|
1
|
Mu J, Zhang Z, Jiang C, Geng H, Duan J. Role of Tau Protein Hyperphosphorylation in Diabetic Retinal Neurodegeneration. J Ophthalmol 2025; 2025:3278794. [PMID: 40109357 PMCID: PMC11922625 DOI: 10.1155/joph/3278794] [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: 01/05/2024] [Revised: 12/25/2024] [Accepted: 02/22/2025] [Indexed: 03/22/2025] Open
Abstract
Diabetic retinal neurodegeneration (DRN) is an early manifestation of diabetic retinopathy (DR) characterized by neurodegeneration that precedes microvascular abnormalities in the retina. DRN is characterized by apoptosis of retinal ganglion cells (involves alterations in retinal ganglion cells [RGCs], photoreceptors, amacrine cells and bipolar cells and so on), reactive gliosis, and reduced retinal neuronal function. Tau, a microtubule-associated protein, is a key mediator of neurotoxicity in neurodegenerative diseases, with functions in phosphorylation-dependent microtubule assembly and stabilization, axonal transport, and neurite outgrowth. The hyperphosphorylated tau (p-tau) loses its ability to bind to microtubules and aggregates to form paired helical filaments (PHFs), which further form neurofibrillary tangles (NFTs), leading to abnormal cell scaffolding and cell death. Studies have shown that p-tau can cause degeneration of RGCs in DR, making tau pathology a new pathophysiological model for DR. Here, we review the mechanisms by which p-tau contribute to DRN, including insulin resistance or lack of insulin, mitochondrial damage such as mitophagy impairment, mitochondrial axonal transport defects, mitochondrial bioenergetics dysfunction, and impaired mitochondrial dynamics, Abeta toxicity, and inflammation. Therefore, this article proposes that tau protein hyperphosphorylation plays a crucial role in the pathogenesis of DRN and may serve as a novel therapeutic target for combating DRN.
Collapse
Affiliation(s)
- Jingyu Mu
- Eye School of Chengdu University of TCM, Chengdu, Sichuan, China
- Key Laboratory of Sichuan Province Ophthalmopathy Prevention & Cure and Visual Function Protection with TCM Laboratory, Chengdu, Sichuan, China
- Retinal Image Technology and Chronic Vascular Disease Prevention & Control and Collaborative Innovation Center, Chengdu, Sichuan, China
| | - Zengrui Zhang
- Eye School of Chengdu University of TCM, Chengdu, Sichuan, China
- Key Laboratory of Sichuan Province Ophthalmopathy Prevention & Cure and Visual Function Protection with TCM Laboratory, Chengdu, Sichuan, China
- Retinal Image Technology and Chronic Vascular Disease Prevention & Control and Collaborative Innovation Center, Chengdu, Sichuan, China
| | - Chao Jiang
- College of Life and Health Sciences, Institute of Neuroscience, Northeastern University, Shenyang, China
| | - Haoming Geng
- Eye School of Chengdu University of TCM, Chengdu, Sichuan, China
- Key Laboratory of Sichuan Province Ophthalmopathy Prevention & Cure and Visual Function Protection with TCM Laboratory, Chengdu, Sichuan, China
- Retinal Image Technology and Chronic Vascular Disease Prevention & Control and Collaborative Innovation Center, Chengdu, Sichuan, China
| | - Junguo Duan
- Eye School of Chengdu University of TCM, Chengdu, Sichuan, China
- Key Laboratory of Sichuan Province Ophthalmopathy Prevention & Cure and Visual Function Protection with TCM Laboratory, Chengdu, Sichuan, China
- Retinal Image Technology and Chronic Vascular Disease Prevention & Control and Collaborative Innovation Center, Chengdu, Sichuan, China
- Ineye Hospital of Chengdu University of TCM, Chengdu, Sichuan, China
| |
Collapse
|
|
2
|
Liu Y, Liu W, Guo C, Bao J, Zhang H, Li W, Li Y, Gui Y, Zeng Y, Wang X, Peng C, Shu X, Liu R. AENK ameliorates cognitive impairment and prevents Tau hyperphosphorylation through inhibiting AEP-mediated cleavage of SET in rats with ischemic stroke. J Neurochem 2025; 169:e16283. [PMID: 39790011 DOI: 10.1111/jnc.16283] [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: 08/08/2024] [Revised: 11/26/2024] [Accepted: 11/27/2024] [Indexed: 01/12/2025]
Abstract
Brain damage induced by ischemia promotes the development of cognitive dysfunction, thus increasing the risk of dementia such as Alzheimer's disease (AD). Studies indicate that cellular acidification-triggered activation of asparagine endopeptidase (AEP) plays a key role in ischemic brain injury, through multiple molecular pathways, including cleavage of its substrates such as SET (inhibitor 2 of PP2A, I2 PP2A) and Tau. However, whether direct targeting AEP can effectively prevent post-stroke cognitive impairment (PSCI) remains unanswered. Here, we explored the therapeutic effect and underlying mechanism of the AEP inhibitor AENK on cognitive impairment of the rats with middle cerebral artery occlusion (MCAO) and on neuronal damage in cultured primary neurons exposed to oxygen and glucose deprivation (OGD). We found that the administration of AENK significantly reduces activated AEP levels in ischemic rat brains, attenuates cognitive deficits, and rescues synaptic dysfunction. For the mechanism, with AEP inhibition, cleavage of SET, inhibition of protein phosphatase 2A (PP2A), and Tau hyperphosphorylation resulted from PP2A inhibition, were all completely or partially reversed. In primary neurons, AENK effectively prevents AEP activation, SET cleavage and cytoplasmic retention, tau hyperphosphorylation and synaptic damage induced by OGD. We conclude that AENK ameliorates cognitive impairment and prevents tau hyperphosphorylation, through inhibiting AEP-mediated cleavage of SET in ischemic brain injury, and direct inhibition of AEP might be a potential therapeutic strategy for preventing synaptic damage and cognitive impairment after stroke.
Collapse
Affiliation(s)
- Yi Liu
- Department of Pathophysiology, School of Basic Medicine, Key Laboratory of Education Ministry/Hubei Province of China for Neurological Disorders, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Wei Liu
- Hubei Key Laboratory of Cognitive and Affective Discorders, Institutes of Biomedical Sciences, School of Medicine, Jianghan University, Wuhan, China
| | - Cuiping Guo
- Department of Pathophysiology, School of Basic Medicine, Key Laboratory of Education Ministry/Hubei Province of China for Neurological Disorders, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Department of Emergency Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Jian Bao
- Hubei Key Laboratory of Cognitive and Affective Discorders, Institutes of Biomedical Sciences, School of Medicine, Jianghan University, Wuhan, China
| | - Huiliang Zhang
- Department of Pathophysiology, School of Basic Medicine, Key Laboratory of Education Ministry/Hubei Province of China for Neurological Disorders, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Wensheng Li
- Department of Pathophysiology, School of Basic Medicine, Key Laboratory of Education Ministry/Hubei Province of China for Neurological Disorders, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Youwei Li
- Hubei Key Laboratory of Cognitive and Affective Discorders, Institutes of Biomedical Sciences, School of Medicine, Jianghan University, Wuhan, China
| | - Yurang Gui
- Hubei Key Laboratory of Cognitive and Affective Discorders, Institutes of Biomedical Sciences, School of Medicine, Jianghan University, Wuhan, China
| | - Yi Zeng
- Key Laboratory for Molecular Diagnosis of Hubei Province, The Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Xiaochuan Wang
- Department of Pathophysiology, School of Basic Medicine, Key Laboratory of Education Ministry/Hubei Province of China for Neurological Disorders, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Hubei Key Laboratory of Cognitive and Affective Discorders, Institutes of Biomedical Sciences, School of Medicine, Jianghan University, Wuhan, China
| | - Caixia Peng
- Key Laboratory for Molecular Diagnosis of Hubei Province, The Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Xiji Shu
- Hubei Key Laboratory of Cognitive and Affective Discorders, Institutes of Biomedical Sciences, School of Medicine, Jianghan University, Wuhan, China
| | - Rong Liu
- Department of Pathophysiology, School of Basic Medicine, Key Laboratory of Education Ministry/Hubei Province of China for Neurological Disorders, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| |
Collapse
|
|
3
|
Sun WJ, An XD, Zhang YH, Tang SS, Sun YT, Kang XM, Jiang LL, Zhao XF, Gao Q, Ji HY, Lian FM. Autophagy-dependent ferroptosis may play a critical role in early stages of diabetic retinopathy. World J Diabetes 2024; 15:2189-2202. [PMID: 39582563 PMCID: PMC11580571 DOI: 10.4239/wjd.v15.i11.2189] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/26/2023] [Revised: 06/10/2024] [Accepted: 09/10/2024] [Indexed: 10/16/2024] Open
Abstract
Diabetic retinopathy (DR), as one of the most common and significant microvascular complications of diabetes mellitus (DM), continues to elude effective targeted treatment for vision loss despite ongoing enrichment of the understanding of its pathogenic mechanisms from perspectives such as inflammation and oxidative stress. Recent studies have indicated that characteristic neuroglial degeneration induced by DM occurs before the onset of apparent microvascular lesions. In order to comprehensively grasp the early-stage pathological changes of DR, the retinal neurovascular unit (NVU) will become a crucial focal point for future research into the occurrence and progression of DR. Based on existing evidence, ferroptosis, a form of cell death regulated by processes like ferritinophagy and chaperone-mediated autophagy, mediates apoptosis in retinal NVU components, including pericytes and ganglion cells. Autophagy-dependent ferroptosis-related factors, including BECN1 and FABP4, may serve as both biomarkers for DR occurrence and development and potentially crucial targets for future effective DR treatments. The aforementioned findings present novel perspectives for comprehending the mechanisms underlying the early-stage pathological alterations in DR and open up innovative avenues for investigating supplementary therapeutic strategies.
