, Jinan, Shandong Province, China
- School of Medicine, Shandong University, Jinan, Shandong Province, China
| | - Sihui Wu
- Department of Ophthalmology, Qilu Hospital of Shandong University, Shandong University, Jinan, Shandong Province, China
- School of Medicine, Shandong University, Jinan, Shandong Province, China
| | - Tianran Chen
- School of Medicine, Shandong University, Jinan, Shandong Province, China
| | - Yan Cui
- Department of Ophthalmology, Qilu Hospital of Shandong University, Shandong University, Jinan, Shandong Province, China
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31
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Pramanik S, Saha C, Chowdhury S, Bose C, Bhattacharyya NP, Mondal LK. Decreased Levels of miR-126 and miR-132 in Plasma and Vitreous Humor of Non-Proliferative Diabetic Retinopathy Among Subjects with Type-2 Diabetes Mellitus. Diabetes Metab Syndr Obes 2022; 15:345-358. [PMID: 35153496 PMCID: PMC8823438 DOI: 10.2147/dmso.s346097] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/02/2021] [Accepted: 01/24/2022] [Indexed: 12/12/2022] Open
Abstract
PURPOSE Diabetic retinopathy (DR), the leading cause of blindness among working adults, is an urgent public health problem as diabetes mellitus (DM) is increasing at an alarming rate. Hyperglycemia-induced endothelial dysfunction is the principal contributing factor leading to the development of microangiopathy. Altered levels of microRNA (miR), the negative regulator of protein-coding genes, have been observed and considered to be markers for DR. Present study aimed to find out whether miR levels in plasma could be effective biomarkers to differentiate between type 2 diabetes mellitus (T2DM) with non-proliferative retinopathy (NPDR) from T2DM with no-DR (DNR). METHODS We recruited 50 T2DM subjects comprising 31 NPDR and 19 DNR individuals. Surrogate markers of systemic oxidative stress and vascular endothelial growth factor (VEGF) were measured in plasma. Levels of miR-126 and miR-132 were determined in plasma and vitreous fluid using real-time PCR. RESULTS We observed that levels of miR-126 and miR-132 were decreased in NPDR subjects in comparison to DNR. Plasma levels of miRs were inversely correlated with secreted levels of VEGF and oxidative stress marker. The levels of these miRs showed discriminating ability between NPDR and DNR. CONCLUSION Circulating miRs 126 and 132 in plasma or vitreous may serve as biomarkers for early diabetic retinopathy risk prediction, provided validated in a larger cohort and other forms of retinal vasculopathy or retinopathy in the future.
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Affiliation(s)
- Subhasish Pramanik
- Department of Endocrinology & Metabolism, Institute of Post Graduate Medical Education & Research and SSKM Hospital, Kolkata, 700020, West Bengal, India
| | - Chinmay Saha
- Department of Endocrinology & Metabolism, Institute of Post Graduate Medical Education & Research and SSKM Hospital, Kolkata, 700020, West Bengal, India
- Genome Science, School of Interdisciplinary Studies, University of Kalyani, Nadia, 741235, West Bengal, India
| | - Subhankar Chowdhury
- Department of Endocrinology & Metabolism, Institute of Post Graduate Medical Education & Research and SSKM Hospital, Kolkata, 700020, West Bengal, India
- Correspondence: Subhankar Chowdhury, Department of Endocrinology & Metabolism, Institute of Post Graduate Medical Education & Research and SSKM Hospital, Kolkata, 700020, West Bengal, India, Email
| | - Chiranjit Bose
- Department of Endocrinology & Metabolism, Institute of Post Graduate Medical Education & Research and SSKM Hospital, Kolkata, 700020, West Bengal, India
| | - Nitai P Bhattacharyya
- Department of Endocrinology & Metabolism, Institute of Post Graduate Medical Education & Research and SSKM Hospital, Kolkata, 700020, West Bengal, India
| | - Lakshmi Kanta Mondal
- Department of Ophthalmology, Regional Institute of Ophthalmology, Medical College Campus, Kolkata, 700 073, West Bengal, India
- Lakshmi Kanta Mondal, Department of Ophthalmology, Regional Institute of Ophthalmology, Medical College Campus, 88, College Street, Kolkata, 700 073, West Bengal, India, Email
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Yu M, Zhang L, Sun S, Zhang Z. Gliquidone improves retinal injury to relieve diabetic retinopathy via regulation of SIRT1/Notch1 pathway. BMC Ophthalmol 2021; 21:451. [PMID: 34961513 PMCID: PMC8711144 DOI: 10.1186/s12886-021-02215-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2021] [Accepted: 12/07/2021] [Indexed: 11/10/2022] Open
Abstract
Background Diabetic retinopathy (DR) is a common and potentially devastating microvascular complication of diabetes mellitus (DM). The main features of DR are inflammation and oxidative damage. Gliquidone (GLI) is confirmed to be a hypoglycemic drug by oral administration. The current study is aimed to investigate the role and mechanism of GLI on the pathogenesis of DR. Methods High glucose (HG)-induced human retinal endothelial cells (HRECs) were used to explore the anti-inflammatory and anti-oxidant effects of GLI on DR in vitro. Streptozotocin (STZ)-induced DM rats were used to investigate the effects of GLI on retinal structures, inflammation, and oxidative stress. The levels of SIRT1/Notch1 pathway-related proteins were determined by western blotting. Results GLI treatment promoted the viability and inhibited the apoptosis of HG-induced HRECs. Meanwhile, the levels of interleukin (IL)-6, IL-1β, tumour necrosis factor alpha and reactive oxygen species were suppressed, while both catalase and superoxide dismutase were elevated after GLI treatment in HG-induced HRECs. Furthermore, we found that Silencing information regulator 2 related enzyme 1 (SIRT1) silencing reversed the inhibiting effects of GLI on the levels of protein Notch1 and effector genes Hes1 and Hey2. Similar anti-inflammatory and anti-oxidant effects of GLI in STZ-induced DM rats were observed. Additionally, GLI administration also repressed vascular hyperpermeability in vivo. Conclusion GLI may be an effective agent to improve DR through repression of inflammation and oxidative stress via SIRT1/Notch1 pathway.
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Affiliation(s)
- Mengdan Yu
- Department of Ophthalmology, Affiliated Qingdao Central Hospital, Qingdao University, No. 127, Siliu South Road, Qingdao City, 266042, Shandong Province, China
| | - Lijun Zhang
- Department of Ophthalmology, Affiliated Qingdao Central Hospital, Qingdao University, No. 127, Siliu South Road, Qingdao City, 266042, Shandong Province, China
| | - Shasha Sun
- Department of Ophthalmology, Affiliated Qingdao Central Hospital, Qingdao University, No. 127, Siliu South Road, Qingdao City, 266042, Shandong Province, China
| | - Zhenhua Zhang
- Department of Ophthalmology, Affiliated Qingdao Central Hospital, Qingdao University, No. 127, Siliu South Road, Qingdao City, 266042, Shandong Province, China.
