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Srirangan P, Shyam M, Radhakrishnan V, Prince SE. NLRP3 as a therapeutic target in cyclophosphamide-associated toxicities. Mol Biol Rep 2025; 52:364. [PMID: 40192868 DOI: 10.1007/s11033-025-10479-2] [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: 01/02/2025] [Accepted: 03/27/2025] [Indexed: 04/20/2025]
Abstract
Cyclophosphamide (CPM), a potent chemotherapeutic agent, while effective against various cancers, can cause significant organ damage. The NLRP3 inflammasome, a key player in the innate immune response, is implicated in this toxicity. This review delves into the intricate relationship between CPM and NLRP3 inflammasome activation, focusing on oxidative stress-mediated organ damage. We explore the mechanisms by which CPM induces NLRP3 activation in the kidneys, heart, liver, and gastrointestinal tract. Additionally, we examine the signaling pathways involved in this process. The review also discusses potential therapeutic interventions, including phytotherapeutic agents, that target NLRP3 inflammasome activation to mitigate CPM-induced organ injury. By highlighting the crucial role of NLRP3 in CPM-related toxicity, this review provides a foundation for future research aimed at developing novel therapeutic strategies to minimize adverse effects and improve patient outcomes.
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Affiliation(s)
- Prathap Srirangan
- School of Bio Sciences and Technology, VIT University, Vellore, Tamil Nadu, India
- Department of Biotechnology, School of Bio Sciences and Technology, Vellore Institute of Technology, Vellore, 632014, India
| | - Mukul Shyam
- School of Bio Sciences and Technology, VIT University, Vellore, Tamil Nadu, India
| | - Vidya Radhakrishnan
- VIT School of Agricultural Innovations and Advanced Learning, VIT University, Vellore, Tamil Nadu, India
| | - Sabina Evan Prince
- School of Bio Sciences and Technology, VIT University, Vellore, Tamil Nadu, India.
- Department of Biotechnology, School of Bio Sciences and Technology, Vellore Institute of Technology, Vellore, 632014, India.
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Cappellani F, Foti R, Malaguarnera G, D’Esposito F, Musumeci C, Rapisarda L, Tognetto D, Gagliano C, Zeppieri M. Nutrients and Natural Substances for Hypoglycemic Effects and Management in Diabetic Retinopathy. Nutrients 2025; 17:1207. [PMID: 40218965 PMCID: PMC11990073 DOI: 10.3390/nu17071207] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2025] [Revised: 03/26/2025] [Accepted: 03/26/2025] [Indexed: 04/14/2025] Open
Abstract
Diabetic retinopathy (DR) is a significant microvascular consequence of diabetes mellitus (DM), resulting in visual impairment and blindness. Controlling hyperglycemia is essential for avoiding and alleviating diabetic retinopathy. Nutrients and natural compounds possessing hypoglycemic characteristics present promising supplementary approaches to conventional therapies. This review assesses the influence of nutrients and natural substances on glycemic regulation and their possible effects on diabetic retinopathy. GOAL To investigate and consolidate knowledge about nutrients and natural compounds exhibiting hypoglycemic properties and their processes in the prevention and management of diabetic retinopathy. APPROACHES Extensive reviews were conducted on pertinent studies from databases including PubMed, Scopus, and Web of Science. Selection criteria encompassed papers that examined natural substances, nutrients, or dietary supplements exhibiting effects on blood glucose levels and pathways associated to diabetic retinopathy. Principal findings were encapsulated according to their mechanisms, efficacy, and safety. OUTCOMES Numerous foods, including omega-3 fatty acids, vitamin D, and polyphenols (e.g., curcumin, resveratrol), have hypoglycemic properties by improving insulin sensitivity and diminishing oxidative stress. Natural substances like berberine, quercetin, and flavonoids demonstrate analogous effects, influencing pathways associated with inflammation, advanced glycation end products (AGEs), and angiogenesis, which are critical factors in the evolution of diabetic retinopathy (DR). The synergistic benefits of integrating natural medicines with conventional antidiabetic medications may enhance glycemic control and reduce retinal damage. The safety profiles of these therapies are predominantly positive; nonetheless, clinical trials are still constrained in both breadth and scale. CONCLUSIONS Nutrients and natural compounds are promising supplementary approaches for glycemic regulation and the therapy of diabetic retinopathy. Additional research, encompassing extensive clinical studies, is required to substantiate their efficacy, determine optimal dose, and verify long-term safety. The use of these natural substances into clinical practice may improve comprehensive management of diabetes and associated consequences.
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Affiliation(s)
- Francesco Cappellani
- Department of Ophthalmology, University of Catania, 95123 Catania, Italy; (F.C.)
| | - Roberta Foti
- Division of Rheumatology, A.O.U. “Policlinico San Marco”, 95123 Catania, Italy
| | - Giulia Malaguarnera
- Department of Human Sciences and Quality of Life Promotion, San Raffaele Roma Open University, 00166 Rome, Italy
| | - Fabiana D’Esposito
- Imperial College Ophthalmic Research Group (ICORG) Unit, Imperial College, 153-173 Marylebone Rd., London NW1 5QH, UK
- Department of Neurosciences, Reproductive Sciences and Dentistry, University of Naples Federico II, Via Pansini 5, 80131 Napoli, Italy
| | - Carlo Musumeci
- Department of Ophthalmology, University of Catania, 95123 Catania, Italy; (F.C.)
| | - Lorenzo Rapisarda
- Department of Medicine and Surgery, University of Enna “Kore”, Piazza dell’Università, 94100 Enna, Italy
| | - Daniele Tognetto
- Department of Medicine, Surgery and Health Sciences, University of Trieste, 34127 Trieste, Italy
| | - Caterina Gagliano
- Department of Medicine and Surgery, University of Enna “Kore”, Piazza dell’Università, 94100 Enna, Italy
- Mediterranean Foundation “G.B. Morgagni”, 95125 Catania, Italy
| | - Marco Zeppieri
- Department of Medicine, Surgery and Health Sciences, University of Trieste, 34127 Trieste, Italy
- Department of Ophthalmology, University Hospital of Udine, 33100 Udine, Italy
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Xiong S, Xie J, Xiang F, Yu J, Li Y, Xia B, Zhang Z, Li C, Lin L. Research progress on pharmacological effects against liver and eye diseases of flavonoids present in Chrysanthum indicum L., Chrysanthemum morifolium Ramat., Buddleja officinalis Maxim. and Sophora japonica L. JOURNAL OF ETHNOPHARMACOLOGY 2025; 338:119094. [PMID: 39532220 DOI: 10.1016/j.jep.2024.119094] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/28/2024] [Revised: 10/07/2024] [Accepted: 11/08/2024] [Indexed: 11/16/2024]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Chrysanthemum indicum L., Chrysanthemum morifolium Ramat., Buddleja officinalis Maxim., and Sophora japonica L. have the effects of "Clearing the liver" and "Improving vision". Flavonoids are their main active ingredients, but there are few reports on their simultaneous liver and eye protective effects. AIM OF THE STUDY Overview of the role of flavonoids of the four medicinal flowers (FFMF) in the prevention and treatment of liver and eye diseases. MATERIALS AND METHODS The Web of Science, PubMed, CNKI, Google Scholar, and WanFang databases were searched for FFMF. Using "hepatitis", "liver fibrosis", "liver cancer", "dry eye syndrome", "cataracts", "glaucoma", "age-related macular degeneration", and "diabetic retinopathy" as the keywords, we summarized the main pathological mechanisms of these diseases and the role of FFMF in their prevention and treatment. RESULTS We found that the four medicinal flowers contained a total of 125 flavonoids. They can maintain liver and eye homeostasis by regulating pathological mechanisms such as oxidative stress, inflammation, endoplasmic reticulum stress, mitochondrial dysfunction, glucose and lipid metabolism disorders, and programmed cell death, exerting the effect of "clearing the liver and improving vision". CONCLUSION FFMF have a series of beneficial properties such as antioxidant, anti-inflammatory, antiviral, and antifibrotic activity, and the regulation of angiogenesis, glycolipid metabolism and programmed cell death, which may explain the efficacy of the four traditional Chinese medicines for "Clearing the liver" and "Improving vision".