Collapse
Affiliation(s)
- Wen-Jie Sun
- Department of Endocrinology, Guang’anmen Hospital, Beijing 100053, China
| | - Xue-Dong An
- Department of Endocrinology, Guang’anmen Hospital, Beijing 100053, China
| | - Yue-Hong Zhang
- Department of Endocrinology, Fangshan Hospital of Beijing University of Chinese Medicine, Beijing 102400, China
| | - Shan-Shan Tang
- Department of Endocrinology, Changchun University of Chinese Medicine, Changchun 130117, Jilin Province, China
| | - Yu-Ting Sun
- Department of Endocrinology, Guang’anmen Hospital, Beijing 100053, China
| | - Xiao-Min Kang
- Department of Endocrinology, Guang’anmen Hospital, Beijing 100053, China
| | - Lin-Lin Jiang
- Department of Endocrinology, Guang’anmen Hospital, Beijing 100053, China
| | - Xue-Fei Zhao
- Department of Endocrinology, Guang’anmen Hospital, Beijing 100053, China
| | - Qing Gao
- Department of Endocrinology, Guang’anmen Hospital, Beijing 100053, China
| | - Hang-Yu Ji
- Department of Endocrinology, Guang’anmen Hospital, Beijing 100053, China
| | - Feng-Mei Lian
- Department of Endocrinology, Guang’anmen Hospital, Beijing 100053, China
| |
Collapse
|
|
4
|
Yin J, Wang H, Zhao F, Liang D, Yang W, Zhang D. The Acute Toxicity and Cardiotoxic Effects of Protocatechuic Aldehyde on Juvenile Zebrafish. TOXICS 2024; 12:799. [PMID: 39590979 PMCID: PMC11598600 DOI: 10.3390/toxics12110799] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/19/2024] [Revised: 10/24/2024] [Accepted: 10/29/2024] [Indexed: 11/28/2024]
Abstract
Protocatechuic aldehyde (PCA) is a natural phenolic acid compound with pharmacological effects such as anti-oxidative stress, antibacterial, anti-apoptotic, anti-inflammatory, anti-platelet aggregation, and anti-tumor. Despite the favorable therapeutic effects of PCA, it is imperative to recognize that adverse drug reactions can arise even with satisfactory quality assurance measures and during standard clinical application and dosing. Additionally, the acute toxicity and cardiotoxic sequelae of PCA are frequently under reported in the available documentation. To investigate the acute toxicity and cardiotoxic effects of PCA, the present study comprehensively assessed the acute toxicity and cardiotoxic effects of PCA by administering different concentrations of PCA and by monitoring the phenotypic changes in zebrafish, using AB wild-type Tg(cmlc2:EGFP) zebrafish as the experimental model organism. Meanwhile, the target genes of PCA that may cause cardiotoxicity were predicted and validated using a network pharmacology approach. Our findings indicated that PCA exhibited severe acute toxicity and cardiotoxic effects in zebrafish at 70 μg/mL and 80 μg/mL. Furthermore, PIK3CA, PARP1, and GSK3β may be involved in the mechanism of action of the cardiotoxicity-inducing effects of this compound. The present investigation has afforded a deeper insight into the acute toxicity and cardiotoxic impacts of PCA on zebrafish and has established a significant theoretical foundation for the evaluation of toxicity in pharmaceuticals incorporating PCA.
Collapse
Affiliation(s)
- Jiufeng Yin
- Institute for Chinese Medicine Innovation, Shandong University of Traditional Chinese Medicine, Jinan 250300, China; (J.Y.); (H.W.); (D.L.)
| | - Hui Wang
- Institute for Chinese Medicine Innovation, Shandong University of Traditional Chinese Medicine, Jinan 250300, China; (J.Y.); (H.W.); (D.L.)
| | - Feng Zhao
- Laboratory Centre, Shandong University of Traditional Chinese Medicine, Jinan 250300, China;
| | - Dan Liang
- Institute for Chinese Medicine Innovation, Shandong University of Traditional Chinese Medicine, Jinan 250300, China; (J.Y.); (H.W.); (D.L.)
| | - Wenqing Yang
- Institute for Chinese Medicine Innovation, Shandong University of Traditional Chinese Medicine, Jinan 250300, China; (J.Y.); (H.W.); (D.L.)
- Department of Classical Theory of Chinese Medicine, Key Laboratory of the Ministry of Education, Jinan 250355, China
| | - Dan Zhang
- Laboratory Centre, Shandong University of Traditional Chinese Medicine, Jinan 250300, China;
- Department of Classical Theory of Chinese Medicine, Key Laboratory of the Ministry of Education, Jinan 250355, China
| |
Collapse
|
|
5
|
Yu H, Zhou D, Wang W, Wang Q, Li M, Ma X. Protective effect of baicalin on oxidative stress injury in retinal ganglion cells through the JAK/STAT signaling pathway in vitro and in vivo. Front Pharmacol 2024; 15:1443472. [PMID: 39555089 PMCID: PMC11565601 DOI: 10.3389/fphar.2024.1443472] [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: 06/04/2024] [Accepted: 10/23/2024] [Indexed: 11/19/2024] Open
Abstract
Background and Purpose The damage or apoptosis of retinal ganglion cells (RGCs) is one of the leading causes of various blinding eye diseases, such as glaucoma, diabetic retinopathy, optic neuritis, and ischemic optic neuropathy. Oxidative stress is involved in RGCs death. Baicalin, a flavonoid compound extracted from Scutellaria baicalensis, has various beneficial effects, including anti-inflammatory, anti-apoptotic, and antioxidant properties. However, the effects of baicalin on RGCs and the underlying mechanisms require further investigation. Methods In this study, a glutamate-induced oxidative stress damage model of R28 cells and a rat retinal injury model were established to investigate the effects of baicalin on oxidative stress damage to RGCs and try to elucidate the underlying mechanism. Results In vitro experiments demonstrated that the survival rate of R28 cells after glutamate treatment dropped to 33.4%, while 10 μM baicalin significantly inhibited glutamate-induced damage in RGCs (P < 0.001) and enhanced cell viability through decreasing ROS levels, increasing antioxidant enzyme activity, and suppressing the expression of inflammatory factors iNOS, TNF-α, IL-6, and IL-1β (P < 0.001). In vivo, baicalin effectively mitigated structural damage to retinal tissue and RGCs morphology induced by glutamate, increasing the thickness of the retinal ganglion cell layer, improving RGCs density, and reducing overall retinal thinning in rats (P < 0.001) in a time- and dose-dependent effects. Mechanistic studies revealed that glutamate evaluated the phosphorylation levels of JAK/STAT, while baicalin effectively inhibited the activation of the JAK/STAT signaling pathway. Conclusion This study confirmed that baicalin protects against glutamate-induced oxidative stress damage in RGCs. It effectively alleviates oxidative stress and inflammatory responses, reduces cell apoptosis, and improves the pathological changes in the retina of rat models of RGCs damage, thereby decreasing RGCs death. Further exploration of its mechanism revealed that baicalin effectively inhibits the JAK/STAT signaling pathway, protecting RGCs from oxidative stress damage. This provides an experimental basis for the application of baicalin in the treatment of RGCs damage.
Collapse
Affiliation(s)
- Huan Yu
- Graduate School of Shanghai University of Traditional Chinese Medicine, Shanghai, China
- Zhoupu Hospital, Shanghai University of Medicine and Health Sciences, Shanghai, China
| | - Dan Zhou
- Zhoupu Hospital, Shanghai University of Medicine and Health Sciences, Shanghai, China
| | - Wei Wang
- Department of Ophthalmology, Shanghai Tenth People’s Hospital, Tongji University, Shanghai, China
| | - Qingxia Wang
- Graduate School of Shanghai University of Traditional Chinese Medicine, Shanghai, China
- Zhoupu Hospital, Shanghai University of Medicine and Health Sciences, Shanghai, China
| | - Min Li
- Department of Ophthalmology, Shanghai Tenth People’s Hospital, Tongji University, Shanghai, China
| | - Xiaoyun Ma
- Zhoupu Hospital, Shanghai University of Medicine and Health Sciences, Shanghai, China
| |
Collapse
|
|
6
|
Li J, Zhang Y, Tang R, Liu H, Li X, Lei W, Chen J, Jin Z, Tang J, Wang Z, Yang Y, Wu X. Glycogen synthase kinase-3β: A multifaceted player in ischemia-reperfusion injury and its therapeutic prospects. J Cell Physiol 2024; 239:e31335. [PMID: 38962880 DOI: 10.1002/jcp.31335] [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: 02/16/2024] [Revised: 05/05/2024] [Accepted: 05/22/2024] [Indexed: 07/05/2024]
Abstract
Ischemia-reperfusion injury (IRI) results in irreversible metabolic dysfunction and structural damage to tissues or organs, posing a formidable challenge in the field of organ implantation, cardiothoracic surgery, and general surgery. Glycogen synthase kinase-3β (GSK-3β) a multifunctional serine/threonine kinase, is involved in a variety of biological processes, including cell proliferation, apoptosis, and immune response. Phosphorylation of its tyrosine 216 and serine 9 sites positively and negatively regulates the activation and inactivation of the enzyme. Significantly, inhibition or inactivation of GSK-3β provides protection against IRI, making it a viable target for drug development. Though numerous GSK-3β inhibitors have been identified to date, the development of therapeutic treatments remains a considerable distance away. In light of this, this review summarizes the complicated network of GSK-3β roles in IRI. First, we provide an overview of GSK-3β's basic background. Subsequently, we briefly review the pathological mechanisms of GSK-3β in accelerating IRI, and highlight the latest progress of GSK-3β in multiorgan IRI, encompassing heart, brain, kidney, liver, and intestine. Finally, we discuss the current development of GSK-3β inhibitors in various organ IRI, offering a thorough and insightful reference for GSK-3β as a potential target for future IRI therapy.