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33
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Jiang LN, Ji X, Liu W, Qi C, Zhai X. Identification of the circ_PRKDC/miR-20a-3p/RASA1 axis in regulating HaCaT keratinocyte migration. Wound Repair Regen 2021; 30:282-291. [PMID: 34897876 DOI: 10.1111/wrr.12988] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2021] [Revised: 10/20/2021] [Accepted: 11/25/2021] [Indexed: 12/11/2022]
Abstract
Migration of keratinocytes plays a crucial role in the re-epithelialization phase during wound healing. Circular RNA (circRNA) protein kinase, DNA-activated, catalytic subunit (circ_PRKDC, hsa_circ_0084443) has been identified as a regulator of keratinocyte migration. However, the molecular basis governing it remains unclear. The levels of circ_PRKDC, microRNA (miR)-20a-3p, and RAS p21 protein activator 1 (RASA1) were assessed by quantitative real-time PCR (qRT-PCR) or western blot. Subcellular localization, Actinomycin D, and Ribonuclease (RNase) R assays were performed to characterise circ_PRKDC. Cell migration was gauged by transwell and wound-healing assays. A direct relationship between miR-20a-3p and circ_PRKDC or RASA1 was verified by dual-luciferase reporter and RNA pull-down assays. Circ_PRKDC expression was reduced in wound skin during wound healing. Circ_PRKDC modulated migration of HaCaT keratinocytes. Mechanistically, circ_PRKDC directly targeted miR-20a-3p. The regulation of circ_PRKDC on HaCaT keratinocyte migration was mediated by miR-20a-3p. RASA1 was identified as a direct and functional target of miR-20a-3p, and miR-20a-3p-mediated inhibition of RASA1 impacted HaCaT keratinocyte migration. Circ_PRKDC acted as a post-transcriptional modulator of RASA1 expression through miR-20a-3p. Moreover, circ_PRKDC modulated migration of HaCaT keratinocytes by RASA1. Our findings demonstrated a novel molecular basis, the miR-20a-3p/RASA1 axis, for the regulation of circ_PRKDC on HaCaT keratinocyte migration.
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Affiliation(s)
- Li-Na Jiang
- Department of Plastic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Xiaohui Ji
- Department of Pathology, The People's Hospital of Zhengzhou, Zhengzhou, Henan, China
| | - Wei Liu
- Department of Breast Surgery, The People's Hospital of Zhengzhou, Zhengzhou, Henan, China
| | - Chuanchuan Qi
- Department of Breast Surgery, The People's Hospital of Zhengzhou, Zhengzhou, Henan, China
| | - Xiaomei Zhai
- Department of Plastic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
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Park YG, Lee JY, Kim C, Park YH. Early Microglial Changes Associated with Diabetic Retinopathy in Rats with Streptozotocin-Induced Diabetes. J Diabetes Res 2021; 2021:4920937. [PMID: 34926698 PMCID: PMC8674052 DOI: 10.1155/2021/4920937] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/23/2021] [Revised: 11/01/2021] [Accepted: 11/15/2021] [Indexed: 11/18/2022] Open
Abstract
Although morphological changes in microglia have been reported to be associated with diabetic retinopathy, little is known about the early changes in the microglia and macrophages during the progression of this condition. The present study was aimed at characterizing retinal microglial activation in the early stages of experimental diabetic retinopathy. Toward this end, a model of diabetic retinopathy was generated by intraperitoneally injecting male Sprague-Dawley rats with streptozotocin. No apparent histological changes were observed during the early stages of experimental diabetic retinopathy. However, at 4 to 16 weeks after the onset of diabetes, the retinas from diabetic rats exhibited higher density of microglia than those from age-matched normal controls, with microglial density peaking at 12 weeks. In particular, the proportion of the activated microglia increased significantly in the diabetic rats, specifically in the nerve fiber and ganglion cell layers, whereas it decreased in the inner plexiform layer within 12 weeks. Furthermore, the resident retinal microglial cells were activated immediately after diabetes induction, peaked at 12 weeks, and remained for up to 16 weeks after disease onset. Thus, experimental diabetic retinopathy causes gradual hypoxia and neuroinflammation, followed by the activation of microglia and the migration of macrophages. The distribution and density of retinal microglial activation changed typically with the progression of the disease in early-stage diabetic rats.
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Affiliation(s)
- Young Gun Park
- Department of Ophthalmology and Visual Science, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Ji-Yeon Lee
- Catholic Institute for Visual Science, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Chongtae Kim
- Catholic Institute for Visual Science, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Young-Hoon Park
- Department of Ophthalmology and Visual Science, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
- Catholic Institute for Visual Science, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
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Guo J, Zhou P, Liu Z, Dai F, Pan M, An G, Han J, Du L, Jin X. The Aflibercept-Induced MicroRNA Profile in the Vitreous of Proliferative Diabetic Retinopathy Patients Detected by Next-Generation Sequencing. Front Pharmacol 2021; 12:781276. [PMID: 34938191 PMCID: PMC8685391 DOI: 10.3389/fphar.2021.781276] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2021] [Accepted: 10/22/2021] [Indexed: 12/23/2022] Open
Abstract
Purpose: Vascular endothelial growth factor-A (VEGF-A) is an important pathogenic factor in proliferative diabetic retinopathy (PDR), and aflibercept (Eylea) is one of the widely used anti-VEGF agents. This study investigated the microRNA (miRNA) profiles in the vitreous of 5 idiopathic macular hole patients (non-diabetic controls), 5 untreated PDR patients (no-treatment group), and 5 PDR patients treated with intravitreal aflibercept injection (treatment group). Methods: Next-generation sequencing was performed to determine the miRNA profiles. Deregulated miRNAs were validated with quantitative real-time PCR (qRT-PCR) in another cohort. The mRNA profile data (GSE160310) of PDR patients were retrieved from the Gene Expression Omnibus (GEO) database. The function of differentially expressed miRNAs and mRNAs was annotated by bioinformatic analysis and literature study. Results: Twenty-nine miRNAs were significantly dysregulated in the three groups, of which 19,984 target mRNAs were predicted. Hsa-miR-3184-3p, hsa-miR-24-3p, and hsa-miR-197-3p were validated to be remarkably upregulated in no-treatment group versus controls, and significantly downregulated in treatment group versus no-treatment group. In the GSE160310 profile, 204 deregulated protein-coding mRNAs were identified, and finally 179 overlapped mRNAs between the 19,984 target mRNAs and 204 deregulated mRNAs were included for further analysis. Function analysis provided several roles of aflibercept-induced miRNAs, promoting the alternation of drug sensitivity or resistance-related mRNAs, and regulating critical mRNAs involved in angiogenesis and retinal fibrosis. Conclusion: Hsa-miR-3184-3p, hsa-miR-24-3p, and hsa-miR-197-3p were highly expressed in PDR patients, and intravitreal aflibercept injection could reverse this alteration. Intravitreal aflibercept injection may involve in regulating cell sensitivity or resistance to drug, angiogenesis, and retinal fibrosis.