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Affiliation(s)
- Suhui Xiong
- School of Pharmacy, Hunan University of Chinese Medicine, Changsha, China; Key Laboratory for Quality Evaluation of Bulk Herbs of Hunan Province, Hunan University of Chinese Medicine, Changsha, China.
| | - Jingchen Xie
- School of Pharmacy, Hunan University of Chinese Medicine, Changsha, China; Key Laboratory for Quality Evaluation of Bulk Herbs of Hunan Province, Hunan University of Chinese Medicine, Changsha, China.
| | - Feng Xiang
- School of Pharmacy, Hunan University of Chinese Medicine, Changsha, China; Key Laboratory for Quality Evaluation of Bulk Herbs of Hunan Province, Hunan University of Chinese Medicine, Changsha, China.
| | - Jiahui Yu
- School of Pharmacy, Hunan University of Chinese Medicine, Changsha, China; Key Laboratory for Quality Evaluation of Bulk Herbs of Hunan Province, Hunan University of Chinese Medicine, Changsha, China.
| | - Yamei Li
- School of Pharmacy, Hunan University of Chinese Medicine, Changsha, China; Key Laboratory for Quality Evaluation of Bulk Herbs of Hunan Province, Hunan University of Chinese Medicine, Changsha, China.
| | - Bohou Xia
- School of Pharmacy, Hunan University of Chinese Medicine, Changsha, China; Key Laboratory for Quality Evaluation of Bulk Herbs of Hunan Province, Hunan University of Chinese Medicine, Changsha, China.
| | - Zhimin Zhang
- School of Pharmacy, Hunan University of Chinese Medicine, Changsha, China; Key Laboratory for Quality Evaluation of Bulk Herbs of Hunan Province, Hunan University of Chinese Medicine, Changsha, China.
| | - Chun Li
- Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing, China.
| | - Limei Lin
- School of Pharmacy, Hunan University of Chinese Medicine, Changsha, China; Key Laboratory for Quality Evaluation of Bulk Herbs of Hunan Province, Hunan University of Chinese Medicine, Changsha, China.
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Wu J, Lv T, Liu Y, Liu Y, Han Y, Liu X, Peng X, Tang F, Cai J. The role of quercetin in NLRP3-associated inflammation. Inflammopharmacology 2024; 32:3585-3610. [PMID: 39306817 DOI: 10.1007/s10787-024-01566-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2024] [Accepted: 08/30/2024] [Indexed: 11/10/2024]
Abstract
Quercetin is a natural flavonoid that is widely found in fruits and vegetables. As an important flavonoid, it exhibits a wide range of biological activities, including antioxidant, anti-inflammatory, antiviral, immunomodulatory, and analgesic activities. Quercetin exerts powerful antioxidant activity by regulating glutathione, enzyme activity, and the production of reactive oxygen species (ROS). Quercetin exerts powerful anti-inflammatory effects by acting on the Nod-like receptor protein 3 (NLRP3) inflammasome. In diabetes, quercetin has been shown to improve insulin sensitivity and reduce high blood sugar level, while, in neurological diseases, it potentially prevents neuronal degeneration and cognitive decline by regulating neuroinflammation. In addition, in liver diseases, quercetin may improve liver inflammation and fibrosis by regulating the NLRP3 activity. In addition, quercetin may improve inflammation in other diseases based on the NLRP3 inflammasome. With this background, in this review, we have discussed the progress in the study on the mechanism of quercetin toward improving inflammation via NLRP3 inflammasome in the past decade. In addition, from the perspective of quercetin glycoside derivatives, the anti-inflammatory mechanism of hyperoside, rutin, and isoquercetin based on NLRP3 inflammasome has been discussed. Moreover, we have discussed the pharmacokinetics of quercetin and its nanoformulation application, with the aim to provide new ideas for further research on the anti-inflammatory effect of quercetin and its glycoside derivatives based on NLRP3 inflammasome, as well as in drug development and application.
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Affiliation(s)
- Jiaqi Wu
- Department of Pathophysiology, School of Basic Medicine, Health Science Center, Yangtze University, Jingzhou, 434023, China
- Laboratory of Oncology, Center for Molecular Medicine, School of Basic Medicine, Health Science Center, Yangtze University, Jingzhou, 434023, China
| | - Tongtong Lv
- Department of Pathophysiology, School of Basic Medicine, Health Science Center, Yangtze University, Jingzhou, 434023, China
- Laboratory of Oncology, Center for Molecular Medicine, School of Basic Medicine, Health Science Center, Yangtze University, Jingzhou, 434023, China
| | - Yu Liu
- Department of Oncology, Gong'an County People's Hospital, Jingzhou, 434000, China
| | - Yifan Liu
- Laboratory of Oncology, Center for Molecular Medicine, School of Basic Medicine, Health Science Center, Yangtze University, Jingzhou, 434023, China
- Department of Oncology, Jingzhou Hospital Affiliated to Yangtze University, Jingzhou, 434023, China
| | - Yukun Han
- Laboratory of Oncology, Center for Molecular Medicine, School of Basic Medicine, Health Science Center, Yangtze University, Jingzhou, 434023, China
- Department of Medical Imaging, School of Medicine, and Positron Emission Computed Tomography (PET) Center of the First Affiliated Hospital, Yangtze University, Jingzhou, 434023, China
| | - Xin Liu
- Department of Pathophysiology, School of Basic Medicine, Health Science Center, Yangtze University, Jingzhou, 434023, China
- Laboratory of Oncology, Center for Molecular Medicine, School of Basic Medicine, Health Science Center, Yangtze University, Jingzhou, 434023, China
| | - Xiaochun Peng
- Department of Pathophysiology, School of Basic Medicine, Health Science Center, Yangtze University, Jingzhou, 434023, China.
- Laboratory of Oncology, Center for Molecular Medicine, School of Basic Medicine, Health Science Center, Yangtze University, Jingzhou, 434023, China.
| | - Fengru Tang
- Radiation Physiology Laboratory, Singapore Nuclear Research and Safety Initiative, National University of Singapore, 1 CREATE Way #04-01, CREATE Tower, Singapore, 138602, Singapore.
| | - Jun Cai
- Department of Oncology, First Affiliated Hospital of Yangtze University, Jingzhou, 434023, China.
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Zheng X, Wang Y, Gong X, Chen W, Zheng W, Chen T. Quercetin activates autophagy in the distal ischemic area of random skin flaps through Beclin1 to enhance the adaptability to energy deficiency. Heliyon 2024; 10:e38181. [PMID: 39497976 PMCID: PMC11533565 DOI: 10.1016/j.heliyon.2024.e38181] [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: 04/15/2024] [Revised: 09/19/2024] [Accepted: 09/19/2024] [Indexed: 11/07/2024] Open
Abstract
Random flaps are frequently employed in treating substantial skin abnormalities and in surgical tissue-rebuilding interventions. The random flap technique provides flaps of specific dimensions and contours to fit the surgical incision. However, blood supply deficiency and subsequent ischemia-reperfusion injury can cause severe oxidative stress and apoptosis, eventually leading to distal necrosis, which limits the clinical application of the flap. Quercetin (QUE) is primarily found in the glycoside form in many plant parts, such as stem bark, flowers, leaves, buds, seeds, and fruits. Cellular, animal, and clinical studies have demonstrated the antioxidant, anti-apoptosis, anti-inflammatory, and activation of autophagy properties of QUE. In previous studies, high doses of QUE effectively suppressed the survival of human umbilical vein endothelial cells (HUVECs) stimulated by hydrogen peroxide. However, different concentration gradients of QUE on HUVECs revealed a significant protective effect at a concentration of 10 mM. The protective impact of QUE on HUVECs was evaluated using scratch tests, CCK-8 assays, and EDU assays. Simultaneously, a mouse model of random skin flap was created, and the impact of QUE on skin flap survival was examined by intragastric injection. The QUE group showed a significantly larger survival area of the random flap and higher blood flow intensity compared to the control group. Furthermore, the beneficial effects of QUE were reversed by the autophagy inhibitor 3-MA. Therefore, autophagy plays a significant role in the therapeutic benefits of QUE on flap survival.