Collapse
Affiliation(s)
- Jiayan Li
- Xi'an Key Laboratory of Innovative Drug Research for Heart Failure, Northwest University First Hospital, Faculty of Life Sciences and Medicine, Northwest University, Xi'an, China
- Faculty of Life Sciences and Medicine, Northwest University, Xi'an, China
| | - Yan Zhang
- Xi'an Key Laboratory of Innovative Drug Research for Heart Failure, Northwest University First Hospital, Faculty of Life Sciences and Medicine, Northwest University, Xi'an, China
- Faculty of Life Sciences and Medicine, Northwest University, Xi'an, China
| | - Ran Tang
- Xi'an Key Laboratory of Innovative Drug Research for Heart Failure, Northwest University First Hospital, Faculty of Life Sciences and Medicine, Northwest University, Xi'an, China
- Faculty of Life Sciences and Medicine, Northwest University, Xi'an, China
| | - Hui Liu
- Xi'an Key Laboratory of Innovative Drug Research for Heart Failure, Northwest University First Hospital, Faculty of Life Sciences and Medicine, Northwest University, Xi'an, China
- Faculty of Life Sciences and Medicine, Northwest University, Xi'an, China
| | - Xiayun Li
- Xi'an Key Laboratory of Innovative Drug Research for Heart Failure, Northwest University First Hospital, Faculty of Life Sciences and Medicine, Northwest University, Xi'an, China
- Faculty of Life Sciences and Medicine, Northwest University, Xi'an, China
| | - Wangrui Lei
- Xi'an Key Laboratory of Innovative Drug Research for Heart Failure, Northwest University First Hospital, Faculty of Life Sciences and Medicine, Northwest University, Xi'an, China
- Faculty of Life Sciences and Medicine, Northwest University, Xi'an, China
| | - Junmin Chen
- Xi'an Key Laboratory of Innovative Drug Research for Heart Failure, Northwest University First Hospital, Faculty of Life Sciences and Medicine, Northwest University, Xi'an, China
- Faculty of Life Sciences and Medicine, Northwest University, Xi'an, China
| | - Zhenxiao Jin
- Department of Cardiovascular Surgery, Xijing Hospital, The Fourth Military Medical University, Xi'an, China
| | - Jiayou Tang
- Department of Cardiovascular Surgery, Xijing Hospital, The Fourth Military Medical University, Xi'an, China
| | - Zheng Wang
- Department of Cardiothoracic Surgery, Central Theater Command General Hospital of Chinese People's Liberation Army, Wuhan, China
| | - Yang Yang
- Xi'an Key Laboratory of Innovative Drug Research for Heart Failure, Northwest University First Hospital, Faculty of Life Sciences and Medicine, Northwest University, Xi'an, China
- Faculty of Life Sciences and Medicine, Northwest University, Xi'an, China
| | - Xiaopeng Wu
- Xi'an Key Laboratory of Innovative Drug Research for Heart Failure, Northwest University First Hospital, Faculty of Life Sciences and Medicine, Northwest University, Xi'an, China
- Faculty of Life Sciences and Medicine, Northwest University, Xi'an, China
| |
Collapse
|
|
7
|
Ma Q, Chen G, Li Y, Guo Z, Zhang X. The molecular genetics of PI3K/PTEN/AKT/mTOR pathway in the malformations of cortical development. Genes Dis 2024; 11:101021. [PMID: 39006182 PMCID: PMC11245990 DOI: 10.1016/j.gendis.2023.04.041] [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: 12/07/2022] [Revised: 04/07/2023] [Accepted: 04/30/2023] [Indexed: 07/16/2024] Open
Abstract
Malformations of cortical development (MCD) are a group of developmental disorders characterized by abnormal cortical structures caused by genetic or harmful environmental factors. Many kinds of MCD are caused by genetic variation. MCD is the common cause of intellectual disability and intractable epilepsy. With rapid advances in imaging and sequencing technologies, the diagnostic rate of MCD has been increasing, and many potential genes causing MCD have been successively identified. However, the high genetic heterogeneity of MCD makes it challenging to understand the molecular pathogenesis of MCD and to identify effective targeted drugs. Thus, in this review, we outline important events of cortical development. Then we illustrate the progress of molecular genetic studies about MCD focusing on the PI3K/PTEN/AKT/mTOR pathway. Finally, we briefly discuss the diagnostic methods, disease models, and therapeutic strategies for MCD. The information will facilitate further research on MCD. Understanding the role of the PI3K/PTEN/AKT/mTOR pathway in MCD could lead to a novel strategy for treating MCD-related diseases.
Collapse
Affiliation(s)
- Qing Ma
- NHC and CAMS Key Laboratory of Molecular Probe and Targeted Theranostics, Harbin Medical University, Harbin, Heilongjiang 150000, China
| | - Guang Chen
- Department of Urology, The Fourth Hospital of Harbin Medical University, Harbin, Heilongjiang 150000, China
| | - Ying Li
- NHC and CAMS Key Laboratory of Molecular Probe and Targeted Theranostics, Harbin Medical University, Harbin, Heilongjiang 150000, China
- Department of Child and Adolescent Health, School of Public Health, Harbin Medical University, Harbin, Heilongjiang 150000, China
| | - Zhenming Guo
- Institute for Regenerative Medicine, Shanghai East Hospital, Frontier Science Center for Stem Cell Research, School of Life Sciences and Technology, Tongji University, Shanghai 200120, China
| | - Xue Zhang
- NHC and CAMS Key Laboratory of Molecular Probe and Targeted Theranostics, Harbin Medical University, Harbin, Heilongjiang 150000, China
| |
Collapse
|
|
8
|
Ye J, Wan H, Chen S, Liu GP. Targeting tau in Alzheimer's disease: from mechanisms to clinical therapy. Neural Regen Res 2024; 19:1489-1498. [PMID: 38051891 PMCID: PMC10883484 DOI: 10.4103/1673-5374.385847] [Citation(s) in RCA: 10] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2023] [Accepted: 08/16/2023] [Indexed: 12/07/2023] Open
Abstract
ABSTRACT Alzheimer's disease is the most prevalent neurodegenerative disease affecting older adults. Primary features of Alzheimer's disease include extracellular aggregation of amyloid-β plaques and the accumulation of neurofibrillary tangles, formed by tau protein, in the cells. While there are amyloid-β-targeting therapies for the treatment of Alzheimer's disease, these therapies are costly and exhibit potential negative side effects. Mounting evidence suggests significant involvement of tau protein in Alzheimer's disease-related neurodegeneration. As an important microtubule-associated protein, tau plays an important role in maintaining the stability of neuronal microtubules and promoting axonal growth. In fact, clinical studies have shown that abnormal phosphorylation of tau protein occurs before accumulation of amyloid-β in the brain. Various therapeutic strategies targeting tau protein have begun to emerge, and are considered possible methods to prevent and treat Alzheimer's disease. Specifically, abnormalities in post-translational modifications of the tau protein, including aberrant phosphorylation, ubiquitination, small ubiquitin-like modifier (SUMO)ylation, acetylation, and truncation, contribute to its microtubule dissociation, misfolding, and subcellular missorting. This causes mitochondrial damage, synaptic impairments, gliosis, and neuroinflammation, eventually leading to neurodegeneration and cognitive deficits. This review summarizes the recent findings on the underlying mechanisms of tau protein in the onset and progression of Alzheimer's disease and discusses tau-targeted treatment of Alzheimer's disease.
Collapse
Affiliation(s)
- Jinwang Ye
- Shenzhen Key Laboratory of Marine Biotechnology and Ecology, College of Life Sciences and Oceanography, Shenzhen University, Shenzhen, Guangdong Province, China
| | - Huali Wan
- Department of Laboratory Medicine, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, Guangdong Province, China
| | - Sihua Chen
- Shenzhen Key Laboratory of Marine Biotechnology and Ecology, College of Life Sciences and Oceanography, Shenzhen University, Shenzhen, Guangdong Province, China
| | - Gong-Ping Liu
- Co-innovation Center of Neurodegeneration, Nantong University, Nantong, Jiangsu Province, China
- Department of Pathophysiology, School of Basic Medicine and the Collaborative Innovation Center for Brain Science, Key Laboratory of Ministry of Education of China and Hubei Province for Neurological Disorders, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, China
| |
Collapse
|
|
9
|
Yen S, Wang Y, Liao LD. Investigating cerebral neurovascular responses to hyperglycemia in a rat model of type 2 diabetes using multimodal assessment techniques. iScience 2024; 27:110108. [PMID: 38952685 PMCID: PMC11215308 DOI: 10.1016/j.isci.2024.110108] [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: 01/02/2024] [Revised: 03/22/2024] [Accepted: 05/23/2024] [Indexed: 07/03/2024] Open
Abstract
To study neurovascular function in type 2 diabetes mellitus (T2DM), we established a high-fat diet/streptozotocin (HFD/STZ) rat model. Electrocorticography-laser speckle contrast imaging (ECoG-LSCI) revealed that the somatosensory-evoked potential (SSEP) amplitude and blood perfusion volume were significantly lower in the HFD/STZ group. Cortical spreading depression (CSD) velocity was used as a measure of neurovascular function, and the results showed that the blood flow velocity and the number of CSD events were significantly lower in the HFD/STZ group. In addition, to compare changes during acute hyperglycemia and hyperglycemia, we used intraperitoneal injection (IPI) of glucose to induce transient hyperglycemia. The results showed that CSD velocity and blood flow were significantly reduced in the IPI group. The significant neurovascular changes observed in the brains of rats in the HFD/STZ group suggest that changes in neuronal apoptosis may play a role in altered glucose homeostasis in T2DM.
Collapse
Affiliation(s)
- Shaoyu Yen
- Institute of Biomedical Engineering and Nanomedicine, National Health Research Institutes, 35, Keyan Road, Zhunan Town, Miaoli County 350, Taiwan
| | - Yuhling Wang
- Institute of Biomedical Engineering and Nanomedicine, National Health Research Institutes, 35, Keyan Road, Zhunan Town, Miaoli County 350, Taiwan
- Department of Electrical Engineering, National United University, No. 2, Lianda, Nanshili, Miaoli City 36063, Taiwan
| | - Lun-De Liao
- Institute of Biomedical Engineering and Nanomedicine, National Health Research Institutes, 35, Keyan Road, Zhunan Town, Miaoli County 350, Taiwan
| |
Collapse
|
|
10
|
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.
Collapse
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.)
| |
Collapse
|
|
11
|
Guo C, Yue Y, Wang B, Chen S, Li D, Zhen F, Liu L, Zhu H, Xie M. Anemoside B4 alleviates arthritis pain via suppressing ferroptosis-mediated inflammation. J Cell Mol Med 2024; 28:e18136. [PMID: 38334255 PMCID: PMC10853948 DOI: 10.1111/jcmm.18136] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2023] [Revised: 11/02/2023] [Accepted: 12/20/2023] [Indexed: 02/10/2024] Open
Abstract
Chronic pain is the key manifestations of rheumatoid arthritis. Neuroinflammation in the spinal cord drives central sensitization and chronic pain. Ferroptosis has potentially important roles in the occurrence of neuroinflammation and chronic pain. In the current study, mouse model of collagen-induced arthritis was established by intradermal injection of type II collagen in complete Freund's adjuvant (CFA) solution. CFA inducement resulted in swollen paw and ankle, mechanical and spontaneous pain, and impaired motor coordination. The spinal inflammation was triggered, astrocytes were activated, and increased NLRP3-mediated inflammatory signal was found in CFA spinal cord. Oxidative stress and ferroptosis in the spinal cord were manifested. Meanwhile, enhancive spinal GSK-3β activity and abnormal phosphorylated Drp1 were observed. To investigate the potential therapeutic options for arthritic pain, mice were intraperitoneally injected with AB4 for three consecutive days. AB4 treatment reduced pain sensitivity and increased the motor coordination. In the spinal cord, AB4 treatment inhibited NLRP3 inflammasome-mediated inflammatory response, increased antioxidation, decreased mitochondrial reactive oxygen species and ferroptosis. Furthermore, AB4 decreased GSK-3β activity by binding with GSK-3β through five electrovalent bonds. Our findings indicated that AB treatment relieves arthritis pain by inhibiting GSK-3β activation, increasing antioxidant capability, reducing Drp1-mediated mitochondrial dysfunction and suppressing neuroinflammation.