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Affiliation(s)
- Ju Guo
- Department of Ophthalmology, Henan Province Eye Hospital, Henan International Joint Research Laboratory for Ocular Immunology and Retinal Injury Repair, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Pengyi Zhou
- Department of Ophthalmology, Henan Province Eye Hospital, Henan International Joint Research Laboratory for Ocular Immunology and Retinal Injury Repair, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Zhenhui Liu
- Department of Ophthalmology, Henan Province Eye Hospital, Henan International Joint Research Laboratory for Ocular Immunology and Retinal Injury Repair, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Fangfang Dai
- People’s Hospital of Zhengzhou University and Henan Eye Institute, Zhengzhou, China
| | - Meng Pan
- Department of Ophthalmology, Henan Province Eye Hospital, Henan International Joint Research Laboratory for Ocular Immunology and Retinal Injury Repair, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Guangqi An
- Department of Ophthalmology, Henan Province Eye Hospital, Henan International Joint Research Laboratory for Ocular Immunology and Retinal Injury Repair, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Jinfeng Han
- People’s Hospital of Zhengzhou University and Henan Eye Institute, Zhengzhou, China
| | - Liping Du
- Department of Ophthalmology, Henan Province Eye Hospital, Henan International Joint Research Laboratory for Ocular Immunology and Retinal Injury Repair, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Xuemin Jin
- Department of Ophthalmology, Henan Province Eye Hospital, Henan International Joint Research Laboratory for Ocular Immunology and Retinal Injury Repair, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
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Barbagallo C, Platania CBM, Drago F, Barbagallo D, Di Pietro C, Purrello M, Bucolo C, Ragusa M. Do Extracellular RNAs Provide Insight into Uveal Melanoma Biology? Cancers (Basel) 2021; 13:5919. [PMID: 34885029 PMCID: PMC8657116 DOI: 10.3390/cancers13235919] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2021] [Revised: 11/22/2021] [Accepted: 11/23/2021] [Indexed: 12/12/2022] Open
Abstract
Uveal melanoma (UM) is the most common primary intraocular malignant tumor in adults, showing a high mortality due to metastasis. Although it is considered a rare disease, a growing number of papers have reported altered levels of RNAs (i.e., coding and non-coding RNAs) in cancerous tissues and biological fluids from UM patients. The presence of circulating RNAs, whose dysregulation is associated with UM, paved the way to the possibility of exploiting it for diagnostic and prognostic purposes. However, the biological meaning and the origin of such RNAs in blood and ocular fluids of UM patients remain unexplored. In this review, we report the state of the art of circulating RNAs in UM and debate whether the amount and types of RNAs measured in bodily fluids mirror the RNA alterations from source cancer cells. Based on literature data, extracellular RNAs in UM patients do not represent, with rare exceptions, a snapshot of RNA dysregulations occurring in cancerous tissues, but rather the complex and heterogeneous outcome of a systemic dysfunction, including immune system activity, that modifies the mechanisms of RNA delivery from several cell types.
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Affiliation(s)
- Cristina Barbagallo
- Department of Biomedical and Biotechnological Sciences—Section of Biology and Genetics, University of Catania, 95123 Catania, Italy; (C.B.); (D.B.); (C.D.P.); (M.P.); (M.R.)
- Department of Clinical and Experimental Medicine, University of Catania, 95123 Catania, Italy
| | - Chiara Bianca Maria Platania
- Department of Biomedical and Biotechnological Sciences—Section of Pharmacology, University of Catania, 95123 Catania, Italy; (C.B.M.P.); (F.D.)
| | - Filippo Drago
- Department of Biomedical and Biotechnological Sciences—Section of Pharmacology, University of Catania, 95123 Catania, Italy; (C.B.M.P.); (F.D.)
- Center of Research in Ocular Pharmacology—CERFO, University of Catania, 95123 Catania, Italy
| | - Davide Barbagallo
- Department of Biomedical and Biotechnological Sciences—Section of Biology and Genetics, University of Catania, 95123 Catania, Italy; (C.B.); (D.B.); (C.D.P.); (M.P.); (M.R.)
| | - Cinzia Di Pietro
- Department of Biomedical and Biotechnological Sciences—Section of Biology and Genetics, University of Catania, 95123 Catania, Italy; (C.B.); (D.B.); (C.D.P.); (M.P.); (M.R.)
| | - Michele Purrello
- Department of Biomedical and Biotechnological Sciences—Section of Biology and Genetics, University of Catania, 95123 Catania, Italy; (C.B.); (D.B.); (C.D.P.); (M.P.); (M.R.)
| | - Claudio Bucolo
- Department of Biomedical and Biotechnological Sciences—Section of Pharmacology, University of Catania, 95123 Catania, Italy; (C.B.M.P.); (F.D.)
- Center of Research in Ocular Pharmacology—CERFO, University of Catania, 95123 Catania, Italy
| | - Marco Ragusa
- Department of Biomedical and Biotechnological Sciences—Section of Biology and Genetics, University of Catania, 95123 Catania, Italy; (C.B.); (D.B.); (C.D.P.); (M.P.); (M.R.)
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Lazzara F, Conti F, Platania CBM, Eandi CM, Drago F, Bucolo C. Effects of Vitamin D 3 and Meso-Zeaxanthin on Human Retinal Pigmented Epithelial Cells in Three Integrated in vitro Paradigms of Age-Related Macular Degeneration. Front Pharmacol 2021; 12:778165. [PMID: 34803719 PMCID: PMC8602342 DOI: 10.3389/fphar.2021.778165] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2021] [Accepted: 09/30/2021] [Indexed: 11/13/2022] Open
Abstract
Age-related macular degeneration (AMD) is a degenerative retinal disease and one of major causes of irreversible vision loss. AMD has been linked to several pathological factors, such as oxidative stress and inflammation. Moreover, Aβ (1-42) oligomers have been found in drusen, the extracellular deposits that accumulate beneath the retinal pigmented epithelium in AMD patients. Hereby, we investigated the hypothesis that treatment with 1,25(OH) 2D3 (vitamin D3) and meso-zeaxathin, physiologically present in the eye, would counteract the toxic effects of three different insults on immortalized human retinal pigmented epithelial cells (ARPE-19). Specifically, ARPE-19 cells have been challenged with Aβ (1-42) oligomers, H2O2, LPS, and TNF-α, respectively. In the present study, we demonstrated that the combination of 1,25(OH)2D3 and meso-zeaxanthin significantly counteracted the cell damage induced by the three insults, at least in these in vitro integrated paradigms of AMD. These results suggest that combination of 1,25(OH)2D3 and meso-zeaxathin could be a useful approach to contrast pathological features of AMD, such as retinal inflammation and oxidative stress.
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Affiliation(s)
- Francesca Lazzara
- Department of Biomedical and Biotechnological Sciences, School of Medicine, University of Catania, Catania, Italy
| | - Federica Conti
- Department of Biomedical and Biotechnological Sciences, School of Medicine, University of Catania, Catania, Italy
| | - Chiara Bianca Maria Platania
- Department of Biomedical and Biotechnological Sciences, School of Medicine, University of Catania, Catania, Italy
| | - Chiara M Eandi
- Department of Ophthalmology, Fondation Asile des Aveugles, Jules Gonin Eye Hospital, University of Lausanne, Lausanne, Switzerland.,Department of Surgical Sciences, University of Torino, Torino, Italy
| | - Filippo Drago
- Department of Biomedical and Biotechnological Sciences, School of Medicine, University of Catania, Catania, Italy.,Center for Research in Ocular Pharmacology-CERFO, University of Catania, Catania, Italy
| | - Claudio Bucolo
- Department of Biomedical and Biotechnological Sciences, School of Medicine, University of Catania, Catania, Italy.,Center for Research in Ocular Pharmacology-CERFO, University of Catania, Catania, Italy
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Liu J, Hou Y, Lin L, Yu N, Zhang Y. MicroRNA-5195-3p alleviates high glucose‑induced injury in human ARPE-19 cells by targeting GMFB. PLoS One 2021; 16:e0260071. [PMID: 34793551 PMCID: PMC8601420 DOI: 10.1371/journal.pone.0260071] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2021] [Accepted: 11/02/2021] [Indexed: 12/15/2022] Open
Abstract
Hyperglycemia is generally considered to be an important cause of diabetic retinopathy (DR). The aim of the present study was to investigate the role of miR-5195-3p in high glucose (HG)-induced human retinal pigment epithelial ARPE-19 cell injury. Here, we first found that the expression level of miR-5195-3p was significantly downregulated in HG-stimulated ARPE-19 cells using reverse transcription quantitative PCR. Overexpression of miR-5195-3p attenuated the impaired cell viability, increased apoptosis and pro-inflammatory cytokines secretion in ARPE-19 cells under HG condition using CCK-8 assay, flow cytometry and ELISA assay, respectively. Luciferase reporter assay showed that miR-5195-3p could specifically bind to the 3’UTR of glia maturation factor-β (GMFB). GMFB overexpression reversed, while knockdown enhanced the protective effects of miR-5195-3p overexpression against HG-induced ARPE-19 cell injury. In summary, miR-5195-3p targeting GMFB might be a potential therapeutic target for DR.