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Affiliation(s)
- Xin Zheng
- Department of Orthopedics, Municipal Hospital Affiliated to Taizhou University, Zhejiang, Taizhou, 318000, China
| | - Yiyu Wang
- Zhejiang Provincial Key Laboratory of Plant Evolutionary Ecology and Conservation, Taizhou Key Laboratory of Biomedicine and Advanced Dosage Forms, School of Life Sciences, Taizhou University, Zhejiang Taizhou, 318000, China
| | - Xiaokang Gong
- Department of Orthopedics, Municipal Hospital Affiliated to Taizhou University, Zhejiang, Taizhou, 318000, China
| | - Weijie Chen
- Department of Orthopedics, Municipal Hospital Affiliated to Taizhou University, Zhejiang, Taizhou, 318000, China
| | - Wenbiao Zheng
- Department of Orthopedics, Municipal Hospital Affiliated to Taizhou University, Zhejiang, Taizhou, 318000, China
| | - Tao Chen
- Department of Orthopedics, Municipal Hospital Affiliated to Taizhou University, Zhejiang, Taizhou, 318000, China
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Ye X, Fung NSK, Lam WC, Lo ACY. Nutraceuticals for Diabetic Retinopathy: Recent Advances and Novel Delivery Systems. Nutrients 2024; 16:1715. [PMID: 38892648 PMCID: PMC11174689 DOI: 10.3390/nu16111715] [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: 04/17/2024] [Revised: 05/22/2024] [Accepted: 05/27/2024] [Indexed: 06/21/2024] Open
Abstract
Diabetic retinopathy (DR) is a major vision-threatening disease among the working-age population worldwide. Present therapeutic strategies such as intravitreal injection of anti-VEGF and laser photocoagulation mainly target proliferative DR. However, there is a need for early effective management in patients with early stage of DR before its progression into the more severe sight-threatening proliferative stage. Nutraceuticals, natural functional foods with few side effects, have been proposed to be beneficial in patients with DR. Over the decades, many studies, either in vitro or in vivo, have demonstrated the advantages of a number of nutraceuticals in DR with their antioxidative, anti-inflammatory, neuroprotective, or vasoprotective effects. However, only a few clinical trials have been conducted, and their outcomes varied. The low bioavailability and instability of many nutraceuticals have indeed hindered their utilization in clinical use. In this context, nanoparticle carriers have been developed to deliver nutraceuticals and to improve their bioavailability. Despite its preclinical nature, research of interventive nutraceuticals for DR may yield promising information in their clinical applications.
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Affiliation(s)
- Xiaoyuan Ye
- Department of Ophthalmology, The University of Hong Kong, Hong Kong 999077, China; (X.Y.); (N.S.K.F.); (W.C.L.)
| | - Nicholas Siu Kay Fung
- Department of Ophthalmology, The University of Hong Kong, Hong Kong 999077, China; (X.Y.); (N.S.K.F.); (W.C.L.)
| | - Wai Ching Lam
- Department of Ophthalmology, The University of Hong Kong, Hong Kong 999077, China; (X.Y.); (N.S.K.F.); (W.C.L.)
- Department of Ophthalmology, University of British Columbia, 2550 Willow Street, Room 301, Vancouver, BC V5Z 3N9, Canada
| | - Amy Cheuk Yin Lo
- Department of Ophthalmology, The University of Hong Kong, Hong Kong 999077, China; (X.Y.); (N.S.K.F.); (W.C.L.)
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Liu F, Zhao L, Wu T, Yu W, Li J, Wang W, Huang C, Diao Z, Xu Y. Targeting autophagy with natural products as a potential therapeutic approach for diabetic microangiopathy. Front Pharmacol 2024; 15:1364616. [PMID: 38659578 PMCID: PMC11039818 DOI: 10.3389/fphar.2024.1364616] [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: 01/02/2024] [Accepted: 03/26/2024] [Indexed: 04/26/2024] Open
Abstract
As the quality of life improves, the incidence of diabetes mellitus and its microvascular complications (DMC) continues to increase, posing a threat to people's health and wellbeing. Given the limitations of existing treatment, there is an urgent need for novel approaches to prevent and treat DMC. Autophagy, a pivotal mechanism governing metabolic regulation in organisms, facilitates the removal of dysfunctional proteins and organelles, thereby sustaining cellular homeostasis and energy generation. Anomalous states in pancreatic β-cells, podocytes, Müller cells, cardiomyocytes, and Schwann cells in DMC are closely linked to autophagic dysregulation. Natural products have the property of being multi-targeted and can affect autophagy and hence DMC progression in terms of nutrient perception, oxidative stress, endoplasmic reticulum stress, inflammation, and apoptosis. This review consolidates recent advancements in understanding DMC pathogenesis via autophagy and proposes novel perspectives on treating DMC by either stimulating or inhibiting autophagy using natural products.
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Affiliation(s)
- Fengzhao Liu
- First Clinical Medical College, Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Lijuan Zhao
- First Clinical Medical College, Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Tao Wu
- College of Traditional Chinese Medicine, Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Wenfei Yu
- First Clinical Medical College, Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Jixin Li
- Xi yuan Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Wenru Wang
- Xi yuan Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Chengcheng Huang
- Department of Endocrinology, Shandong University of Traditional Chinese Medicine Affiliated Hospital, Jinan, China
| | - Zhihao Diao
- College of Acupuncture and Massage, Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Yunsheng Xu
- Department of Endocrinology, Second Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, China
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Saikia L, Barbhuiya SAA, Saikia K, Kalita P, Dutta PP. Therapeutic Potential of Quercetin in Diabetic Neuropathy and Retinopathy: Exploring Molecular Mechanisms. Curr Top Med Chem 2024; 24:2351-2361. [PMID: 39253913 DOI: 10.2174/0115680266330678240821060623] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2024] [Revised: 07/03/2024] [Accepted: 07/23/2024] [Indexed: 09/11/2024]
Abstract
Diabetes mellitus poses a significant health challenge globally, often leading to debilitating complications, such as neuropathy and retinopathy. Quercetin, a flavonoid prevalent in fruits and vegetables, has demonstrated potential therapeutic effects in these conditions due to its antioxidant, anti-inflammatory, and neuroprotective properties. This review summarizes and provides a comprehensive understanding of the molecular mechanisms underlying the efficacy of quercetin in ameliorating diabetic neuropathy and retinopathy. A thorough search was carried out across scientific databases, such as SciFinder, PubMed, and Google Scholar, to gather pertinent literature regarding the effect of quercetin on diabetic neuropathy and retinopathy till February 2024. Preclinical studies indicate that quercetin mitigates neuropathic pain, sensory deficits, and nerve damage associated with diabetic neuropathy by improving neuronal function, reducing DNA damage, regulating pro-inflammatory cytokines, enhancing antioxidant enzyme levels and endothelial function, as well as restoring nerve injuries. In diabetic retinopathy, quercetin shows the potential to preserve retinal structure and function, inhibiting neovascularization, preventing retinal cell death, reducing pro-inflammatory cytokines, and increasing neurotrophic factor levels. Moreover, through modulating key signaling pathways, such as AMP-activated Protein Kinase (AMPK) activation, Glucose Transporter 4 (GLUT 4) upregulation, and insulin secretion regulation, quercetin demonstrates efficacy in reducing oxidative stress and inflammation, thereby protecting nerve and retinal tissues. Despite promising preclinical findings, challenges, such as limited bioavailability, necessitate further research to optimize quercetin's clinical application in order to establish its optimal dosage, formulation, and long-term efficacy in clinical settings.
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Affiliation(s)
- Lunasmrita Saikia
- Faculty of Pharmaceutical Science, Assam down town University, Sankar Madhab Path, Gandhi Nagar Panikhaiti, Guwahati, 781026, Assam, India
| | - Sm Abdul Aziz Barbhuiya
- Faculty of Pharmaceutical Science, Assam down town University, Sankar Madhab Path, Gandhi Nagar Panikhaiti, Guwahati, 781026, Assam, India
| | - Kalyani Saikia
- Faculty of Pharmaceutical Science, Assam down town University, Sankar Madhab Path, Gandhi Nagar Panikhaiti, Guwahati, 781026, Assam, India
| | - Pratap Kalita
- Pratiksha Institute of Pharmaceutical Sciences, Guwahati, Assam, 781026, India
| | - Partha Pratim Dutta
- Faculty of Pharmaceutical Science, Assam down town University, Sankar Madhab Path, Gandhi Nagar Panikhaiti, Guwahati, 781026, Assam, India
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Wang L, Yu T, Dong F, Xu J, Fu J, Sun H. Tongqiao Mingmu formula alleviates retinal ganglion cell autophagy through PI3K/AKT/mTOR pathway. Anat Rec (Hoboken) 2023; 306:3120-3130. [PMID: 36098527 DOI: 10.1002/ar.25060] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2022] [Revised: 06/20/2022] [Accepted: 07/12/2022] [Indexed: 11/06/2022]
Abstract
Glaucoma is a severe blindness-causing optic nerve disease characterized by a loss of retinal ganglion cells (RGCs). Previous studies have shown that the Tongqiao Mingmu (TQMM) formula can reduce retinal and optic nerve damage, but its mechanism of action requires further elucidation. In this study, an RGC injury model was prepared using glutamate and then treated with serum-containing drug from the TQMM formula (hereafter called "TQMM formula serum"). In the glutamate-induced RGC injury model, cell viability decreased with an increase in glutamate concentration, whereas the expression of autophagy-related biomarkers LC3 and Belicin-1 increased. An adenovirus transfection experiment revealed that glutamate markedly promoted autophagic flux in RGCs. Notably, TQMM formula serum inhibited the expression of autophagy-related biomarkers, reduced autophagy flux, and reversed the damage caused by glutamate to RGCs. Furthermore, the PI3K inhibitor LY294002 was used to intervene in the RGC autophagy model and was found to suppress the PI3K/AKT/mTOR pathway and enhance RGC autophagy. However, TQMM formula serum could generate an opposite effect and upregulate the expressions of the PI3K/AKT/mTOR pathway genes and proteins. In conclusion, the TQMM formula can prevent glutamate-induced autophagy in RGCs, possibly by activating the PI3K/AKT/mTOR pathway and reducing the expression of autophagy-related biomarkers LC3 and Belicin-1 to attenuate autophagy and maintain RGC viability.