Collapse
Affiliation(s)
- Chenlu Guo
- School of PharmacyHubei University of Science and TechnologyXianningChina
| | - Yuanfen Yue
- Department of ObstetricsXianning Central Hospital, First Affiliated Hospital of Hubei University of Science and TechnologyXianningChina
| | - Bojun Wang
- Hubei Key Laboratory of Diabetes and Angiopathy, School of Basic Medical Sciences, Xianning Medical CollegeHubei University of Science and TechnologyXianningChina
| | - Shaohui Chen
- Hubei Key Laboratory of Diabetes and Angiopathy, School of Basic Medical Sciences, Xianning Medical CollegeHubei University of Science and TechnologyXianningChina
| | - Dai Li
- Hubei Key Laboratory of Diabetes and Angiopathy, School of Basic Medical Sciences, Xianning Medical CollegeHubei University of Science and TechnologyXianningChina
| | - Fangshou Zhen
- Department of PharmacyMatang Hospital of Traditional Chinese MedicineXianningChina
| | - Ling Liu
- Hubei Key Laboratory of Diabetes and Angiopathy, School of Basic Medical Sciences, Xianning Medical CollegeHubei University of Science and TechnologyXianningChina
| | - Haili Zhu
- Hubei Key Laboratory of Diabetes and Angiopathy, School of Basic Medical Sciences, Xianning Medical CollegeHubei University of Science and TechnologyXianningChina
| | - Min Xie
- Hubei Key Laboratory of Diabetes and Angiopathy, School of Basic Medical Sciences, Xianning Medical CollegeHubei University of Science and TechnologyXianningChina
| |
Collapse
|
|
12
|
Liang CJ, Wu RC, Huang XQ, Qin QP, Liang H, Tan MX. Synthesis and anticancer mechanisms of four novel platinum(II) 4'-substituted-2,2':6',2''-terpyridine complexes. Dalton Trans 2024; 53:2143-2152. [PMID: 38189098 DOI: 10.1039/d3dt03197g] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2024]
Abstract
Mitophagy, a selective autophagic process, has emerged as a pathway involved in degrading dysfunctional mitochondria. Herein, new platinum(II)-based chemotherapeutics with mitophagy-targeting properties are proposed. Four novel binuclear anticancer Pt(II) complexes with 4'-substituted-2,2':6',2''-terpyridine derivatives (tpy1-tpy4), i.e., [Pt2(tpy1)(DMSO)2Cl4]·CH3OH (tpy1Pt), [Pt(tpy2)Cl][Pt(DMSO)Cl3]·CH3COCH3 (tpy2Pt), [Pt(tpy3)Cl][Pt(DMSO)Cl3] (tpy3Pt), and [Pt(tpy4)Cl]Cl·CH3OH (tpy4Pt), were designed and prepared. Moreover, their potential antitumor mechanism was studied. Tpy1Pt-tpy4Pt exhibited more selective cytotoxicity against cisplatin-resistant SK-OV-3/DDP (SKO3cisR) cancer cells compared with those against ovarian SK-OV-3 (SKO3) cancer cells and normal HL-7702 liver (H702) cells. This selective cytotoxicity of Tpy1Pt-tpy4Pt was better than that of its ligands (i.e., tpy1-tpy4), the clinical drug cisplatin, and cis-Pt(DMSO)2Cl2. The results of various experiments indicated that tpy1Pt and tpy2Pt kill SKO3cisR cancer cells via a mitophagy pathway, which involves the disruption of the mitophagy-related protein expression, dissipation of the mitochondrial membrane potential, elevation of the [Ca2+] and reactive oxygen species levels, promotion of mitochondrial DNA damage, and reduction in the adenosine triphosphate and mitochondrial respiratory chain levels. Furthermore, in vivo experiments indicated that the dinuclear anticancer Pt(II) coordination compound (tpy1Pt) has remarkable therapeutic efficiency (ca. 52.4%) and almost no toxicity. Therefore, the new 4'-substituted-2,2':6',2''-terpyridine Pt(II) coordination compound (tpy1Pt) is a potential candidate for next-generation mitophagy-targeting dinuclear Pt(II)-based anticancer drugs.
Collapse
Affiliation(s)
- Chun-Jie Liang
- Guangxi Key Lab of Agricultural Resources Chemistry and Biotechnology, College of Chemistry and Food Science, Yulin Normal University, 1303 Jiaoyudong Road, Yulin 537000, PR China.
| | - Run-Chun Wu
- Guangxi Key Lab of Agricultural Resources Chemistry and Biotechnology, College of Chemistry and Food Science, Yulin Normal University, 1303 Jiaoyudong Road, Yulin 537000, PR China.
| | - Xiao-Qiong Huang
- Guangxi Key Lab of Agricultural Resources Chemistry and Biotechnology, College of Chemistry and Food Science, Yulin Normal University, 1303 Jiaoyudong Road, Yulin 537000, PR China.
| | - Qi-Pin Qin
- Guangxi Key Lab of Agricultural Resources Chemistry and Biotechnology, College of Chemistry and Food Science, Yulin Normal University, 1303 Jiaoyudong Road, Yulin 537000, PR China.
| | - Hong Liang
- State Key Laboratory for the Chemistry and Molecular Engineering of Medicinal Resources, School of Chemistry and Pharmacy, Guangxi Normal University, 15 Yucai Road, Guilin 541004, PR China
| | - Ming-Xiong Tan
- Guangxi Key Lab of Agricultural Resources Chemistry and Biotechnology, College of Chemistry and Food Science, Yulin Normal University, 1303 Jiaoyudong Road, Yulin 537000, PR China.
| |
Collapse
|
|
13
|
Li J, Chen K, Li X, Zhang X, Zhang L, Yang Q, Xia Y, Xie C, Wang X, Tong J, Shen Y. Mechanistic insights into the alterations and regulation of the AKT signaling pathway in diabetic retinopathy. Cell Death Discov 2023; 9:418. [PMID: 37978169 PMCID: PMC10656479 DOI: 10.1038/s41420-023-01717-2] [Citation(s) in RCA: 19] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2023] [Revised: 11/05/2023] [Accepted: 11/08/2023] [Indexed: 11/19/2023] Open
Abstract
In the early stages of diabetic retinopathy (DR), diabetes-related hyperglycemia directly inhibits the AKT signaling pathway by increasing oxidative stress or inhibiting growth factor expression, which leads to retinal cell apoptosis, nerve proliferation and fundus microvascular disease. However, due to compensatory vascular hyperplasia in the late stage of DR, the vascular endothelial growth factor (VEGF)/phosphatidylinositol 3 kinase (PI3K)/AKT cascade is activated, resulting in opposite levels of AKT regulation compared with the early stage. Studies have shown that many factors, including insulin, insulin-like growth factor-1 (IGF-1), VEGF and others, can regulate the AKT pathway. Disruption of the insulin pathway decreases AKT activation. IGF-1 downregulation decreases the activation of AKT in DR, which abrogates the neuroprotective effect, upregulates VEGF expression and thus induces neovascularization. Although inhibiting VEGF is the main treatment for neovascularization in DR, excessive inhibition may lead to apoptosis in inner retinal neurons. AKT pathway substrates, including mammalian target of rapamycin (mTOR), forkhead box O (FOXO), glycogen synthase kinase-3 (GSK-3)/nuclear factor erythroid 2-related factor 2 (Nrf2), and nuclear factor kappa-B (NF-κB), are a research focus. mTOR inhibitors can delay or prevent retinal microangiopathy, whereas low mTOR activity can decrease retinal protein synthesis. Inactivated AKT fails to inhibit FOXO and thus causes apoptosis. The GSK-3/Nrf2 cascade regulates oxidation and inflammation in DR. NF-κB is activated in diabetic retinas and is involved in inflammation and apoptosis. Many pathways or vital activities, such as the Janus kinase (JAK)/signal transducer and activator of transcription (STAT) and mitogen-activated protein kinase (MAPK) signaling pathways, interact with the AKT pathway to influence DR development. Numerous regulatory methods can simultaneously impact the AKT pathway and other pathways, and it is essential to consider both the connections and interactions between these pathways. In this review, we summarize changes in the AKT signaling pathway in DR and targeted drugs based on these potential sites.
Collapse
Affiliation(s)
- Jiayuan Li
- Department of Ophthalmology, The First Affiliated Hospital of Zhejiang University, Hangzhou, Zhejiang, China
- Department of Cardiology, The Second Affiliated Hospital of Zhejiang University, Hangzhou, Zhejiang, China
| | - Kuangqi Chen
- Department of Ophthalmology, The First Affiliated Hospital of Zhejiang University, Hangzhou, Zhejiang, China
| | - Xiang Li
- Department of Ophthalmology, The First Affiliated Hospital of Zhejiang University, Hangzhou, Zhejiang, China
| | - Xuhong Zhang
- Department of Ophthalmology, The First Affiliated Hospital of Zhejiang University, Hangzhou, Zhejiang, China
| | - Liyue Zhang
- Department of Ophthalmology, The First Affiliated Hospital of Zhejiang University, Hangzhou, Zhejiang, China
| | - Qianjie Yang
- Department of Ophthalmology, The First Affiliated Hospital of Zhejiang University, Hangzhou, Zhejiang, China
| | - Yutong Xia
- Department of Ophthalmology, The First Affiliated Hospital of Zhejiang University, Hangzhou, Zhejiang, China
| | - Chen Xie
- Department of Ophthalmology, The First Affiliated Hospital of Zhejiang University, Hangzhou, Zhejiang, China
| | - Xiawei Wang
- Department of Ophthalmology, The First Affiliated Hospital of Zhejiang University, Hangzhou, Zhejiang, China
| | - Jianping Tong
- Department of Ophthalmology, The First Affiliated Hospital of Zhejiang University, Hangzhou, Zhejiang, China.
| | - Ye Shen
- Department of Ophthalmology, The First Affiliated Hospital of Zhejiang University, Hangzhou, Zhejiang, China.
| |
Collapse
|
|
14
|
Ebrahimi M, Thompson P, Lauer AK, Sivaprasad S, Perry G. The retina-brain axis and diabetic retinopathy. Eur J Ophthalmol 2023; 33:2079-2095. [PMID: 37259525 DOI: 10.1177/11206721231172229] [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: 06/02/2023]
Abstract
Diabetic retinopathy (DR) is a major contributor to permanent vision loss and blindness. Changes in retinal neurons, glia, and microvasculature have been the focus of intensive study in the quest to better understand DR. However, the impact of diabetes on the rest of the visual system has received less attention. There are reports of associations of changes in the visual system with preclinical and clinical manifestations of diabetes. Simultaneous investigation of the retina and the brain may shed light on the mechanisms underlying neurodegeneration in diabetics. Additionally, investigating the links between DR and other neurodegenerative disorders of the brain including Alzheimer's and Parkinson's disease may reveal shared mechanisms for neurodegeneration and potential therapy options.