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Affiliation(s)
- Jingjing Liu
- Eye Hospital, the First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China
- * E-mail:
| | - Yongsheng Hou
- Eye Hospital, the First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China
| | - Lili Lin
- Eye Hospital, the First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China
| | - Nannan Yu
- Eye Hospital, the First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China
| | - Yanyan Zhang
- Eye Hospital, the First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China
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Sun L, Liu X, Zuo Z. Regulatory role of miRNA-23a in diabetic retinopathy. Exp Ther Med 2021; 22:1477. [PMID: 34765018 PMCID: PMC8576621 DOI: 10.3892/etm.2021.10912] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2020] [Accepted: 03/12/2021] [Indexed: 11/21/2022] Open
Abstract
The present study aimed to investigate the expression of microRNA (miRNA)-23a in blood and tear samples from diabetic retinopathy (DR) patients. Blood and tear samples were obtained from 33 patients with proliferative DR. Additionally, a rat model of DR was established. Reverse transcription-quantitative PCR was used to determine vascular endothelial growth factor (VEGF) mRNA and miRNA-23a expression levels, while ELISA and western blot analysis were performed to determine protein expression levels. Bioinformatics analysis and dual luciferase reporter assay were used to predict and validate the interaction between miRNA-23a and VEGF and cell proliferative ability was assessed with the MTT assay. In comparison to control patients VEGF mRNA and protein expression levels were significantly elevated in the blood and tear samples from patients with DR, while the expression level of miRNA-23a was significantly reduced. In blood and retinal tissues from a rat model of DR, the mRNA and protein expression levels of VEGF were significantly increased, while the miRNA-23a expression level was significantly decreased relative to controls. Dual luciferase reporter assay showed that miRNA-23a bound to the 3'-untranslated region (UTR) of VEGF. Moreover, over-expression of miRNA-23a significantly reduced the expression level of VEGF and the proliferative activity of human retinal microvascular endothelial cells. The elevated VEGF expression in the blood and tears of patients with DR may be related to the reduced miRNA-23a expression. miRNA-23a may regulate microvascular growth at the retina via VEGF and contribute to DR progression.
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Affiliation(s)
- Lihui Sun
- Department of Anatomy, Histology and Embryology, Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region 530021, P.R. China.,The Fifth Department of General Surgery, The Third Affiliated Hospital of Jinzhou Medical University, Jinzhou, Liaoning 121000, P.R. China
| | - Xuezheng Liu
- Department of Anatomy, Histology and Embryology, Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region 530021, P.R. China.,Liaoning Key Laboratory of Diabetic Cognitive and Perceptive Dysfunction, Department of Anatomy, Histology and Embryology, Jinzhou Medical University, Jinzhou, Liaoning 121000, P.R. China
| | - Zhongfu Zuo
- Liaoning Key Laboratory of Diabetic Cognitive and Perceptive Dysfunction, Department of Anatomy, Histology and Embryology, Jinzhou Medical University, Jinzhou, Liaoning 121000, P.R. China.,Department of Anatomy, Histology and Embryology, Postdoctoral Research Station, Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region 530021, P.R. China
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Jiang J, Ou W, Luo X, Xiang J, Liu G, Huang S, Li H, He L, Gan J, Han S, Nie C. Effect of Probenecid on Endothelial Cell Growth Rate and Retinal Angiogenesis in an Oxygen-Induced Retinopathy Model. Front Pharmacol 2021; 12:717351. [PMID: 34690760 PMCID: PMC8526964 DOI: 10.3389/fphar.2021.717351] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2021] [Accepted: 09/01/2021] [Indexed: 12/02/2022] Open
Abstract
Objectives: Probenecid is an anion transport inhibitor, which, according to the connectivity map (CMap; a biological application database), interferes with hypoxia-induced gene expression changes in retinal vascular endothelial cells (ECs). Here, we investigated the influence of probenecid on retinal EC cytotoxicity and retinal neovascularization in a murine oxygen-induced retinopathy (OIR) model. Methods: The retinal EC growth rate in the presence of hypoxia-mimicking concentrations of cobalt chloride (CoCl2) was determined using the thiazolyl blue tetrazolium bromide (MTT) assay and proliferating cell nuclear antigen (PCNA) expression. In OIR rats, probenecid was administered by intraperitoneal injection (i.p.) from postnatal day (P) 1 to P7. The concentrations of vitreous humor vascular endothelial growth factor (VEGF), hypoxia-inducible factor (HIF)-1α, and placental growth factor (PlGF) were determined by using the ELISA kit at P21. The amount of newly formed vascular lumen was evaluated by histopathological examination. Retinopathy and neovascularization were assessed by scoring isolectin B4 fluorescein–stained retinal flat mounts. Western blots for liver tissue HIF-1α and hepcidin (HAMP) were performed. Results:In vitro, probenecid led to the recession of the hypoxia-induced EC growth rate. In vivo, compared to the OIR retina, the upregulation of VEGF, HIF-1α, and PlGF in phase II retinopathy of prematurity (ROP) was inhibited by probenecid administration. Moreover, probenecid ameliorated neovascularization and resulted in significantly reduced relative leakage fluorescence signal intensity in fluorescein-stained retinal flat mounts (p < 0.05). Probenecid alleviated the liver overactivation of HAMP and downregulation of HIF-1α in OIR rats. Conclusions: This is the first demonstration that implies that probenecid might be a protective compound against retinal angiogenesis in OIR. These changes are accompanied with decreased hyperoxia-mediated hepcidin overproduction. Although the relevance of the results to ROP needs further research, these findings may help establish potential pharmacological targets based on the CMap database.
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Affiliation(s)
- Jingbo Jiang
- Neonatology Department, Shenzhen Children's Hospital, Shenzhen, China
| | - Weiming Ou
- Department of Pediatrics, The First Affiliated Hospital, Jinan University, Guangzhou, China
| | - Xianqiong Luo
- Neonatology Department, Guangdong Women and Children Hospital, Guangzhou, China
| | - Jianwen Xiang
- Neonatology Department, Guangdong Women and Children Hospital, Guangzhou, China
| | - Guosheng Liu
- Department of Neonatology and Pediatrics, The First Affiliated Hospital, Jinan University, Guangzhou, China
| | - Shuiqing Huang
- Neonatology Department, Guangdong Women and Children Hospital, Guangzhou, China
| | - Hongping Li
- Neonatology Department, Shenzhen Children's Hospital, Shenzhen, China
| | - Longkai He
- Department of Neonatology and Pediatrics, The First Affiliated Hospital, Jinan University, Guangzhou, China
| | - Jiamin Gan
- Neonatology Department, Guangdong Women and Children's Hospital, Guangzhou Medical University, Guangzhou, China
| | - Shasha Han
- Department of Neonatology and Pediatrics, The First Affiliated Hospital, Jinan University, Guangzhou, China
| | - Chuan Nie
- Neonatology Department, Guangdong Women and Children Hospital, Guangzhou, China
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Meng C, Gu C, He S, Su T, Lhamo T, Draga D, Qiu Q. Pyroptosis in the Retinal Neurovascular Unit: New Insights Into Diabetic Retinopathy. Front Immunol 2021; 12:763092. [PMID: 34737754 PMCID: PMC8560732 DOI: 10.3389/fimmu.2021.763092] [Citation(s) in RCA: 38] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2021] [Accepted: 09/28/2021] [Indexed: 12/15/2022] Open
Abstract
Diabetic retinopathy (DR) is prevalent among people with long-term diabetes mellitus (DM) and remains the leading cause of visual impairment in working-aged people. DR is related to chronic low-level inflammatory reactions. Pyroptosis is an emerging type of inflammatory cell death mediated by gasdermin D (GSDMD), NOD-like receptors and inflammatory caspases that promote interleukin-1β (IL-1β) and IL-18 release. In addition, the retinal neurovascular unit (NVU) is the functional basis of the retina. Recent studies have shown that pyroptosis may participate in the destruction of retinal NVU cells in simulated hyperglycemic DR environments. In this review, we will clarify the importance of pyroptosis in the retinal NVU during the development of DR.