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Affiliation(s)
- Liyuan Wang
- Heilongjiang University of Chinese Medicine, Harbin, China
- Department of Ophthalmology, First Affiliated Hospital of Heilongjiang University of Chinese Medicine, Harbin, China
- Heilongjiang Academy of Sciences of Traditional Chinese Medicine, Harbin, China
| | - Tianyang Yu
- Heilongjiang University of Chinese Medicine, Harbin, China
- Department of Acupuncture, Second Affiliated Hospital of Heilongjiang University of Chinese Medicine, Harbin, China
| | - Feixue Dong
- Heilongjiang University of Chinese Medicine, Harbin, China
- Department of Ophthalmology, First Affiliated Hospital of Heilongjiang University of Chinese Medicine, Harbin, China
| | - Jiayu Xu
- Heilongjiang University of Chinese Medicine, Harbin, China
| | - Jin Fu
- Heilongjiang University of Chinese Medicine, Harbin, China
| | - He Sun
- Heilongjiang University of Chinese Medicine, Harbin, China
- Department of Ophthalmology, First Affiliated Hospital of Heilongjiang University of Chinese Medicine, Harbin, China
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Du G, Yan Y, Gao JF, Guo CY, Shen X, Lei XW. Therapeutic effect of folic acid combined with decitabine on diabetic mice. Int J Ophthalmol 2023; 16:1766-1772. [PMID: 38028519 PMCID: PMC10626348 DOI: 10.18240/ijo.2023.11.05] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2023] [Accepted: 08/15/2023] [Indexed: 12/01/2023] Open
Abstract
AIM To evaluate the therapeutic effect of folic acid combined with decitabine on diabetic mice. METHODS The diabetic model of db/db mice were randomly divided into model group, folic acid group, decitabine group, folic acid combined with decitabine group, and C57 mice as normal control group. The density of retinal blood vessels and retinal thickness were detected by fundus photography and optical coherence tomography, respectively. Pathological changes of retina were observed by hematoxylin-eosin (HE) staining. The homocysteine (Hcy) in serum was detected by enzyme linked immunosorbent assay (ELISA). TdT-mediated dUTP nick-end labeling (TUNEL) was used to detect apoptosis in retinal tissue. Evans blue dye was used to detect the permeability of retinal blood vessels. The platelet endothelial cell adhesion molecule-1 (CD31) and vascular endothelial growth factor receptor (VEGFR) protein were detected by Western blot. The 3-nitrotyrosine (3-NT) and 4-hydroxynonanine (4-HNE) were detected by immunohistochemistry. RESULTS The density of retinal blood vessels, retinal thickness, retinal vascular permeability and the proportion of apoptotic cells of retinal tissue in the model group increased significantly than control group (P<0.05). The Hcy in serum and the levels of CD31, VEGFR, 3-NT, and 4-HNE in retinal tissue increased significantly in the model group (P<0.01). Folic acid and decitabine both reversed these changes significantly, and the combination of the folic acid and decitabine worked best. CONCLUSION The combination of folic acid and decitabine has a more significant protective effect on the retina in diabetic mice.
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Affiliation(s)
- Gang Du
- The First Hospital of Lanzhou University, Lanzhou 730000, Gansu Province, China
| | - Yong Yan
- Huining Second People's Hospital, Baiyin 730700, Gansu Province, China
| | - Jun-Feng Gao
- The Fourth People's Hospital of Tianshui, Tianshui 741000, Gansu Province, China
| | - Chun-Yan Guo
- Dingxi People's Hospital, Dingxi 743000, Gansu Province, China
| | - Xiao Shen
- The First Hospital of Lanzhou University, Lanzhou 730000, Gansu Province, China
| | - Xun-Wen Lei
- The First Hospital of Lanzhou University, Lanzhou 730000, Gansu Province, China
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Zhao X, Bie LY, Pang DR, Li X, Yang LF, Chen DD, Wang YR, Gao Y. The role of autophagy in the treatment of type II diabetes and its complications: a review. Front Endocrinol (Lausanne) 2023; 14:1228045. [PMID: 37810881 PMCID: PMC10551182 DOI: 10.3389/fendo.2023.1228045] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/27/2023] [Accepted: 08/24/2023] [Indexed: 10/10/2023] Open
Abstract
Type II diabetes mellitus (T2DM) is a chronic metabolic disease characterized by prolonged hyperglycemia and insulin resistance (IR). Its incidence is increasing annually, posing a significant threat to human life and health. Consequently, there is an urgent requirement to discover effective drugs and investigate the pathogenesis of T2DM. Autophagy plays a crucial role in maintaining normal islet structure. However, in a state of high glucose, autophagy is inhibited, resulting in impaired islet function, insulin resistance, and complications. Studies have shown that modulating autophagy through activation or inhibition can have a positive impact on the treatment of T2DM and its complications. However, it is important to note that the specific regulatory mechanisms vary depending on the target organ. This review explores the role of autophagy in the pathogenesis of T2DM, taking into account both genetic and external factors. It also provides a summary of reported chemical drugs and traditional Chinese medicine that target the autophagic pathway for the treatment of T2DM and its complications.
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Affiliation(s)
- Xuan Zhao
- Institute of Pharmaceutical Research, Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Lu-Yao Bie
- Tsinghua University-Peking University Joint Center for Life Sciences, School of Life Sciences, Tsinghua University, Beijing, China
| | - Dao-Ran Pang
- Institute of Pharmaceutical Research, Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Xiao Li
- Innovative Institute of Chinese Medicine and Pharmacy, Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Long-Fei Yang
- Institute of Pharmaceutical Research, Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Dan-Dan Chen
- Institute of Pharmaceutical Research, Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Yue-Rui Wang
- College of Traditional Chinese Medicine, Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Yan Gao
- Institute of Pharmaceutical Research, Shandong University of Traditional Chinese Medicine, Jinan, China
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12
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Ren HW, Yu W, Wang YN, Zhang XY, Song SQ, Gong SY, Meng LY, Gan C, Liu BJ, Gong Q. Effects of autophagy inhibitor 3-methyladenine on a diabetic mice model. Int J Ophthalmol 2023; 16:1456-1464. [PMID: 37724274 PMCID: PMC10475630 DOI: 10.18240/ijo.2023.09.12] [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: 07/14/2022] [Accepted: 06/21/2023] [Indexed: 09/20/2023] Open
Abstract
AIM To investigate the role of autophagy inhibitor 3-methyladenine (3-MA) on a diabetic mice model (DM) and the potential mechanism. METHODS Male C57BL/6J mice were randomly divided into a normal control group (NC group) and an DM group. DM were induced by multiple low-dose intraperitoneal injection of streptozotocin (STZ) 60 mg/kg·d for 5 consecutive days. DM mice were randomly subdivided into untreated group (DM group), 3-MA (10 mg/kg·d by gavage) treated group (DM+3-MA group) and chloroquine (CQ; 50 mg/kg by intraperitoneal injection) treated group (DM+CQ group). The fasting blood glucose (FBG) levels were recorded every week. At the end of experiment, retinal samples were collected. The expression levels of pro-apoptotic proteins cleaved caspase-3, cleaved poly ADP-ribose polymerase 1 (PARP1) and Bax, anti-apoptotic protein Bcl-2, fibrosis-associated proteins Fibronectin and type 1 collagen α1 chain (COL1A1), vascular endothelial growth factor (VEGF), inflammatory factors interleukin (IL)-1β and tumor necrosis factor (TNF)-α, as well as autophagy related proteins LC3, Beclin-1 and P62 were determined by Western blotting. The oxidative stress indicators 8-hydroxydeoxyguanosine (8-OHdG) and malondialdehyde (MDA) were detected by commercial kits. RESULTS Both 3-MA and CQ had short-term hypoglycemic effect on FBG and reduced the expression of VEGF and inflammatory factors IL-1β and TNF-α in DM mice. 3-MA also significantly alleviated oxidative stress indicators 8-OHdG and MDA, decreased the expression of fibrosis-related proteins Fibronectin and COL1A1, pro-apoptotic proteins cleaved caspase-3, cleaved PARP1, as well as the ratio of Bax/Bcl-2. CQ had no significant impact on the oxidative stress indicators, fibrosis, and apoptosis related proteins. The results of Western blotting for autophagy related proteins showed that the ratio of LC3 II/LC3 I and the expression of Beclin-1 in the retina of DM mice were decreased by 3-MA treatment, and the expression of P62 was further increased by CQ treatment. CONCLUSION 3-MA has anti-apoptotic and anti-fibrotic effects on the retina of DM mice, and can attenuate retinal oxidative stress, VEGF expression and the production of inflammatory factors in the retina of DM mice. The underlying mechanism of the above effects of 3-MA may be related to its inhibition of early autophagy and hypoglycemic effect.