Collapse
Affiliation(s)
- Moein Ebrahimi
- School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
- Network of Immunity in Infection, Malignancy, and Autoimmunity, Universal Scientific Education and Research Network (USERN), Tehran, Iran
| | - Paul Thompson
- Imaging Genetics Center, Mark and Mary Stevens Institute for Neuroimaging and Informatics, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
| | - Andreas K Lauer
- Department of Ophthalmology, Casey Eye Institute, Oregon Health & Science University, Portland, Oregon, USA
| | - Sobha Sivaprasad
- National Institute of Health and Care Research Moorfields Biomedical Research Centre, Moorfields Eye Hospital, London, UK
| | - George Perry
- Department of Neuroscience, Developmental and Regenerative Biology, University of Texas and San Antonio, San Antonio, TX, USA
| |
Collapse
|
|
15
|
García-Bermúdez MY, Vohra R, Freude K, van Wijngaarden P, Martin K, Thomsen MS, Aldana BI, Kolko M. Potential Retinal Biomarkers in Alzheimer's Disease. Int J Mol Sci 2023; 24:15834. [PMID: 37958816 PMCID: PMC10649108 DOI: 10.3390/ijms242115834] [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: 09/01/2023] [Revised: 10/18/2023] [Accepted: 10/25/2023] [Indexed: 11/15/2023] Open
Abstract
Alzheimer's disease (AD) represents a major diagnostic challenge, as early detection is crucial for effective intervention. This review examines the diagnostic challenges facing current AD evaluations and explores the emerging field of retinal alterations as early indicators. Recognizing the potential of the retina as a noninvasive window to the brain, we emphasize the importance of identifying retinal biomarkers in the early stages of AD. However, the examination of AD is not without its challenges, as the similarities shared with other retinal diseases introduce complexity in the search for AD-specific markers. In this review, we address the relevance of using the retina for the early diagnosis of AD and the complex challenges associated with the search for AD-specific retinal biomarkers. We provide a comprehensive overview of the current landscape and highlight avenues for progress in AD diagnosis by retinal examination.
Collapse
Affiliation(s)
| | - Rupali Vohra
- Eye Translational Research Unit, Department of Drug Design and Pharmacology, University of Copenhagen, 2100 Copenhagen, Denmark
- Department of Ophthalmology, Copenhagen University Hospital, Rigshospitalet, 2600 Glostrup, Denmark
| | - Kristine Freude
- Group of Stem Cell Models and Embryology, Department of Veterinary and Animal Sciences, University of Copenhagen, 1870 Frederiksberg, Denmark
| | - Peter van Wijngaarden
- Center for Eye Research Australia, Royal Victorian Eye and Ear Hospital, East Melbourne, VIC 3002, Australia
- Ophthalmology, Department of Surgery, University of Melbourne, Melbourne, VIC 3010, Australia
| | - Keith Martin
- Center for Eye Research Australia, Royal Victorian Eye and Ear Hospital, East Melbourne, VIC 3002, Australia
- Ophthalmology, Department of Surgery, University of Melbourne, Melbourne, VIC 3010, Australia
- Department of Clinical Neurosciences, University of Cambridge, Cambridge CB2 0QQ, UK
| | - Maj Schneider Thomsen
- Neurobiology Research and Drug Delivery, Department of Health, Science and Technology, Aalborg University, 9220 Aalborg, Denmark
| | - Blanca Irene Aldana
- Neurometabolism Research Group, Department of Drug Design and Pharmacology, University of Copenhagen, 2100 Copenhagen, Denmark
| | - Miriam Kolko
- Eye Translational Research Unit, Department of Drug Design and Pharmacology, University of Copenhagen, 2100 Copenhagen, Denmark
- Department of Ophthalmology, Copenhagen University Hospital, Rigshospitalet, 2600 Glostrup, Denmark
| |
Collapse
|
|
16
|
Fukiyama Y, Hirokawa T, Takai S, Kida T, Oku H. Involvement of Glycogen Synthase Kinase 3β (GSK3β) in Formation of Phosphorylated Tau and Death of Retinal Ganglion Cells of Rats Caused by Optic Nerve Crush. Curr Issues Mol Biol 2023; 45:6941-6957. [PMID: 37754222 PMCID: PMC10527756 DOI: 10.3390/cimb45090438] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2023] [Revised: 08/10/2023] [Accepted: 08/20/2023] [Indexed: 09/28/2023] Open
Abstract
Tauopathy is a neurodegenerative condition associated with oligomeric tau formation through abnormal phosphorylation. We previously showed that tauopathy is involved in death of retinal ganglion cells (RGCs) after optic nerve crush (ONC). It has been proposed that glycogen synthase kinase 3β (GSK3β) is involved in the hyperphosphorylation of tau in Alzheimer's disease. To determine the roles of GSK3β in tauopathy-related death of RGCs, lithium chloride (LiCl), a GSK3β inhibitor, was injected intravitreally just after ONC. The neuroprotective effects of LiCl were determined by counting Tuj-1-stained RGCs on day 7. Changes of phosphorylated (ser 396) tau in the retina were determined by Simple Western analysis (WES) on day 3. Retinal GSK3β levels were determined by immunohistochemistry (IHC) and an ELISA. There was a 1.9- and 2.1-fold increase in the levels of phosphorylated tau monomers and dimers on day 3 after ONC. LiCl significantly suppressed the increase in the levels of phosphorylated tau induced by ONC. GSK3β was mainly present in somas of RGCs, and ELISA showed that retinal levels increased to 2.0-fold on day 7. IHC showed that the GSK3β expression increased over time and remained in RGCs that were poorly stained by Tuj-1. The GSK3β and tau expression was colocalized in RGCs. The number of RGCs decreased from 1881 ± 188 (sham control) to 1150 ± 192 cells/mm2 on day 7, and LiCl preserved the levels at 1548 ± 173 cells/mm2. Accordingly, GSK3β may be a promising target for some optic nerve injuries.
Collapse
Affiliation(s)
- Yurie Fukiyama
- Department of Ophthalmology, Osaka Medical and Pharmaceutical University, Osaka 569-8686, Japan; (Y.F.); (T.H.); (T.K.)
| | - Takahisa Hirokawa
- Department of Ophthalmology, Osaka Medical and Pharmaceutical University, Osaka 569-8686, Japan; (Y.F.); (T.H.); (T.K.)
| | - Shinji Takai
- Department of Innovative Medicine, Osaka Medical and Pharmaceutical University, Osaka 569-8686, Japan;
| | - Teruyo Kida
- Department of Ophthalmology, Osaka Medical and Pharmaceutical University, Osaka 569-8686, Japan; (Y.F.); (T.H.); (T.K.)
| | - Hidehiro Oku
- Department of Ophthalmology, Osaka Medical and Pharmaceutical University, Osaka 569-8686, Japan; (Y.F.); (T.H.); (T.K.)
| |
Collapse
|
|
17
|
Ma J, Pan Z, Du H, Chen X, Zhu X, Hao W, Zheng Q, Tang X. Luteolin induces apoptosis by impairing mitochondrial function and targeting the intrinsic apoptosis pathway in gastric cancer cells. Oncol Lett 2023; 26:327. [PMID: 37415631 PMCID: PMC10320424 DOI: 10.3892/ol.2023.13913] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2022] [Accepted: 03/29/2023] [Indexed: 07/08/2023] Open
Abstract
Gastric cancer is one of the most lethal cancers worldwide. Research has focused on exploring natural medicines to improve the systematic chemotherapy for gastric cancer. Luteolin, a natural flavonoid, possesses anticancer activities. Nevertheless, the mechanism of the anticancer effects of luteolin is still not clear. The present study aimed to verify the inhibitory effect of luteolin on gastric cancer HGC-27, MFC and MKN-45 cells and to explore the underlying mechanism. A Cell Counting Kit-8 cell viability assay, flow cytometry, western blot, an ATP content assay and an enzyme activity testing assay were used. Luteolin inhibited the proliferation of gastric cancer HGC-27, MFC and MKN-45 cells. Further, it impaired mitochondrial integrity and function by destroying the mitochondrial membrane potential, downregulating the activities of mitochondrial electron transport chain complexes (mainly complexes I, III and V), and unbalancing the expression of B cell lymphoma-2 family member proteins, eventually leading to apoptosis of gastric cancer HGC-27, MFC and MKN-45 cells. The intrinsic apoptosis pathway was involved in luteolin's anti-gastric cancer effects. Furthermore, mitochondria were the main target in luteolin-induced gastric cancer apoptosis. The present study may provide a theoretical basis for the research on the effect of luteolin on the mitochondrial metabolism in cancer cells, and pave the way for its practical application in the future.