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Affiliation(s)
- Chunren Meng
- Department of Ophthalmology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- National Clinical Research Center for Eye Diseases; Shanghai Key Laboratory of Ocular Fundus Diseases, Shanghai Engineering Center for Visual Science and Photomedicine, Shanghai Engineering Center for Precise Diagnosis and Treatment of Eye Diseases, Shanghai, China
| | - Chufeng Gu
- Department of Ophthalmology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- National Clinical Research Center for Eye Diseases; Shanghai Key Laboratory of Ocular Fundus Diseases, Shanghai Engineering Center for Visual Science and Photomedicine, Shanghai Engineering Center for Precise Diagnosis and Treatment of Eye Diseases, Shanghai, China
| | - Shuai He
- Department of Ophthalmology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- National Clinical Research Center for Eye Diseases; Shanghai Key Laboratory of Ocular Fundus Diseases, Shanghai Engineering Center for Visual Science and Photomedicine, Shanghai Engineering Center for Precise Diagnosis and Treatment of Eye Diseases, Shanghai, China
| | - Tong Su
- Department of Ophthalmology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- National Clinical Research Center for Eye Diseases; Shanghai Key Laboratory of Ocular Fundus Diseases, Shanghai Engineering Center for Visual Science and Photomedicine, Shanghai Engineering Center for Precise Diagnosis and Treatment of Eye Diseases, Shanghai, China
| | - Thashi Lhamo
- Department of Ophthalmology, Shigatse People’s Hospital, Shigatse, China
| | - Deji Draga
- Department of Ophthalmology, Shigatse People’s Hospital, Shigatse, China
| | - Qinghua Qiu
- Department of Ophthalmology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- National Clinical Research Center for Eye Diseases; Shanghai Key Laboratory of Ocular Fundus Diseases, Shanghai Engineering Center for Visual Science and Photomedicine, Shanghai Engineering Center for Precise Diagnosis and Treatment of Eye Diseases, Shanghai, China
- Department of Ophthalmology, Shigatse People’s Hospital, Shigatse, China
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Investigation of Key Signaling Pathways Associating miR-204 and Common Retinopathies. BIOMED RESEARCH INTERNATIONAL 2021; 2021:5568113. [PMID: 34646884 PMCID: PMC8505061 DOI: 10.1155/2021/5568113] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/30/2021] [Revised: 06/15/2021] [Accepted: 09/08/2021] [Indexed: 02/07/2023]
Abstract
MicroRNAs are a large group of small noncoding RNAs that work in multiple cellular pathways. miR-204, as one of the key axes in the development, maintenance, and pathogenesis of the retina, plays several roles by modulating its target genes. This study was aimed at evaluating the target genes of miR-204 involved in the development and progression of common retinopathies such as glaucoma, retinoblastoma, and age-related macular degeneration. In this study, three datasets related to retinopathies (GSE50195, GSE27276, and GSE97508) were selected from Gene Expression Omnibus. miR-204 target genes were isolated from TargeScan. The shares between retinopathy and miR-204 target genes were then categorized. Using Enrichr and STRING, we highlighted the signaling pathways and the relationships between the proteins. SHC1 events in ERBB2, adherent junction's interactions, NGF signaling via TRKA from the plasma membrane, IRF3-mediated activation of type 1 IFN, pathways in upregulated genes and G0 and early G1, RORA-activated gene expression, PERK-regulated gene expression, adherent junction's interactions, and CREB phosphorylation pathways in downregulated genes were identified in glaucoma, retinoblastoma, and age-related macular degeneration. WEE1, SMC2, HMGB1, RRM2, and POLA1 proteins were also observed to be involved in the progression and invasion of retinoblastoma; SLC24A2 and DTX4 in age-related macular degeneration; and EPHB6, EFNB3, and SHC1 in glaucoma. Continuous bioinformatics analysis has shown that miR-204 has a significant presence and expression in retinal tissue, and approximately 293 genes are controlled and regulated by miR-204 in this tissue; also, target genes of miR-204 have the potential to develop various retinopathies; thus, a study of related target genes can provide appropriate treatment strategies in the future.
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Burgaletto C, Platania CBM, Di Benedetto G, Munafò A, Giurdanella G, Federico C, Caltabiano R, Saccone S, Conti F, Bernardini R, Bucolo C, Cantarella G. Targeting the miRNA-155/TNFSF10 network restrains inflammatory response in the retina in a mouse model of Alzheimer's disease. Cell Death Dis 2021; 12:905. [PMID: 34611142 PMCID: PMC8492692 DOI: 10.1038/s41419-021-04165-x] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2021] [Revised: 08/25/2021] [Accepted: 09/15/2021] [Indexed: 12/18/2022]
Abstract
Age-related disorders, such as Alzheimer’s disease (AD) and age-related macular degeneration (AMD) share common features such as amyloid-β (Aβ) protein accumulation. Retinal deposition of Aβ aggregates in AMD patients has suggested a potential link between AMD and AD. In the present study, we analyzed the expression pattern of a focused set of miRNAs, previously found to be involved in both AD and AMD, in the retina of a triple transgenic mouse model of AD (3xTg-AD) at different time-points. Several miRNAs were differentially expressed in the retina of 3xTg-AD mice, compared to the retina of age-matched wild-type (WT) mice. In particular, bioinformatic analysis revealed that miR-155 had a central role in miRNA-gene network stability, regulating several pathways, including apoptotic and inflammatory signaling pathways modulated by TNF-related apoptosis-inducing ligand (TNFSF10). We showed that chronic treatment of 3xTg-AD mice with an anti-TNFSF10 monoclonal antibody was able to inhibit the retinal expression of miR-155, which inversely correlated with the expression of its molecular target SOCS-1. Moreover, the fine-tuned mechanism related to TNFSF10 immunoneutralization was tightly linked to modulation of TNFSF10 itself and its death receptor TNFRSF10B, along with cytokine production by microglia, reactive gliosis, and specific AD-related neuropathological hallmarks (i.e., Aβ deposition and Tau phosphorylation) in the retina of 3xTg-AD mice. In conclusion, immunoneutralization of TNFSF10 significantly preserved the retinal tissue in 3xTg-AD mice, suggesting its potential therapeutic application in retinal degenerative disorders.