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Affiliation(s)
- Hai-Wen Ren
- Health Science Center, Yangtze University, Jingzhou 434023, Hubei Province, China
- Department of Clinical Laboratory, Bishan Hospital of Chongqing Medical University, Chongqing 402760, China
| | - Wen Yu
- Health Science Center, Yangtze University, Jingzhou 434023, Hubei Province, China
| | - Ya-Nan Wang
- Health Science Center, Yangtze University, Jingzhou 434023, Hubei Province, China
| | - Xin-Yi Zhang
- Health Science Center, Yangtze University, Jingzhou 434023, Hubei Province, China
| | - Shun-Qiong Song
- Health Science Center, Yangtze University, Jingzhou 434023, Hubei Province, China
| | - Shu-Yu Gong
- Health Science Center, Yangtze University, Jingzhou 434023, Hubei Province, China
| | - Ling-Yao Meng
- Health Science Center, Yangtze University, Jingzhou 434023, Hubei Province, China
| | - Chen Gan
- Health Science Center, Yangtze University, Jingzhou 434023, Hubei Province, China
| | - Ben-Ju Liu
- Department of Human Anatomy, Medical School of Yangtze University, Jingzhou 434023, Hubei Province, China
| | - Quan Gong
- Clinical Molecular Immunology Center, Medical School of Yangtze University, Jingzhou 434023, Hubei Province, China
- Department of Immunology, Medical School of Yangtze University, Jingzhou 434023, Hubei Province, China
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Li HD, Li MX, Zhang WH, Zhang SW, Gong YB. Effectiveness and safety of traditional Chinese medicine for diabetic retinopathy: A systematic review and network meta-analysis of randomized clinical trials. World J Diabetes 2023; 14:1422-1449. [PMID: 37771328 PMCID: PMC10523233 DOI: 10.4239/wjd.v14.i9.1422] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/17/2023] [Revised: 06/14/2023] [Accepted: 07/29/2023] [Indexed: 09/13/2023] Open
Abstract
BACKGROUND Diabetic retinopathy (DR) is currently recognized as one of the most serious diabetic microangiopathies and a major cause of adult blindness. Commonly used clinical approaches include etiological control, microvascular improvement, and surgical intervention, but they are ineffective and have many side effects. Oral Chinese medicine (OCM) has been used for thousands of years to treat DR and is still widely used today, but it is unclear which OCM is more effective for DR. AIM To estimate relative effectiveness and safety profiles for different classes of OCMs for DR, and provide rankings of the available OCMs. METHODS The search time frame was from the creation of the database to January 2023. RevMan 5.3 and Stata 14.0 software were used to perform the systematic review and Network meta-analyses (NMA). RESULTS A total of 107 studies and 9710 patients were included, including 4767 cases in the test group and 4973 cases in the control group. Based on previous studies and clinical reports, and combined with the recommendations of Chinese guidelines for the prevention and treatment of DR, 9 OCMs were finally included in this study, namely Compound Xueshuantong Capsules, Qiming Granules, Compound Danshen Dripping Pills, Hexue Mingmu Tablets (HXMM), Qiju Dihuang Pills (QJDH), Shuangdan Mingmu Capsules (SDMM), Danggui Buxue Decoction (DGBX), Xuefu Zhuyu Decoction and Buyang Huanwu Decoction. When these nine OCMs were analyzed in combination with conventional western medicine treatment (CT) compared with CT alone, the NMA results showed that HXMM + CT has better intervention effect on the overall efficacy of DR patients, HXMM + CT has better effect on improving patients' visual acuity, SDMM + CT has better effect on inhibiting vascular endothelial growth factor, DGBX + CT has better effect on reducing fundus hemorrhage area, HXMM + CT has better effect on reducing fasting blood glucose, and QJDH + CT has better effect on reducing glycated hemoglobin. When there are not enough clinical indicators for reference, SDMM + CT or HXMM + CT treatments can be chosen because they are effective for more indicators and demonstrate multidimensional efficacy. CONCLUSION This study provides evidence that combining OCMs with CT leads to better outcomes in all aspects of DR compared to using CT alone. Based on the findings, we highly recommend the use of SDMM or HXMM for the treatment of DR. These two OCMs have demonstrated outstanding efficacy across multiple indicators.
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Affiliation(s)
- Hong-Dian Li
- Dongfang Hospital, Beijing University of Chinese Medicine, Beijing 100700, China
| | - Ming-Xuan Li
- Capital Medical University, Beijing Hospital of Traditional Chinese Medicine, Beijing 100010, China
| | - Wen-Hua Zhang
- Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing 100700, China
| | - Shu-Wen Zhang
- Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing 100700, China
| | - Yan-Bing Gong
- Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing 100700, China
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Fanaro GB, Marques MR, Calaza KDC, Brito R, Pessoni AM, Mendonça HR, Lemos DEDA, de Brito Alves JL, de Souza EL, Cavalcanti Neto MP. New Insights on Dietary Polyphenols for the Management of Oxidative Stress and Neuroinflammation in Diabetic Retinopathy. Antioxidants (Basel) 2023; 12:1237. [PMID: 37371967 PMCID: PMC10295526 DOI: 10.3390/antiox12061237] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2023] [Revised: 06/05/2023] [Accepted: 06/06/2023] [Indexed: 06/29/2023] Open
Abstract
Diabetic retinopathy (DR) is a neurodegenerative and vascular pathology that is considered one of the leading causes of blindness worldwide, resulting from complications of advanced diabetes mellitus (DM). Current therapies consist of protocols aiming to alleviate the existing clinical signs associated with microvascular alterations limited to the advanced disease stages. In response to the low resolution and limitations of the DR treatment, there is an urgent need to develop more effective alternative therapies to optimize glycemic, vascular, and neuronal parameters, including the reduction in the cellular damage promoted by inflammation and oxidative stress. Recent evidence has shown that dietary polyphenols reduce oxidative and inflammatory parameters of various diseases by modulating multiple cell signaling pathways and gene expression, contributing to the improvement of several chronic diseases, including metabolic and neurodegenerative diseases. However, despite the growing evidence for the bioactivities of phenolic compounds, there is still a lack of data, especially from human studies, on the therapeutic potential of these substances. This review aims to comprehensively describe and clarify the effects of dietary phenolic compounds on the pathophysiological mechanisms involved in DR, especially those of oxidative and inflammatory nature, through evidence from experimental studies. Finally, the review highlights the potential of dietary phenolic compounds as a prophylactic and therapeutic strategy and the need for further clinical studies approaching the efficacy of these substances in DR management.