Collapse
Affiliation(s)
- Jun Ma
- College of Marine Life Sciences, Ocean University of China, Qingdao, Shandong 266003, P.R. China
- Yantai Key Laboratory of Pharmacology of Traditional Chinese Medicine in Tumor Metabolism, School of Integrated Traditional Chinese and Western Medicine, Binzhou Medical University, Yantai, Shandong 264003, P.R. China
| | - Zhaohai Pan
- Yantai Key Laboratory of Pharmacology of Traditional Chinese Medicine in Tumor Metabolism, School of Integrated Traditional Chinese and Western Medicine, Binzhou Medical University, Yantai, Shandong 264003, P.R. China
| | - Hongchao Du
- Department of General Surgery, Binzhou Medical University Affiliated Yantai Yeda Hospital, Yantai, Shandong 265599, P.R. China
| | - Xiaojie Chen
- Yantai Key Laboratory of Pharmacology of Traditional Chinese Medicine in Tumor Metabolism, School of Integrated Traditional Chinese and Western Medicine, Binzhou Medical University, Yantai, Shandong 264003, P.R. China
| | - Xuejie Zhu
- Yantai Key Laboratory of Pharmacology of Traditional Chinese Medicine in Tumor Metabolism, School of Integrated Traditional Chinese and Western Medicine, Binzhou Medical University, Yantai, Shandong 264003, P.R. China
| | - Wenjin Hao
- School of Life Sciences, Nantong University, Nantong, Jiangsu 226019, P.R. China
| | - Qiusheng Zheng
- Yantai Key Laboratory of Pharmacology of Traditional Chinese Medicine in Tumor Metabolism, School of Integrated Traditional Chinese and Western Medicine, Binzhou Medical University, Yantai, Shandong 264003, P.R. China
- Key Laboratory of Xinjiang Endemic Phytomedicine Resources, Pharmacy School, Shihezi University, Shihezi, Xinjiang 832099, P.R. China
| | - Xuexi Tang
- College of Marine Life Sciences, Ocean University of China, Qingdao, Shandong 266003, P.R. China
| |
Collapse
|
|
18
|
Ramakrishna K, Nalla LV, Naresh D, Venkateswarlu K, Viswanadh MK, Nalluri BN, Chakravarthy G, Duguluri S, Singh P, Rai SN, Kumar A, Singh V, Singh SK. WNT-β Catenin Signaling as a Potential Therapeutic Target for Neurodegenerative Diseases: Current Status and Future Perspective. Diseases 2023; 11:89. [PMID: 37489441 PMCID: PMC10366863 DOI: 10.3390/diseases11030089] [Citation(s) in RCA: 82] [Impact Index Per Article: 41.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2023] [Revised: 06/20/2023] [Accepted: 06/23/2023] [Indexed: 07/26/2023] Open
Abstract
Wnt/β-catenin (WβC) signaling pathway is an important signaling pathway for the maintenance of cellular homeostasis from the embryonic developmental stages to adulthood. The canonical pathway of WβC signaling is essential for neurogenesis, cell proliferation, and neurogenesis, whereas the noncanonical pathway (WNT/Ca2+ and WNT/PCP) is responsible for cell polarity, calcium maintenance, and cell migration. Abnormal regulation of WβC signaling is involved in the pathogenesis of several neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), and spinal muscular atrophy (SMA). Hence, the alteration of WβC signaling is considered a potential therapeutic target for the treatment of neurodegenerative disease. In the present review, we have used the bibliographical information from PubMed, Google Scholar, and Scopus to address the current prospects of WβC signaling role in the abovementioned neurodegenerative diseases.
Collapse
Affiliation(s)
- Kakarla Ramakrishna
- KL College of Pharmacy, Koneru Lakshmaiah Education Foundation Deemed to be University (KLU), Green Fields, Vaddeswaram, Guntur 522502, India
| | - Lakshmi Vineela Nalla
- KL College of Pharmacy, Koneru Lakshmaiah Education Foundation Deemed to be University (KLU), Green Fields, Vaddeswaram, Guntur 522502, India
| | - Dumala Naresh
- KL College of Pharmacy, Koneru Lakshmaiah Education Foundation Deemed to be University (KLU), Green Fields, Vaddeswaram, Guntur 522502, India
| | - Kojja Venkateswarlu
- Department of Pharmaceutical Engineering and Technology, Indian Institute of Technology, IIT BHU, Varanasi 221005, India
| | - Matte Kasi Viswanadh
- KL College of Pharmacy, Koneru Lakshmaiah Education Foundation Deemed to be University (KLU), Green Fields, Vaddeswaram, Guntur 522502, India
| | - Buchi N Nalluri
- KL College of Pharmacy, Koneru Lakshmaiah Education Foundation Deemed to be University (KLU), Green Fields, Vaddeswaram, Guntur 522502, India
| | - Guntupalli Chakravarthy
- KL College of Pharmacy, Koneru Lakshmaiah Education Foundation Deemed to be University (KLU), Green Fields, Vaddeswaram, Guntur 522502, India
| | - Sajusha Duguluri
- Department of Biotechnology, Bharathi Institute of Higher Education and Research, Chennai 600073, India
| | - Payal Singh
- Department of Zoology, Mahila Maha Vidyalaya, Banaras Hindu University, Varanasi 221005, India
| | - Sachchida Nand Rai
- Centre of Experimental Medicine and Surgery, Institute of Medical Sciences, Banaras Hindu University, Varanasi 221005, India
| | - Ashish Kumar
- ICMR-Rajendra Memorial Research Institute of Medical Sciences, Agamkuan, Patna 800007, India
| | - Veer Singh
- ICMR-Rajendra Memorial Research Institute of Medical Sciences, Agamkuan, Patna 800007, India
| | - Santosh Kumar Singh
- Centre of Experimental Medicine and Surgery, Institute of Medical Sciences, Banaras Hindu University, Varanasi 221005, India
| |
Collapse
|
|
19
|
Wang X, Zhu X, Huang G, Wu L, Meng Z, Wu Y. Knockout of PERK protects rat Müller glial cells against OGD-induced endoplasmic reticulum stress-related apoptosis. BMC Ophthalmol 2023; 23:286. [PMID: 37353739 DOI: 10.1186/s12886-023-03022-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2022] [Accepted: 06/06/2023] [Indexed: 06/25/2023] Open
Abstract
BACKGROUND The pathological basis for many retinal diseases, retinal ischemia is also one of the most common causes of visual impairment. Numerous ocular diseases have been linked to Endoplasmic reticulum(ER)stress. However, there is still no clear understanding of the relationship between ER stress and Müller glial cells during retinal ischemia and hypoxia. This study examined the effects of ER stress on autophagy and apoptosis-related proteins, as well as the microtubule-related protein tau in rMC-1 cells. METHODS rMC-1 cells were cultured in vitro. RT-PCR、immunofluorescence and Western blotting revealed the expression levels of associated mRNAs and proteins, and the CCK-8 and flow cytometry assays detected cell apoptosis. RESULTS The results showed that under OGD(Oxygen-glucose deprivation) conditions, the number of rMC-1 cells was decreased, the PERK/eIF2a pathway was activated, and the expressions of p-tau, LC3、Beclin1 and Caspase-12 proteins were increased. After the PERK knockout, the expression of the above proteins was decreased, and the apoptosis was also decreased. CONCLUSION According to the findings of this study, specific downregulation of PERK expression had an anti-apoptotic effect on OGD-conditioned rMC-1 cells. There is a possibility that this is one of the mechanisms of MG cell apoptosis during retinal ischemic injury.
Collapse
Affiliation(s)
- Xiaorui Wang
- Department of Ophthalmology, Second Affiliated Hospital of Fujian Medical University, No.950, Donghai Street, Quanzhou, 362000, Fujian Province, China
| | - Xinxing Zhu
- Department of Ophthalmology, Second Affiliated Hospital of Fujian Medical University, No.950, Donghai Street, Quanzhou, 362000, Fujian Province, China
| | - Guangqian Huang
- Department of Ophthalmology, Second Affiliated Hospital of Fujian Medical University, No.950, Donghai Street, Quanzhou, 362000, Fujian Province, China
| | - Lili Wu
- Department of Ophthalmology, Second Affiliated Hospital of Fujian Medical University, No.950, Donghai Street, Quanzhou, 362000, Fujian Province, China
| | - Zhiyong Meng
- Department of Ophthalmology, Second Affiliated Hospital of Fujian Medical University, No.950, Donghai Street, Quanzhou, 362000, Fujian Province, China
| | - Yuyu Wu
- Department of Ophthalmology, Second Affiliated Hospital of Fujian Medical University, No.950, Donghai Street, Quanzhou, 362000, Fujian Province, China.
| |
Collapse
|
|
20
|
Zeng Z, You M, Fan C, Rong R, Li H, Xia X. Pathologically high intraocular pressure induces mitochondrial dysfunction through Drp1 and leads to retinal ganglion cell PANoptosis in glaucoma. Redox Biol 2023; 62:102687. [PMID: 36989574 PMCID: PMC10074988 DOI: 10.1016/j.redox.2023.102687] [Citation(s) in RCA: 48] [Impact Index Per Article: 24.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2023] [Revised: 03/10/2023] [Accepted: 03/20/2023] [Indexed: 03/28/2023] Open
Abstract
Glaucoma is a common neurodegenerative disease characterized by progressive retinal ganglion cell (RGC) loss and visual field defects. Pathologically high intraocular pressure (ph-IOP) is an important risk factor for glaucoma, and it triggers molecularly distinct cascades that control RGC death and axonal degeneration. Dynamin-related protein 1 (Drp1)-mediated abnormalities in mitochondrial dynamics are involved in glaucoma pathogenesis; however, little is known about the precise pathways that regulate RGC injury and death. Here, we aimed to investigate the role of the ERK1/2-Drp1-reactive oxygen species (ROS) axis in RGC death and the relationship between Drp1-mediated mitochondrial dynamics and PANoptosis in ph-IOP injury. Our results suggest that inhibiting the ERK1/2-Drp1-ROS pathway is a potential therapeutic strategy for treating ph-IOP-induced injuries. Furthermore, inhibiting Drp1 can regulate RGC PANoptosis by modulating caspase3-dependent, nucleotide-binding oligomerization domain-like receptor-containing pyrin domain 3(NLRP3)-dependent, and receptor-interacting protein (RIP)-dependent pathways in the ph-IOP model. Overall, our findings provide new insights into possible protective interventions that could regulate mitochondrial dynamics to improve RGC survival.
Collapse
|
|
21
|
Xu Y, Chen B, Yi J, Tian F, Liu Y, Ouyang Y, Yuan C, Liu B. Buyang Huanwu Decoction alleviates cerebral ischemic injury through modulating caveolin-1-mediated mitochondrial quality control. Front Pharmacol 2023; 14:1137609. [PMID: 37234709 PMCID: PMC10206009 DOI: 10.3389/fphar.2023.1137609] [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: 01/04/2023] [Accepted: 04/10/2023] [Indexed: 05/28/2023] Open
Abstract
Introduction: Mitochondrial quality control (MQC) is an important mechanism of neural repair after cerebral ischemia (CI). Recent studies have shown that caveolin-1 (Cav-1) is an important signaling molecule in the process of CI injury, but its mechanism of regulating MQC after CI is still unclear. Buyang Huanwu Decoction (BHD) is a classic traditional Chinese medicine formula that is often used to treat CI. Unfortunately, its mechanism of action is still obscure. Methods: In this study, we tested the hypothesis that BHD can regulate MQC through Cav-1 and exert an anti-cerebral ischemia injury effect. We used Cav-1 knockout mice and their homologous wild-type mice, replicated middle cerebral artery occlusion (MCAO) model and BHD intervention. Neurobehavioral scores and pathological detection were used to evaluate neurological function and neuron damage, transmission electron microscopy and enzymology detection of mitochondrial damage. Finally, western blot and RT-qPCR expression of MQC-related molecules were tested. Results: After CI, mice showed neurologic impairment, neuronal damage, and significant destruction of mitochondrial morphology and function, and MQC was imbalanced. Cav-1 deletion aggravated the damage to neurological function, neurons, mitochondrial morphology and mitochondrial function after CI, aggravated the imbalance of mitochondrial dynamics, and inhibited mitophagy and biosynthesis. BHD can maintain MQC homeostasis after CI through Cav-1 and improve CI injury. Discussion: Cav-1 can affect CI injury by regulating MQC, and this mechanism may be another target of BHD for anti-cerebral ischemia injury.