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Affiliation(s)
- Chiara Burgaletto
- Department of Biomedical and Biotechnological Sciences, Section of Pharmacology, University of Catania School of Medicine, Catania, Italy
| | - Chiara Bianca Maria Platania
- Department of Biomedical and Biotechnological Sciences, Section of Pharmacology, University of Catania School of Medicine, Catania, Italy
| | - Giulia Di Benedetto
- Department of Biomedical and Biotechnological Sciences, Section of Pharmacology, University of Catania School of Medicine, Catania, Italy
| | - Antonio Munafò
- Department of Biomedical and Biotechnological Sciences, Section of Pharmacology, University of Catania School of Medicine, Catania, Italy
| | - Giovanni Giurdanella
- Department of Biomedical and Biotechnological Sciences, Section of Biochemistry, University of Catania School of Medicine, Catania, Italy
| | - Concetta Federico
- Department of Biological, Geological and Environmental Sciences, Section of Animal Biology, University of Catania, Catania, Italy
| | - Rosario Caltabiano
- Department Gian Filippo Ingrassia, Section of Anatomic Pathology, University of Catania, Catania, Italy
| | - Salvatore Saccone
- Department of Biological, Geological and Environmental Sciences, Section of Animal Biology, University of Catania, Catania, Italy
| | - Federica Conti
- Department of Biomedical and Biotechnological Sciences, Section of Pharmacology, University of Catania School of Medicine, Catania, Italy
| | - Renato Bernardini
- Department of Biomedical and Biotechnological Sciences, Section of Pharmacology, University of Catania School of Medicine, Catania, Italy. .,Clinical Toxicology Unit, University Hospital, University of Catania, Catania, Italy.
| | - Claudio Bucolo
- Department of Biomedical and Biotechnological Sciences, Section of Pharmacology, University of Catania School of Medicine, Catania, Italy
| | - Giuseppina Cantarella
- Department of Biomedical and Biotechnological Sciences, Section of Pharmacology, University of Catania School of Medicine, Catania, Italy
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Gesualdo C, Balta C, Platania CBM, Trotta MC, Herman H, Gharbia S, Rosu M, Petrillo F, Giunta S, Della Corte A, Grieco P, Bellavita R, Simonelli F, D'Amico M, Hermenean A, Rossi S, Bucolo C. Fingolimod and Diabetic Retinopathy: A Drug Repurposing Study. Front Pharmacol 2021; 12:718902. [PMID: 34603029 PMCID: PMC8484636 DOI: 10.3389/fphar.2021.718902] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2021] [Accepted: 08/20/2021] [Indexed: 01/11/2023] Open
Abstract
This study aimed to investigate the interactions between fingolimod, a sphingosine 1-phosphate receptor (S1PR) agonist, and melanocortin receptors 1 and 5 (MCR1, MCR5). In particular, we investigated the effects of fingolimod, a drug approved to treat relapsing-remitting multiple sclerosis, on retinal angiogenesis in a mouse model of diabetic retinopathy (DR). We showed, by a molecular modeling approach, that fingolimod can bind with good-predicted affinity to MC1R and MC5R. Thereafter, we investigated the fingolimod actions on retinal MC1Rs/MC5Rs in C57BL/6J mice. Diabetes was induced in C57BL/6J mice through streptozotocin injection. Diabetic and control C57BL/6J mice received fingolimod, by oral route, for 12 weeks and a monthly intravitreally injection of MC1R antagonist (AGRP), MC5R antagonist (PG20N), and the selective S1PR1 antagonist (Ex 26). Diabetic animals treated with fingolimod showed a decrease of retinal vascular endothelial growth factor A (VEGFA) and vascular endothelial growth factor receptors 1 and 2 (VEGFR1 and VEGFR2), compared to diabetic control group. Fingolimod co-treatment with MC1R and MC5R selective antagonists significantly (p < 0.05) increased retinal VEGFR1, VEGFR2, and VEGFA levels compared to mice treated with fingolimod alone. Diabetic animals treated with fingolimod plus Ex 26 (S1PR1 selective blocker) had VEGFR1, VEGFR2, and VEGFA levels between diabetic mice group and the group of diabetic mice treated with fingolimod alone. This vascular protective effect of fingolimod, through activation of MC1R and MC5R, was evidenced also by fluorescein angiography in mice. Finally, molecular dynamic simulations showed a strong similarity between fingolimod and the MC1R agonist BMS-470539. In conclusion, the anti-angiogenic activity exerted by fingolimod in DR seems to be mediated not only through S1P1R, but also by melanocortin receptors.
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Affiliation(s)
- Carlo Gesualdo
- Multidisciplinary Department of Medical, Surgical and Dental Sciences, University of Campania "Luigi Vanvitelli", Naples, Italy
| | - Cornel Balta
- "Aurel Ardelean" Institute of Life Sciences, Vasile Godis Western University of Arad, Arad, Romania
| | - Chiara Bianca Maria Platania
- Department of Biomedical and Biotechnological Sciences, School of Medicine, University of Catania, Catania, Italy
| | - Maria Consiglia Trotta
- Department of Experimental Medicine, University of Campania "Luigi Vanvitelli", Naples, Italy
| | - Hildegard Herman
- "Aurel Ardelean" Institute of Life Sciences, Vasile Godis Western University of Arad, Arad, Romania
| | - Sami Gharbia
- "Aurel Ardelean" Institute of Life Sciences, Vasile Godis Western University of Arad, Arad, Romania
| | - Marcel Rosu
- "Aurel Ardelean" Institute of Life Sciences, Vasile Godis Western University of Arad, Arad, Romania
| | | | - Salvatore Giunta
- Department of Biomedical and Biotechnological Sciences, School of Medicine, University of Catania, Catania, Italy
| | - Alberto Della Corte
- Multidisciplinary Department of Medical, Surgical and Dental Sciences, University of Campania "Luigi Vanvitelli", Naples, Italy
| | - Paolo Grieco
- Pharmacy Department, University of Naples Federico II, Naples, Italy
| | - Rosa Bellavita
- Pharmacy Department, University of Naples Federico II, Naples, Italy
| | - Francesca Simonelli
- Multidisciplinary Department of Medical, Surgical and Dental Sciences, University of Campania "Luigi Vanvitelli", Naples, Italy
| | - Michele D'Amico
- Department of Experimental Medicine, University of Campania "Luigi Vanvitelli", Naples, Italy
| | - Anca Hermenean
- "Aurel Ardelean" Institute of Life Sciences, Vasile Godis Western University of Arad, Arad, Romania.,Department of Histology, Faculty of Medicine, Vasile Goldis Western University of Arad, Arad, Romania
| | - Settimio Rossi
- Multidisciplinary Department of Medical, Surgical and Dental Sciences, University of Campania "Luigi Vanvitelli", Naples, Italy
| | - Claudio Bucolo
- Department of Biomedical and Biotechnological Sciences, School of Medicine, University of Catania, Catania, Italy
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Zhang R, Feng Y, Lu J, Ge Y, Li H. lncRNA Ttc3-209 Promotes the Apoptosis of Retinal Ganglion Cells in Retinal Ischemia Reperfusion Injury by Targeting the miR-484/Wnt8a Axis. Invest Ophthalmol Vis Sci 2021; 62:13. [PMID: 33687475 PMCID: PMC7960841 DOI: 10.1167/iovs.62.3.13] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023] Open
Abstract
Purpose Apoptosis of the retinal ganglion cells (RGCs) can cause irreversible damage to visual function after retinal ischemia reperfusion injury (RIR). Using a lncRNA chip assay, we selected lncRNA Ttc-209 and characterized its role in RGCs during ischemia reperfusion (I/R)–induced apoptosis. Methods We created an ischemic model of RGCs by applying Hank's balanced salt solution containing 10 µM antimycin A and 2 µM calcium ionophore for 2 hours. RIR was induced in mice by elevating the intraocular pressure to 120 mm Hg for 1 hour by cannulation of the cornea; this was followed by reperfusion. Real-time quantitative PCR was used to detect the expression levels of long noncoding RNA (lncRNA), microRNA (miRNA), and target gene mRNA. Western blotting, flow cytometry, immunofluorescent staining, and TUNEL assays were performed to detect cell apoptosis. Dual-luciferase reporter assays and FISH were used to identify endogenous competitive RNA (ceRNA) mechanisms that link lncRNAs, miRNAs, and target genes. We also used scotopic electroretinography examinations to evaluate visual function in treated mice. Results lncRNA Ttc3-209 was significantly upregulated after I/R injury and played a proapoptotic role in RGCs during I/R-induced apoptosis. Mechanistically, lncRNA Ttc3-209 is a ceRNA that competitively binds to miR-484 and upregulates the translation of its target (Wnt8a mRNA), thus promoting apoptosis in RGCs. Conclusions Reducing the expression of lncRNA Ttc3-209 had a protective effect against apoptosis in RGCs. This may provide a new therapeutic option for the prevention of RGC apoptosis in response to RIR injury.