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Affiliation(s)
- Gustavo Bernardes Fanaro
- Institute of Health and Biotechnology, Federal University of Amazonas, Manaus 69460000, Amazonas, Brazil;
| | | | - Karin da Costa Calaza
- Department of Neurobiology, Institute of Biology, Fluminense Federal University, Niterói 24210201, Rio de Janeiro, Brazil;
| | - Rafael Brito
- Department of Cellular and Molecular Biology, Institute of Biology, Fluminense Federal University, Niterói 24210201, Rio de Janeiro, Brazil;
| | | | - Henrique Rocha Mendonça
- Institute of Biodiversity and Sustainability (NUPEM), Federal University of Rio de Janeiro, Macaé 27965045, Rio de Janeiro, Brazil; (H.R.M.); (M.P.C.N.)
| | | | - José Luiz de Brito Alves
- Department of Nutrition, Health Sciences Center, Federal University of Paraíba, João Pessoa 58051900, Paraíba, Brazil; (D.E.d.A.L.); (J.L.d.B.A.)
| | - Evandro Leite de Souza
- Department of Nutrition, Health Sciences Center, Federal University of Paraíba, João Pessoa 58051900, Paraíba, Brazil; (D.E.d.A.L.); (J.L.d.B.A.)
| | - Marinaldo Pacífico Cavalcanti Neto
- Institute of Biodiversity and Sustainability (NUPEM), Federal University of Rio de Janeiro, Macaé 27965045, Rio de Janeiro, Brazil; (H.R.M.); (M.P.C.N.)
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Accipe L, Abadie A, Neviere R, Bercion S. Antioxidant Activities of Natural Compounds from Caribbean Plants to Enhance Diabetic Wound Healing. Antioxidants (Basel) 2023; 12:antiox12051079. [PMID: 37237945 DOI: 10.3390/antiox12051079] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2023] [Revised: 04/23/2023] [Accepted: 04/28/2023] [Indexed: 05/28/2023] Open
Abstract
Diabetic wound healing is a global medical challenge. Several studies showed that delayed healing in diabetic patients is multifactorial. Nevertheless, there is evidence that excessive production of ROS and impaired ROS detoxification in diabetes are the main cause of chronic wounds. Indeed, increased ROS promotes the expression and activity of metalloproteinase, resulting in a high proteolytic state in the wound with significant destruction of the extracellular matrix, which leads to a stop in the repair process. In addition, ROS accumulation increases NLRP3 inflammasome activation and macrophage hyperpolarization in the M1 pro-inflammatory phenotype. Oxidative stress increases the activation of NETosis. This leads to an elevated pro-inflammatory state in the wound and prevents the resolution of inflammation, an essential step for wound healing. The use of medicinal plants and natural compounds can improve diabetic wound healing by directly targeting oxidative stress and the transcription factor Nrf2 involved in the antioxidant response or the mechanisms impacted by the elevation of ROS such as NLRP3 inflammasome, the polarization of macrophages, and expression or activation of metalloproteinases. This study of the diabetic pro-healing activity of nine plants found in the Caribbean highlights, more particularly, the role of five polyphenolic compounds. At the end of this review, research perspectives are presented.
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Affiliation(s)
- Laura Accipe
- UR5_3 PC2E Cardiac Pathology, Environmental Toxicity and Envenomations, Université des Antilles, BP 250, CEDEX, 97157 Pointe à Pitre, France
| | - Alisson Abadie
- UR5_3 PC2E Cardiac Pathology, Environmental Toxicity and Envenomations, Université des Antilles, BP 250, CEDEX, 97157 Pointe à Pitre, France
| | - Remi Neviere
- UR5_3 PC2E Cardiac Pathology, Environmental Toxicity and Envenomations, Université des Antilles, BP 250, CEDEX, 97157 Pointe à Pitre, France
- CHU Martinique, University Hospital of Martinique, 97200 Fort de France, France
| | - Sylvie Bercion
- UR5_3 PC2E Cardiac Pathology, Environmental Toxicity and Envenomations, Université des Antilles, BP 250, CEDEX, 97157 Pointe à Pitre, France
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16
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Wang T, Xu H, Dong R, Wu S, Guo Y, Wang D. Effectiveness of targeting the NLRP3 inflammasome by using natural polyphenols: A systematic review of implications on health effects. Food Res Int 2023; 165:112567. [PMID: 36869555 DOI: 10.1016/j.foodres.2023.112567] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2022] [Revised: 10/13/2022] [Accepted: 01/30/2023] [Indexed: 02/05/2023]
Abstract
Globally, inflammation and metabolic disorders pose serious public health problems and are major health concerns. It has been shown that natural polyphenols are effective in the treatment of metabolic diseases, including anti-inflammation, anti-diabetes, anti-obesity, neuron-protection, and cardio-protection. NLRP3 inflammasome, which are multiprotein complexes located within the cytosol, play an important role in the innate immune system. However, aberrant activation of the NLRP3 inflammasome were discovered as essential molecular mechanisms in triggering inflammatory processes as well as implicating it in several major metabolic diseases, such as type 2 diabetes mellitus, obesity, atherosclerosis or cardiovascular disease. Recent studies indicate that natural polyphenols can inhibit NLRP3 inflammasome activation. In this review, the progress of natural polyphenols preventing inflammation and metabolic disorders via targeting NLRP3 inflammasome is systemically summarized. From the viewpoint of interfering NLRP3 inflammasome activation, the health effects of natural polyphenols are explained. Recent advances in other beneficial effects, clinical trials, and nano-delivery systems for targeting NLRP3 inflammasome are also reviewed. NLRP3 inflammasome is targeted by natural polyphenols to exert multiple health effects, which broadens the understanding of polyphenol mechanisms and provides valuable guidance to new researchers in this field.
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Affiliation(s)
- Taotao Wang
- Department of Clinical Nutrition, Affiliated Hospital of Jiangsu University, 212000 Zhenjiang, China
| | - Hong Xu
- School of Grain Science and Technology, Jiangsu University of Science and Technology, 212100 Zhenjiang, China
| | - Ruixia Dong
- College of Horticulture, Jinling Institute of Technology, 211169 Nanjing, China
| | - Shanshan Wu
- College of Agriculture & Biotechnology, Zhejiang University, 310058 Hanzhou, China
| | - Yuanxin Guo
- School of Grain Science and Technology, Jiangsu University of Science and Technology, 212100 Zhenjiang, China.
| | - Dongxu Wang
- School of Grain Science and Technology, Jiangsu University of Science and Technology, 212100 Zhenjiang, China.
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Zhang HX, Li YY, Liu ZJ, Wang JF. Quercetin effectively improves LPS-induced intestinal inflammation, pyroptosis, and disruption of the barrier function through the TLR4/NF-κB/NLRP3 signaling pathway in vivo and in vitro. Food Nutr Res 2022; 66:8948. [PMID: 36793340 PMCID: PMC9899048 DOI: 10.29219/fnr.v66.8948] [Citation(s) in RCA: 26] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2022] [Revised: 11/16/2022] [Accepted: 11/21/2022] [Indexed: 12/31/2022] Open
Abstract
Background Inflammatory bowel diseases are characterized by the alterations of the mucosa and gastrointestinal physiology, and the core of these alterations is endothelial cells. Quercetin is a flavonoid presents in some traditional Chinese medicine, plants, and fruits. Its protective effects in several gastrointestinal tumors have been demonstrated, but its effects on bacterial enteritis and pyroptosis-related diseases have rarely been studied. Objective This study aimed to evaluate the effect of quercetin on bacterial enteritis and pyroptosis. Design In vitro experiments were performed using rat intestinal microvascular endothelial cells divided into seven groups: control group (no treatment), model group (10 μg/mL lipopolysaccharide (LPS)+1 mM adenosine triphosphate [ATP]), LPS group (10 μg/mL LPS), ATP group (1 mM ATP), and treatment groups (10 μg/mL LPS+1 mM ATP and 5, 10, and 20 μM quercetin). The expression of pyroptosis-associated proteins, inflammatory factors, tight junction proteins, and the percentage of late apoptotic and necrotic cells were measured. In vivo analysis was performed using specific pathogen-free Kunming mice pretreated with quercetin and the water extract of Cacumen Platycladi for 2 weeks followed by 6 mg/kg LPS on day 15. Inflammation in the blood and intestinal pathological changes were evaluated. Results Quercetin used in vitro significantly reduced the expression of Toll-like receptor 4 (TLR4), NOD-like receptor 3 (NLRP3), caspase-1, gasdermin D, interleukin (IL)-1β, IL-18, IL-6, and tumor necrosis factor-α. It also inhibited phosphorylation of nuclear factor-kappa B (NF-κB) p65 and increased cell migration and the expression of zonula occludens 1 and claudins, while reduced the number of late apoptotic cells. The in vivo results showed that Cacumen Platycladi and quercetin significantly reduced inflammation, protected the structure of the colon and cecum, and prevent fecal occult blood induced by LPS. Conclusions These findings suggested the ability of quercetin to reduce inflammation induced by LPS and pyroptosis through TLR4/NF-κB/NLRP3 pathway.