Collapse
Affiliation(s)
- Yaqian Xu
- The First Hospital of Hunan University of Chinese Medicine, Changsha, China
- MOE Key Laboratory of Research and Translation on Prevention and Treatment of Major Diseases in Internal Medicine of Traditional Chinese Medicine, Hunan University of Chinese Medicine, Changsha, China
| | - Bowei Chen
- The First Hospital of Hunan University of Chinese Medicine, Changsha, China
- MOE Key Laboratory of Research and Translation on Prevention and Treatment of Major Diseases in Internal Medicine of Traditional Chinese Medicine, Hunan University of Chinese Medicine, Changsha, China
| | - Jian Yi
- The First Hospital of Hunan University of Chinese Medicine, Changsha, China
- MOE Key Laboratory of Research and Translation on Prevention and Treatment of Major Diseases in Internal Medicine of Traditional Chinese Medicine, Hunan University of Chinese Medicine, Changsha, China
| | - Fengming Tian
- The First Hospital of Hunan University of Chinese Medicine, Changsha, China
- MOE Key Laboratory of Research and Translation on Prevention and Treatment of Major Diseases in Internal Medicine of Traditional Chinese Medicine, Hunan University of Chinese Medicine, Changsha, China
| | - Yingfei Liu
- The First Hospital of Hunan University of Chinese Medicine, Changsha, China
- MOE Key Laboratory of Research and Translation on Prevention and Treatment of Major Diseases in Internal Medicine of Traditional Chinese Medicine, Hunan University of Chinese Medicine, Changsha, China
| | - Yin Ouyang
- The First Hospital of Hunan University of Chinese Medicine, Changsha, China
- MOE Key Laboratory of Research and Translation on Prevention and Treatment of Major Diseases in Internal Medicine of Traditional Chinese Medicine, Hunan University of Chinese Medicine, Changsha, China
| | - Chunyun Yuan
- Hunan Hospital of Integrated Traditional Chinese and Western Medicine, Changsha, China
- Affiliated Hospital of Hunan Academy of Chinese Medicine, Changsha, China
| | - Baiyan Liu
- The First Hospital of Hunan University of Chinese Medicine, Changsha, China
- MOE Key Laboratory of Research and Translation on Prevention and Treatment of Major Diseases in Internal Medicine of Traditional Chinese Medicine, Hunan University of Chinese Medicine, Changsha, China
- Hunan Academy of Chinese Medicine, Changsha, China
| |
Collapse
|
|
22
|
Wang Y, Hu H, Liu X, Guo X. Hypoglycemic medicines in the treatment of Alzheimer's disease: Pathophysiological links between AD and glucose metabolism. Front Pharmacol 2023; 14:1138499. [PMID: 36909158 PMCID: PMC9995522 DOI: 10.3389/fphar.2023.1138499] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2023] [Accepted: 02/13/2023] [Indexed: 02/25/2023] Open
Abstract
Alzheimer's Disease (AD) is a global chronic disease in adults with beta-amyloid (Aβ) deposits and hyperphosphorylated tau protein as the pathologic characteristics. Although the exact etiology of AD is still not fully elucidated, aberrant metabolism including insulin signaling and mitochondria dysfunction plays an important role in the development of AD. Binding to insulin receptor substrates, insulin can transport through the blood-brain barrier (BBB), thus mediating insulin signaling pathways to regulate physiological functions. Impaired insulin signaling pathways, including PI3K/Akt/GSK3β and MAPK pathways, could cause damage to the brain in the pathogenesis of AD. Mitochondrial dysfunction and overexpression of TXNIP could also be causative links between AD and DM. Some antidiabetic medicines may have benefits in the treatment of AD. Metformin can be beneficial for cognition improvement in AD patients, although results from clinical trials were inconsistent. Exendin-4 may affect AD in animal models but there is a lack of clinical trials. Liraglutide and dulaglutide could also benefit AD patients in adequate clinical studies but not semaglutide. Dipeptidyl peptidase IV inhibitors (DPP4is) such as saxagliptin, vildagliptin, linagliptin, and sitagliptin could boost cognitive function in animal models. And SGLT2 inhibitors such as empagliflozin and dapagliflozin were also considerably protective against new-onset dementia in T2DM patients. Insulin therapy is a promising therapy but some studies indicated that it may increase the risk of AD. Herbal medicines are helpful for cognitive function and neuroprotection in the brain. For example, polyphenols, alkaloids, glycosides, and flavonoids have protective benefits in cognition function and glucose metabolism. Focusing on glucose metabolism, we summarized the pharmacological mechanism of hypoglycemic drugs and herbal medicines. New treatment approaches including antidiabetic synthesized drugs and herbal medicines would be provided to patients with AD. More clinical trials are needed to produce definite evidence for the effectiveness of hypoglycemic medications.
Collapse
Affiliation(s)
- Yixuan Wang
- Dongfang Hospital of Beijing University of Chinese Medicine, Beijing, China
| | - Hao Hu
- Dongfang Hospital of Beijing University of Chinese Medicine, Beijing, China
| | - Xinyu Liu
- Dongfang Hospital of Beijing University of Chinese Medicine, Beijing, China
| | - Xiangyu Guo
- Dongfang Hospital of Beijing University of Chinese Medicine, Beijing, China
| |
Collapse
|
|
23
|
Xu J, Guo Y, Liu Q, Yang H, Ma M, Yu J, Chen L, Ou C, Liu X, Wu J. Pregabalin Mediates Retinal Ganglion Cell Survival From Retinal Ischemia/Reperfusion Injury Via the Akt/GSK3β/β-Catenin Signaling Pathway. Invest Ophthalmol Vis Sci 2022; 63:7. [PMID: 36326725 PMCID: PMC9645359 DOI: 10.1167/iovs.63.12.7] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022] Open
Abstract
Purpose Progressive retinal ganglion cell (RGC) loss induced by retinal ischemia/reperfusion (RIR) injury leads to irreversible visual impairment. Pregabalin (PGB) is a promising drug for neurodegenerative diseases. However, with regard to RGC survival, its specific role and exact mechanism after RIR injury remain unclear. In this study, we sought to investigate whether PGB could protect RGCs from mitochondria-related apoptosis induced by RIR and explore the possible mechanisms. Methods C57BL/6J mice and primary RGCs were pretreated with PGB prior to ischemia/reperfusion modeling. The retinal structure and cell morphology were assessed by immunochemical assays and optical coherence tomography. CCK8 was used to assay cell viability, and an electroretinogram was performed to detect RGC function. Mitochondrial damage was assessed by a reactive oxygen species (ROS) assay kit and transmission electron microscopy. Western blot and immunofluorescence assays quantified the expression of proteins associated with the Akt/GSK3β/β-catenin pathway. Results Treatment with PGB increased the viability of RGCs in vitro. Consistently, PGB preserved the normal thickness of the retina, upregulated Bcl-2, reduced the ratio of cleaved caspase-3/caspase-3 and the expression of Bax in vivo. Meanwhile, PGB improved mitochondrial structure and prevented excessive ROS production. Moreover, PGB restored the amplitudes of oscillatory potentials and photopic negative responses following RIR. The mechanisms underlying its neuroprotective effects were attributed to upregulation of the Akt/GSK3β/β-catenin pathway. However, PGB-mediated neuroprotection was suppressed when using MK2206 (an Akt inhibitor), whereas it was preserved when treated with TWS119 (a GSK3β inhibitor). Conclusions PGB exerts a protective effect against RGC apoptosis induced by RIR injury, mediated by the Akt/GSK3β/β-catenin pathway.
Collapse
Affiliation(s)
- Jing Xu
- Department of Ophthalmology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China
| | - Yuyan Guo
- Department of Ophthalmology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China
| | - Qiong Liu
- Department of Ophthalmology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China
| | - Hui Yang
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Ming Ma
- Department of Ophthalmology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China
| | - Jian Yu
- Department of Ophthalmology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China
| | - Linjiang Chen
- Department of Ophthalmology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China
| | - Chunlian Ou
- Department of General Practice, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China
| | - Xiaohui Liu
- Department of Ophthalmology, The Second People's Hospital of Foshan, Foshan, Guangdong, China
| | - Jing Wu
- Huiqiao Medical Center, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China
| |
Collapse
|
|
24
|
Hottin C, Perron M, Roger JE. GSK3 Is a Central Player in Retinal Degenerative Diseases but a Challenging Therapeutic Target. Cells 2022; 11:cells11182898. [PMID: 36139472 PMCID: PMC9496697 DOI: 10.3390/cells11182898] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2022] [Revised: 09/12/2022] [Accepted: 09/13/2022] [Indexed: 11/24/2022] Open
Abstract
Glycogen synthase kinase 3 (GSK3) is a key regulator of many cellular signaling processes and performs a wide range of biological functions in the nervous system. Due to its central role in numerous cellular processes involved in cell degeneration, a rising number of studies have highlighted the interest in developing therapeutics targeting GSK3 to treat neurodegenerative diseases. Although recent works strongly suggest that inhibiting GSK3 might also be a promising therapeutic approach for retinal degenerative diseases, its full potential is still under-evaluated. In this review, we summarize the literature on the role of GSK3 on the main cellular functions reported as deregulated during retinal degeneration, such as glucose homeostasis which is critical for photoreceptor survival, or oxidative stress, a major component of retinal degeneration. We also discuss the interest in targeting GSK3 for its beneficial effects on inflammation, for reducing neovascularization that occurs in some retinal dystrophies, or for cell-based therapy by enhancing Müller glia cell proliferation in diseased retina. Together, although GSK3 inhibitors hold promise as therapeutic agents, we highlight the complexity of targeting such a multitasked kinase and the need to increase our knowledge of the impact of reducing GSK3 activity on these multiple cellular pathways and biological processes.