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Affiliation(s)
- Ran Zhang
- Department of Ophthalmology, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, China.,Hunan Clinical Research Center of Ophthalmic Disease, Changsha, Hunan 410011, China
| | - Yuqing Feng
- Department of Ophthalmology, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, China.,Hunan Clinical Research Center of Ophthalmic Disease, Changsha, Hunan 410011, China
| | - Jinfang Lu
- Department of Ophthalmology, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, China.,Hunan Clinical Research Center of Ophthalmic Disease, Changsha, Hunan 410011, China
| | - Yanni Ge
- Department of Ophthalmology, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, China.,Hunan Clinical Research Center of Ophthalmic Disease, Changsha, Hunan 410011, China
| | - Huiling Li
- Department of Ophthalmology, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, China.,Hunan Clinical Research Center of Ophthalmic Disease, Changsha, Hunan 410011, China
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Li XQ, Huang TY. Notoginsenoside R1 alleviates high glucose-induced inflammation and oxidative stress in HUVECs via upregulating miR-147a. Kaohsiung J Med Sci 2021; 37:1101-1112. [PMID: 34369659 DOI: 10.1002/kjm2.12433] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2021] [Revised: 06/06/2021] [Accepted: 06/24/2021] [Indexed: 01/22/2023] Open
Abstract
Endothelial dysfunction in atherosclerotic cardiovascular diseases has become one of the main characteristics in patients with diabetes mellitus, which is usually caused by abnormal inflammation and oxidative stress response. Presently, we focused on the role of Notoginsenoside R1 (NR1), a major component isolated from Panax notoginseng, in endothelial dysfunction caused by high glucose (HG). Human umbilical vein endothelial cells (HUVECs) were treated with HG and then dealt with NR1. Cell counting kit-8 assay and 5-bromo-2'-dexoyuridine assay were conducted to examine cell proliferation and viability. Flow cytometry was used to measure apoptosis. The angiogenesis of HUVECs was determined by tube formation assay. Moreover, the expressions of miR-147a, inflammatory cytokines (TNF-α, IL-6, and IL-10) and oxidative stress markers malondialdehyde, superoxide dismutase, and glutathione peroxidase were measured. The protein levels of MyD88/TRAF6/NF-κB axis, Bax, Bcl2, and Caspase3 were detected by Western blot. Furthermore, gain and loss of functional assays of miR-147a were performed to verify the role of miR-147a in NR1-mediated effects. Our data confirmed that NR1 (at 10-40 μM) reduces HG-induced HUVECs proliferation and viability inhibition, mitigates apoptosis, and enhances tube formation ability. Meanwhile, NR1 inhibited oxidative stress and inflammatory response and blocked the activation of the MyD88/TRAF6/NF-κB pathway induced by HG. In addition, NR1 promoted the expression of miR-147a, which targeted MyD88. Overexpression of miR-147a markedly inactivated MyD88/TRAF6/NF-κB pathway, while the miR-147a inhibitors reversed NR1-mediated protective effect in HG-induced HUVECs through activating MyD88/TRAF6/NF-κB pathway. In conclusion, NR1 relieves HG-induced endothelial cell injury by downregulating the MyD88/TRAF6/NF-κB pathway via upregulating miR-147a.
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Affiliation(s)
- Xiao-Qing Li
- Department of Chinese Medicine Surgery, Beijing Hospital of Traditional Chinese Medicine, Capital Medical University, Beijing, China
| | - Tian-Yi Huang
- Department of Peripheral Vascular, Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, China
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Guo Y, Du F, Tan YL, Luo J, Xiong D, Song WT. VEGF-mediated angiogenesis in retinopathy of prematurity is co-regulated by miR-17-5p and miR-20a-5p. Biochem Cell Biol 2021; 99:414-423. [PMID: 34319836 DOI: 10.1139/bcb-2020-0357] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
Abstract
The microRNAs miR-17-5p and miR-20a-5p play important roles on angiogenesis; however, it is arguable whether they regulate the formation of retinal blood vessels in retinopathy of prematurity (ROP). We used a mouse model of oxygen-induced retinopathy (OIR) to simulate the development of retinas in mice suffering from ROP, and the expression levels of miR-20a-5p, miR-17-5p, hypoxia-inducible factor 1-alpha (HIF-1α), and vascular endothelial growth factor (VEGF) were measured by RT-qPCR and Western blotting. Cell proliferation, apoptosis, and angiogenesis in the OIR model mice were measured using MTT assays, flow cytometry, and Matrigel assays, respectively. The interaction between HIF-1α/VEGF and miR-20a-5p/miR-17-5p were further validated using dual-luciferase reporter assays, biotin-labeled RNA-pulldown, and RNA immunoprecipitation (RIP) assays. In our OIR model, retinal angiogenesis in the mice was associated with down-regulation of miR-20a-5p and miR-17-5p, as well as up-regulation of HIF-1α and VEGF. In addition, the miR-20a-5p and miR-17-5p inhibited cell proliferation and angiogenesis through regulating HIF-1α and VEGF in the retinal cells of the OIR model mice. Moreover, it was found that miR-20a-5p and miR-17-5p bind to HIF-1α and VEGF at the 3'UTR, and there was a combined effect between miR-20a-5p and miR-17-5p on the regulation of HIF-1α and VEGF. It is worth noting that miR-17-5p and miR-20a-5p can preferentially regulate HIF-1α, then act on VEGF, thereby affecting the angiogenesis associated with ROP.