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Affiliation(s)
| | | | - Zhong-Jie Liu
- Zhong-Jie Liu, Department of Veterinary Clinic Medicine, College of Veterinary Medicine, China Agricultural University, Beijing 100193, P. R. China.
| | - Jiu-Feng Wang
- Jiu-Feng Wang, Department of Veterinary Clinic Medicine College of Veterinary Medicine, China Agricultural University, Beijing 100193, P. R. China.
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Li R, Yao G, Zhou L, Zhang M, Yan J. The ghrelin-GHSR-1a pathway inhibits high glucose-induced retinal angiogenesis in vitro by alleviating endoplasmic reticulum stress. EYE AND VISION 2022; 9:20. [PMID: 35668539 PMCID: PMC9172001 DOI: 10.1186/s40662-022-00291-5] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/14/2021] [Accepted: 05/17/2022] [Indexed: 11/18/2022]
Abstract
Background To investigate the effect of ghrelin, a brain-gut peptide hormone, on high glucose-induced retinal angiogenesis in vitro and explore its association with endoplasmic reticulum (ER) stress. Methods Human retinal microvascular endothelial cells (HRMECs) were first divided into control and high-glucose groups, and the mRNA and protein expression levels of the receptor for ghrelin [growth hormone secretin receptor 1a, (GHSR-1a)] in cells were determined. HRMECs were then treated with high glucose alone or in combination with ghrelin or siGHSR-1a, and cell viability, migration, tube formation and the expression of the ER stress-related proteins PERK, ATF4 and CHOP were detected. Finally, to clarify whether the effects of ghrelin are related to ER stress, tunicamycin, an inducer of ER stress, was used to treat HRMECs, and cell viability, cell migration, and tube formation were evaluated. Results GHSR-1a expression in HRMECs at both the mRNA and protein levels was inhibited by high-glucose treatment. Under high-glucose conditions, ghrelin promoted cell viability and inhibited migration and tube formation, which were blocked by siGHSR-1a treatment. Ghrelin inhibited the increases in the protein levels of p-PERK, ATF4 and CHOP induced by high-glucose treatment, and combination treatment with siGHSR-1a reversed this effect of ghrelin. When tunicamycin was added, the effects of ghrelin on cell viability, migration and tube formation were all weakened. Conclusions This study experimentally revealed that ghrelin can inhibit high glucose-induced retinal angiogenesis in vitro through GHSR-1a, and alleviation of ER stress may be one of the mechanisms underlying this effect.
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Wang M, Sheng KJ, Fang JC, Zhao H, Lu SM, Liu ZY, Chen BT. Redox signaling in diabetic retinopathy and opportunity for therapeutic intervention through natural products. Eur J Med Chem 2022; 244:114829. [DOI: 10.1016/j.ejmech.2022.114829] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2022] [Revised: 09/14/2022] [Accepted: 10/01/2022] [Indexed: 11/28/2022]
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Yan L, Vaghari-Tabari M, Malakoti F, Moein S, Qujeq D, Yousefi B, Asemi Z. Quercetin: an effective polyphenol in alleviating diabetes and diabetic complications. Crit Rev Food Sci Nutr 2022; 63:9163-9186. [PMID: 35468007 DOI: 10.1080/10408398.2022.2067825] [Citation(s) in RCA: 48] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
Various studies, especially in recent years, have shown that quercetin has beneficial therapeutic effects in various human diseases, including diabetes. Quercetin has significant anti-diabetic effects and may be helpful in lowering blood sugar and increasing insulin sensitivity. Quercetin appears to affect many factors and signaling pathways involved in insulin resistance and the pathogenesis of type 2 of diabetes. TNFα, NFKB, AMPK, AKT, and NRF2 are among the factors that are affected by quercetin. In addition, quercetin can be effective in preventing and ameliorating the diabetic complications, including diabetic nephropathy, cardiovascular complications, neuropathy, delayed wound healing, and retinopathy, and affects the key mechanisms involved in the pathogenesis of these complications. These positive effects of quercetin may be related to its anti-inflammatory and anti-oxidant properties. In this article, after a brief review of the pathogenesis of insulin resistance and type 2 diabetes, we will review the latest findings on the anti-diabetic effects of quercetin with a molecular perspective. Then we will review the effects of quercetin on the key mechanisms of pathogenesis of diabetes complications including nephropathy, cardiovascular complications, neuropathy, delayed wound healing, and retinopathy. Finally, clinical trials investigating the effect of quercetin on diabetes and diabetes complications will be reviewed.
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Affiliation(s)
- Lei Yan
- Clinical Experimental Centre, Xi'an International Medical Center Hospital, Xi'an, China
- Department of Pre-Clinical Sciences, Faculty of Medicine and Health Sciences, Universiti Tunku Abdul Rahman, Kajang, Malaysia
| | - Mostafa Vaghari-Tabari
- Student's Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran
- Department of Clinical Biochemistry and Laboratory Medicine, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Faezeh Malakoti
- Student's Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Soheila Moein
- Medicinal Plants Processing Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Durdi Qujeq
- Cellular and Molecular Biology Research Center (CMBRC), Health Research Institute, Babol University of Medical Sciences, Babol, Iran
| | - Bahman Yousefi
- Molecular Medicine Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Zatollah Asemi
- Research Center for Biochemistry and Nutrition in Metabolic Diseases, Kashan University of Medical Sciences, Kashan, Iran
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Jiang C, Li D, Chen L, Liu Y, Zhao Y, Mei G, Tang Y, Yang Y, Yao P, Gao C. Quercetin ameliorated cardiac injury via reducing inflammatory actions and the glycerophospholipid metabolism dysregulation in a diabetic cardiomyopathy mouse model. Food Funct 2022; 13:7847-7856. [DOI: 10.1039/d2fo00912a] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
Quercetin has multiple protective effects against cardiometabolic diseases, but the biological mechanisms underlying the benefits in diabetic cardiomyopathy (DCM) are unclear. A mouse DCM model was established by high-fat diet...
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22
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Ge K, Wang Y, Li P, Li M, Zhang W, Dan H, Hu X, Zhou J, Yang Q, Wang J, Song Z. Down-expression of the NLRP3 inflammasome delays the progression of diabetic retinopathy. Microvasc Res 2022; 139:104265. [PMID: 34662588 DOI: 10.1016/j.mvr.2021.104265] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2021] [Revised: 10/02/2021] [Accepted: 10/12/2021] [Indexed: 12/29/2022]
Abstract
The investigation aimed to evaluate the effects of Mcc950, an inhibitor of the NLRP3 inflammasome, on diabetic retinopathy (DR) mice. The general physiological condition of each group of mice was recorded. Retinal blood vessels were stained for observation of the density of blood vessels, and retinas were used for further morphological examination and fluorescent staining after the intravitreal injection of Mcc950. Mcc950 partially reversed hyperglycemia-induced vascular damage and had reduced histological changes compared to DR mice. IL-1β production in mice retinas in the diabetic model (DM) group increased, but pretreatment with Mcc950 significantly reversed these changes. Additionally, Mcc950 engineered reduced FITC dextran extravasation and vascular leakage. Therefore, it played an apparent protective role in DR and could be a new treatment strategy for DR.
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Affiliation(s)
- Keke Ge
- Zhengzhou University People's Hospital, Henan Provincial People's Hospital, Henan Eye Hospital, Zhengzhou 450003, Henan, China
| | - Yatao Wang
- Lanzhou University, The First Hospital of Lanzhou University, Lanzhou 730000, Gansu, China
| | - Pan Li
- Zhengzhou University People's Hospital, Henan Provincial People's Hospital, Henan Eye Hospital, Zhengzhou 450003, Henan, China
| | - Miao Li
- Henan Eye Institute, Henan Eye Hospital, Henan Provincial People's Hospital and Zhengzhou University People's Hospital, Zhengzhou 450003, Henan, China
| | - Wenhua Zhang
- Henan University People's Hospital, Henan Provincial People's Hospital, Henan Eye Hospital, Zhengzhou 450003, Henan, China
| | - Handong Dan
- Henan Eye Institute, Henan Eye Hospital, Henan Provincial People's Hospital and Zhengzhou University People's Hospital, Zhengzhou 450003, Henan, China
| | - Xumeng Hu
- Zhengzhou University People's Hospital, Henan Provincial People's Hospital, Henan Eye Hospital, Zhengzhou 450003, Henan, China
| | - Jiamu Zhou
- Zhengzhou University People's Hospital, Henan Provincial People's Hospital, Henan Eye Hospital, Zhengzhou 450003, Henan, China
| | - Qixiang Yang
- Zhengzhou University People's Hospital, Henan Provincial People's Hospital, Henan Eye Hospital, Zhengzhou 450003, Henan, China
| | - Jiaojiao Wang
- Henan Eye Institute, Henan Eye Hospital, Henan Provincial People's Hospital and Zhengzhou University People's Hospital, Zhengzhou 450003, Henan, China.
| | - Zongming Song
- Henan Eye Institute, Henan Eye Hospital, Henan Provincial People's Hospital and Zhengzhou University People's Hospital, Zhengzhou 450003, Henan, China.
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23
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24
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Behl T, Kumar K, Singh S, Sehgal A, Sachdeva M, Bhatia S, Al-Harrasi A, Buhas C, Teodora Judea-Pusta C, Negrut N, Alexandru Munteanu M, Brisc C, Bungau S. Unveiling the role of polyphenols in diabetic retinopathy. J Funct Foods 2021. [DOI: https://doi.org/10.1016/j.jff.2021.104608] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022] Open
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25
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Berdugo M, Delaunay K, Lebon C, Naud MC, Radet L, Zennaro L, Picard E, Daruich A, Beltrand J, Kermorvant-Duchemin E, Polak M, Crisanti P, Behar-Cohen FF. Long-Term Oral Treatment with Non-Hypoglycemic Dose of Glibenclamide Reduces Diabetic Retinopathy Damage in the Goto-KakizakiRat Model. Pharmaceutics 2021; 13:pharmaceutics13071095. [PMID: 34371786 PMCID: PMC8308933 DOI: 10.3390/pharmaceutics13071095] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2021] [Revised: 07/13/2021] [Accepted: 07/15/2021] [Indexed: 01/02/2023] Open
Abstract
Diabetic retinopathy (DR) remains a major cause of vision loss, due to macular edema, retinal ischemia and death of retinal neurons. We previously demonstrated that acute administration of glibenclamide into the vitreous, or given orally at a non-hypoglycemic dose, protected the structure and the function of the retina in three animal models that each mimic aspects of diabetic retinopathy in humans. In this pilot study, we investigated whether one year of chronic oral glibenclamide, in a non-hypoglycemic regimen (Amglidia®, 0.4 mg/kg, Ammtek/Nordic Pharma, 5 d/week), could alleviate the retinopathy that develops in the Goto-Kakizaki (GK) rat. In vivo, retinal function was assessed by electroretinography (ERG), retinal thickness by optical coherence tomography (OCT) and retinal perfusion by fluorescein and indocyanin green angiographies. The integrity of the retinal pigment epithelium (RPE) that constitutes the outer retinal barrier was evaluated by quantitative analysis of the RPE morphology on flat-mounted fundus ex vivo. Oral glibenclamide did not significantly reduce the Hb1Ac levels but still improved retinal function, as witnessed by the reduction in scotopic implicit times, limited diabetes-induced neuroretinal thickening and the extension of ischemic areas, and it improved the capillary coverage. These results indicate that low doses of oral glibenclamide could still be beneficial for the prevention of type 2 diabetic retinopathy. Whether the retinas ofpatients treated specifically with glibenclamideare less at risk of developing diabetic complications remains to be demonstrated.
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Affiliation(s)
- Marianne Berdugo
- Physiopathology of Ocular Diseases: Therapeutic Innovations, Sorbonne University and Universityof Paris, Inserm UMRS 1138, F-75006 Paris, France; (M.B.); (K.D.); (C.L.); (M.-C.N.); (L.R.); (L.Z.); (E.P.); (A.D.); (E.K.-D.); (P.C.)
| | - Kimberley Delaunay
- Physiopathology of Ocular Diseases: Therapeutic Innovations, Sorbonne University and Universityof Paris, Inserm UMRS 1138, F-75006 Paris, France; (M.B.); (K.D.); (C.L.); (M.-C.N.); (L.R.); (L.Z.); (E.P.); (A.D.); (E.K.-D.); (P.C.)
| | - Cécile Lebon
- Physiopathology of Ocular Diseases: Therapeutic Innovations, Sorbonne University and Universityof Paris, Inserm UMRS 1138, F-75006 Paris, France; (M.B.); (K.D.); (C.L.); (M.-C.N.); (L.R.); (L.Z.); (E.P.); (A.D.); (E.K.-D.); (P.C.)
| | - Marie-Christine Naud
- Physiopathology of Ocular Diseases: Therapeutic Innovations, Sorbonne University and Universityof Paris, Inserm UMRS 1138, F-75006 Paris, France; (M.B.); (K.D.); (C.L.); (M.-C.N.); (L.R.); (L.Z.); (E.P.); (A.D.); (E.K.-D.); (P.C.)
| | - Lolita Radet
- Physiopathology of Ocular Diseases: Therapeutic Innovations, Sorbonne University and Universityof Paris, Inserm UMRS 1138, F-75006 Paris, France; (M.B.); (K.D.); (C.L.); (M.-C.N.); (L.R.); (L.Z.); (E.P.); (A.D.); (E.K.-D.); (P.C.)
| | - Léa Zennaro
- Physiopathology of Ocular Diseases: Therapeutic Innovations, Sorbonne University and Universityof Paris, Inserm UMRS 1138, F-75006 Paris, France; (M.B.); (K.D.); (C.L.); (M.-C.N.); (L.R.); (L.Z.); (E.P.); (A.D.); (E.K.-D.); (P.C.)
| | - Emilie Picard
- Physiopathology of Ocular Diseases: Therapeutic Innovations, Sorbonne University and Universityof Paris, Inserm UMRS 1138, F-75006 Paris, France; (M.B.); (K.D.); (C.L.); (M.-C.N.); (L.R.); (L.Z.); (E.P.); (A.D.); (E.K.-D.); (P.C.)
| | - Alejandra Daruich
- Physiopathology of Ocular Diseases: Therapeutic Innovations, Sorbonne University and Universityof Paris, Inserm UMRS 1138, F-75006 Paris, France; (M.B.); (K.D.); (C.L.); (M.-C.N.); (L.R.); (L.Z.); (E.P.); (A.D.); (E.K.-D.); (P.C.)
- Department of Ophthalmology, AP-HP Hospital University Necker-Sick Children, F-75015 Paris, France
| | - Jacques Beltrand
- Department of Paediatric Endocrinology, Gynecology and Diabetology, AP-HP Hospital University Necker-Sick Children, F-75015 Paris, France; (J.B.); (M.P.)
- Faculté de Santé, University of Paris, F-75006 Paris, France
- Institut Cochin, InsermU1016, F-75005 Paris, France
| | - Elsa Kermorvant-Duchemin
- Physiopathology of Ocular Diseases: Therapeutic Innovations, Sorbonne University and Universityof Paris, Inserm UMRS 1138, F-75006 Paris, France; (M.B.); (K.D.); (C.L.); (M.-C.N.); (L.R.); (L.Z.); (E.P.); (A.D.); (E.K.-D.); (P.C.)
- Neonatal and Intensive Care Unit, AP-HP Hospital University Necker-Sick Children, F-75015 Paris, France
| | - Michel Polak
- Department of Paediatric Endocrinology, Gynecology and Diabetology, AP-HP Hospital University Necker-Sick Children, F-75015 Paris, France; (J.B.); (M.P.)
- Faculté de Santé, University of Paris, F-75006 Paris, France
- Institut Cochin, InsermU1016, F-75005 Paris, France
- Institute Imagine, InsermU1163, F-75015 Paris, France
| | - Patricia Crisanti
- Physiopathology of Ocular Diseases: Therapeutic Innovations, Sorbonne University and Universityof Paris, Inserm UMRS 1138, F-75006 Paris, France; (M.B.); (K.D.); (C.L.); (M.-C.N.); (L.R.); (L.Z.); (E.P.); (A.D.); (E.K.-D.); (P.C.)
| | - Francine F. Behar-Cohen
- Physiopathology of Ocular Diseases: Therapeutic Innovations, Sorbonne University and Universityof Paris, Inserm UMRS 1138, F-75006 Paris, France; (M.B.); (K.D.); (C.L.); (M.-C.N.); (L.R.); (L.Z.); (E.P.); (A.D.); (E.K.-D.); (P.C.)
- Ophthalmology, AP-HP Hospital Cochin, F-75005 Paris, France
- Correspondence:
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