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Affiliation(s)
- Yan Guo
- Department of Ophthalmology, Hunan Children's Hospital, Changsha 410007, Hunan Province, P.R. China
| | - Fen Du
- Department of Ophthalmology, Hunan Children's Hospital, Changsha 410007, Hunan Province, P.R. China
| | - Yi-Lan Tan
- Department of Ophthalmology, Hunan Children's Hospital, Changsha 410007, Hunan Province, P.R. China
| | - Jun Luo
- Department of Ophthalmology, Hunan Children's Hospital, Changsha 410007, Hunan Province, P.R. China
| | - Dan Xiong
- Department of Ophthalmology, Hunan Children's Hospital, Changsha 410007, Hunan Province, P.R. China
| | - Wei-Tao Song
- Department of Ophthalmology, Xiangya Hospital, Central South University, Changsha 410008, Central South University, P.R. China
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Wang H, Su X, Zhang QQ, Zhang YY, Chu ZY, Zhang JL, Ren Q. MicroRNA-93-5p participates in type 2 diabetic retinopathy through targeting Sirt1. Int Ophthalmol 2021; 41:3837-3848. [PMID: 34313929 DOI: 10.1007/s10792-021-01953-4] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2021] [Accepted: 07/09/2021] [Indexed: 12/18/2022]
Abstract
OBJECTIVE To investigate the role of miR-93-5p in rats with type 2 diabetic retinopathy (DR) through targeting Sirt1. METHODS The targeting correlation between miR-93-5p and Sirt1 was validated by dual-luciferase reporter gene assay. Type 2 diabetes mellitus (T2DM) rat models were received intravitreal injection of antagomir NC (negative control), miR-93-5p antagomir, miR-93-5p agomir and/or recombinant Sirt1, followed by observation of pathological changes in retina via HE staining. Besides, retinal vascular permeability was determined by fluorescein isothiocyanate-bovine serum albumin (FITC-BSA), while the retinal vasculature was observed through retinal trypsin digestion. Expression of miR-93-5p and Sirt1 was measured by qRT-PCR and Western blotting, while the levels of VEGF, proinflammatory cytokines and anti-oxidative indicators were determined using corresponding kits. RESULTS MiR-93-5p could target Sirt1 as analyzed by the luciferase reporter gene assay. Rats in the T2DM group presented the up-regulation of miR-93-5p and down-regulation of Sirt1 in the retina, and miR-93-5p inhibition could up-regulate Sirt1 expression in the T2DM rats. Recombinant Sirt1 decreased retinal vascular permeability and acellular capillaries with improved pathological changes in retina from T2DM rats, which was abolished by miR-93-5p agomir. Moreover, miR-93-5p inhibition or Sirt1 overexpression decreased the levels of VEGF and proinflammatory cytokines while enhancing the activity of anti-oxidative indicators. However, indicators above had no significant differences between T2DM group and T2DM + agomir + Sirt1 group. CONCLUSION MiR-93-5p, via targeting Sirt1, could affect the vascular permeability and acellular capillaries and mitigate the inflammation and oxidative stress in the retinas, which may play a critical role in DR.
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Affiliation(s)
- Hui Wang
- Department of Ophthalmology, Shijiazhuang People's Hospital, No. 365, Jianhua South Street, Yuhua District, Shijiazhuang, 050030, Hebei Province, China
| | - Xian Su
- Department of Ophthalmology, Shijiazhuang People's Hospital, No. 365, Jianhua South Street, Yuhua District, Shijiazhuang, 050030, Hebei Province, China
| | - Qian-Qian Zhang
- Department of Ophthalmology, Shijiazhuang People's Hospital, No. 365, Jianhua South Street, Yuhua District, Shijiazhuang, 050030, Hebei Province, China
| | - Ying-Ying Zhang
- Department of Ophthalmology, Shijiazhuang People's Hospital, No. 365, Jianhua South Street, Yuhua District, Shijiazhuang, 050030, Hebei Province, China
| | - Zhan-Ya Chu
- Department of Ophthalmology, Shijiazhuang People's Hospital, No. 365, Jianhua South Street, Yuhua District, Shijiazhuang, 050030, Hebei Province, China
| | - Jin-Ling Zhang
- Department of Ophthalmology, Shijiazhuang People's Hospital, No. 365, Jianhua South Street, Yuhua District, Shijiazhuang, 050030, Hebei Province, China
| | - Qian Ren
- Department of Ophthalmology, Shijiazhuang People's Hospital, No. 365, Jianhua South Street, Yuhua District, Shijiazhuang, 050030, Hebei Province, China.
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Liu L, Jiang Y, Steinle J. Epac1 regulates TLR4 signaling in the diabetic retinal vasculature. Cytokine 2021; 144:155576. [PMID: 34020266 DOI: 10.1016/j.cyto.2021.155576] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2021] [Revised: 04/09/2021] [Accepted: 05/04/2021] [Indexed: 01/08/2023]
Abstract
Toll-like receptor 4 (TLR4) polymorphisms occur in diabetic patients. Previous work showed that TLR4 is in the retina of diabetic mice, as well as in retinal endothelial cells (REC) and Müller cells. Since we have shown that exchange protein activated by cAMP 1 (Epac1) can reduce inflammatory mediators, we hypothesized that Epac1 would inhibit TLR4 signaling. We also hypothesized that direct TLR4 inhibition would protect the diabetic retina. Human REC in normal and high glucose were treated with an Epac1 agonist to explore the actions of Epac1 on TLR4 signaling in vitro. Subsequently, 2-month diabetic endothelial cell specific knockout mice for Epac1 (Cdh5Cre-Epac1) and Epac1 floxed mice retinas were used for Western blotting for TLR4 signaling pathways. We also used direct inhibition of TLR4 via Tak242 to investigate diabetes-induced changes in retinal permeability and neuronal loss in the mice. The Epac1 agonist reduced TLR4 signaling in REC grown in high glucose. TLR4 levels and both MyD88-dependent and -independent signaling pathways are increased in Cdh5Cre-Epac1 mice compared to Epac1 floxed mice. Tak242 reduced TLR4 signaling in diabetic mice and reduced diabetes-induced increases in permeability and cell loss in the ganglion cell layer in the Epac1 floxed and Cdh5Cre-Epac1 mice. In conclusion, Epac1 reduced TLR4 signaling in the retina and in REC. Direct inhibition of TLR4 was able to protect the retina against diabetes-induced changes in permeability and cell numbers in the ganglion cell layer.
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Affiliation(s)
- Li Liu
- Department of Ophthalmology, Visual, and Anatomical Sciences, Wayne State University School of Medicine, Detroit, MI 48201, United States
| | - Youde Jiang
- Department of Ophthalmology, Visual, and Anatomical Sciences, Wayne State University School of Medicine, Detroit, MI 48201, United States
| | - Jena Steinle
- Department of Ophthalmology, Visual, and Anatomical Sciences, Wayne State University School of Medicine, Detroit, MI 48201, United States.
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Plasma miR-26a-5p is a biomarker for retinal neurodegeneration of early diabetic retinopathy. Eye (Lond) 2021; 35:1587-1599. [PMID: 33931763 DOI: 10.1038/s41433-021-01393-5] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2020] [Revised: 11/24/2020] [Accepted: 01/05/2021] [Indexed: 11/09/2022] Open
Abstract
PURPOSE Retinal neurodegeneration is an early pathological change in diabetic retinopathy (DR). Early-stage retinal neurodegeneration is usually asymptomatic. This study aims to identify circulating microRNAs (miRNAs) as sensitive biomarkers for early retinal neurodegeneration. METHODS We profiled the plasma miRNA expression in three mild nonproliferative diabetic retinopathy (NPDR) cases and three matched non-DR patients using RNA sequencing. The differential miRNAs were validated with qRT-PCR. The retinal nerve fibre layer (RNFL) thickness of the eyes was measured using spectral-domain Optical coherence tomography (SD-OCT). The association between differential miRNAs and RNFL thickness was analysed using the Pearson correlation analysis. Bioinformatics tools were used to predict potential targets of miRNA associated with RNFL thickness and investigate the functions of the potential target genes. RESULTS RNA sequencing identified 69 differential miRNAs and eight of them were reported to be associated with DR. The qRT-PCR for these eight miRNAs validated the down-regulation of circulating miR-26a-5p and miR-126-5p in a larger validating cohort. A positive correlation between plasma miR-26a-5p level and the RNFL thickness of the superior quadrant of both eyes was identified in another cohort, including 33 mild NPDR cases, 33 matched non-DR patients and 20 healthy controls. Furthermore, 367 candidate targets of miR-26a-5p were predicted. The functional studies revealed that these target genes are profoundly involved in various cellular functions and signalling pathways. CONCLUSIONS Circulating miR-26a-5p is a potential biomarker for early-stage retinal neurodegeneration and it may be involved in the development of DR via profoundly influencing the functions of retinal cells.
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