Collapse
Affiliation(s)
- Catherine Hottin
- Paris-Saclay Institute of Neuroscience, CERTO-Retina France, CNRS, Université Paris-Saclay, 91400 Saclay, France
| | - Muriel Perron
- Paris-Saclay Institute of Neuroscience, CERTO-Retina France, CNRS, Université Paris-Saclay, 91400 Saclay, France
| | - Jérôme E Roger
- Paris-Saclay Institute of Neuroscience, CERTO-Retina France, CNRS, Université Paris-Saclay, 91400 Saclay, France
| |
Collapse
|
|
25
|
Zhou Z, Du LQ, Huang XM, Zhu LG, Wei QC, Qin QP, Bian H. Novel glycosylation zinc(II)-cryptolepine complexes perturb mitophagy pathways and trigger cancer cell apoptosis and autophagy in SK-OV-3/DDP cells. Eur J Med Chem 2022; 243:114743. [PMID: 36116236 DOI: 10.1016/j.ejmech.2022.114743] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2022] [Revised: 08/31/2022] [Accepted: 09/02/2022] [Indexed: 11/04/2022]
Abstract
With the aim of shedding some light on the mechanism of action of zinc(II) complexes in antiproliferative processes and molecular signaling pathways, three novel glycosylated zinc(II)-cryptolepine complexes, i.e., [Zn(QA1)Cl2] (Zn(QA1)), [Zn(QA2)Cl2] (Zn(QA2)), and [Zn(QA3)Cl2] (Zn(QA3)), were prepared by conjugating a glucose moiety with cryptolepine, followed by complexation of the resulting glycosylated cryptolepine compounds N-((1-(2-morpholinoethyl)-1H-1,2,3-triazol-4-yl)methyl)-benzofuro[3,2-b]quinolin-11-amine (QA1), 2-(4-((benzofuro[3,2-b]quinolin-11-ylamino)methyl)-1H-1,2,3-triazol-1-yl)ethan-1-ol (QA2), and (2S,3S,4R,5R,6S)-2-(4-((benzofuro[3,2-b]quinolin-11-ylamino)-methyl)-1H-1,2,3-triazol-1-yl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol (QA3) with zinc(II), and their anticancer activity was evaluated. In MTT assays, Zn(QA1)-Zn(QA3) were more active against cisplatin-resistant ovarian SK-OV-3/DDP cancer cells (SK-OV-3cis) than ZnCl2 and the QA1-QA3 ligands, with IC50 values of 1.81 ± 0.50, 2.92 ± 0.32, and 1.01 ± 0.11 μM, respectively. Complexation of glycosylated cryptolepine QA3 with zinc(II) increased the antiproliferative activity of the ligand, suggesting that Zn(QA3) could act as a chaperone to deliver the active ligand intracellularly, in contrast with other cryptolepine metal complexes previously reported. In vivo and in vitro investigations suggested that Zn(QA3) exhibited enhanced anticancer activity with treatment effects comparable to those of the clinical drug cisplatin. Furthermore, Zn(QA1)-Zn(QA3) triggered SK-OV-3cis cell apoptosis through mitophagy pathways in the order Zn(QA1) > Zn(QA1) > Zn(QA2). These results demonstrate the potential of glycosylated zinc(II)-cryptolepine complexes for the development of chemotherapy drugs against cisplatin-resistant SK-OV-3cis cells.
Collapse
Affiliation(s)
- Zhen Zhou
- Guangxi Key Laboratory of Chemistry and Engineering of Forest Products, Guangxi Collaborative Innovation Center for Chemistry and Engineering of Forest Products, School of Chemistry and Chemical Engineering, Guangxi University for Nationalities (Guangxi Minzu University), Nanning, 530006, China; Guangxi Key Lab of Agricultural Resources Chemistry and Biotechnology, College of Chemistry and Food Science, Yulin Normal University, 1303 Jiaoyudong Road, Yulin, 537000, PR China
| | - Ling-Qi Du
- Guangxi Key Lab of Agricultural Resources Chemistry and Biotechnology, College of Chemistry and Food Science, Yulin Normal University, 1303 Jiaoyudong Road, Yulin, 537000, PR China
| | - Xiao-Mei Huang
- Guangxi Key Lab of Agricultural Resources Chemistry and Biotechnology, College of Chemistry and Food Science, Yulin Normal University, 1303 Jiaoyudong Road, Yulin, 537000, PR China
| | - Li-Gang Zhu
- Guangxi Key Lab of Agricultural Resources Chemistry and Biotechnology, College of Chemistry and Food Science, Yulin Normal University, 1303 Jiaoyudong Road, Yulin, 537000, PR China.
| | - Qiao-Chang Wei
- Guangxi Key Lab of Agricultural Resources Chemistry and Biotechnology, College of Chemistry and Food Science, Yulin Normal University, 1303 Jiaoyudong Road, Yulin, 537000, PR China
| | - Qi-Pin Qin
- Guangxi Key Lab of Agricultural Resources Chemistry and Biotechnology, College of Chemistry and Food Science, Yulin Normal University, 1303 Jiaoyudong Road, Yulin, 537000, PR China; State Key Laboratory for the Chemistry and Molecular Engineering of Medicinal Resources, School of Chemistry and Pharmacy, Guangxi Normal University, 15 Yucai Road, Guilin, 541004, PR China.
| | - Hedong Bian
- Guangxi Key Laboratory of Chemistry and Engineering of Forest Products, Guangxi Collaborative Innovation Center for Chemistry and Engineering of Forest Products, School of Chemistry and Chemical Engineering, Guangxi University for Nationalities (Guangxi Minzu University), Nanning, 530006, China.
| |
Collapse
|
|
26
|
Zhang SH, Wang ZF, Tan H. Novel zinc(II)−curcumin molecular probes bearing berberine and jatrorrhizine derivatives as potential mitochondria-targeting anti-neoplastic drugs. Eur J Med Chem 2022; 243:114736. [DOI: 10.1016/j.ejmech.2022.114736] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2022] [Revised: 08/17/2022] [Accepted: 08/29/2022] [Indexed: 11/04/2022]
|
|
27
|
PP2A-associated tau hyperphosphorylation was involved in sevoflurane induced neonatal neurotoxicity. Psychopharmacology (Berl) 2022; 239:2799-2807. [PMID: 35579686 DOI: 10.1007/s00213-022-06161-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/10/2022] [Accepted: 05/04/2022] [Indexed: 10/18/2022]
Abstract
BACKGROUND The effects of sevoflurane anesthesia on childhood neurodevelopment and adult brain function have attracted increasing scientific attentions. However, the exact mechanisms underlying hyperphosphorylation of tau protein in sevoflurane induced abnormalities in central nervous system (CNS) development, particularly in the hippocampus, have not been fully determined. METHODS We utilized molecular biological and behavioral approaches to compare the changes in cognitive function in mice exposed to repeated sevoflurane during the neonatal stage, and to assess whether PP2A-associated tau hyperphosphorylation is involved in sevoflurane induced neonatal neurotoxicity. RESULTS We reported that mice anesthetized with repeated sevoflurane during the neonatal period caused cognitive dysfunction during the adulthood. More importantly, we found that hyperphosphorylation of tau protein and decreased level of protein phosphatase 2A (PP2A) were detected in the hippocampus of mice after neonatal exposure of sevoflurane. Meanwhile, GSK-3β activity was found to be increased with repeated sevoflurane exposure, but not for more than 2 weeks. CONCLUSION Our results suggest that PP2A-associated hyperphosphorylation of tau protein might contribute to sevoflurane induced developmental neurotoxicity. These findings could provide a theoretical basis for the safely usage of sevoflurane in pediatric surgeries, and offer a valuable reference and potential therapeutic targets for the development of neuroprotective drugs.
Collapse
|
|
28
|
Ren J, Zhang S, Pan Y, Jin M, Li J, Luo Y, Sun X, Li G. Diabetic retinopathy: Involved cells, biomarkers, and treatments. Front Pharmacol 2022; 13:953691. [PMID: 36016568 PMCID: PMC9396039 DOI: 10.3389/fphar.2022.953691] [Citation(s) in RCA: 24] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2022] [Accepted: 07/06/2022] [Indexed: 11/13/2022] Open
Abstract
Diabetic retinopathy (DR), a leading cause of vision loss and blindness worldwide, is caused by retinal neurovascular unit dysfunction, and its cellular pathology involves at least nine kinds of retinal cells, including photoreceptors, horizontal and bipolar cells, amacrine cells, retinal ganglion cells, glial cells (Müller cells, astrocytes, and microglia), endothelial cells, pericytes, and retinal pigment epithelial cells. Its mechanism is complicated and involves loss of cells, inflammatory factor production, neovascularization, and BRB impairment. However, the mechanism has not been completely elucidated. Drug treatment for DR has been gradually advancing recently. Research on potential drug targets relies upon clear information on pathogenesis and effective biomarkers. Therefore, we reviewed the recent literature on the cellular pathology and the diagnostic and prognostic biomarkers of DR in terms of blood, protein, and clinical and preclinical drug therapy (including synthesized molecules and natural molecules). This review may provide a theoretical basis for further DR research.
Collapse
Affiliation(s)
- Jiahui Ren
- Institute of Medicinal Plant Development, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China
- Beijing Key Laboratory of Innovative Drug Discovery of Traditional Chinese Medicine (Natural Medicine) and Translational Medicine, Beijing, China
- Key Laboratory of Bioactive Substances and Resource Utilization of Chinese Herbal Medicine, Ministry of Education, Beijing, China
- Yunnan Branch, Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences and Peking Union Medical College, Jinghong, China
- Yunnan Key Laboratory of Southern Medicine Utilization, Kunming, China
| | - Shuxia Zhang
- Institute of Medicinal Plant Development, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China
- Beijing Key Laboratory of Innovative Drug Discovery of Traditional Chinese Medicine (Natural Medicine) and Translational Medicine, Beijing, China
- Key Laboratory of Bioactive Substances and Resource Utilization of Chinese Herbal Medicine, Ministry of Education, Beijing, China
| | - Yunfeng Pan
- Institute of Medicinal Plant Development, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China
- Beijing Key Laboratory of Innovative Drug Discovery of Traditional Chinese Medicine (Natural Medicine) and Translational Medicine, Beijing, China
- Key Laboratory of Bioactive Substances and Resource Utilization of Chinese Herbal Medicine, Ministry of Education, Beijing, China
| | - Meiqi Jin
- Institute of Medicinal Plant Development, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China
- Beijing Key Laboratory of Innovative Drug Discovery of Traditional Chinese Medicine (Natural Medicine) and Translational Medicine, Beijing, China
- Key Laboratory of Bioactive Substances and Resource Utilization of Chinese Herbal Medicine, Ministry of Education, Beijing, China
| | - Jiaxin Li
- Yunnan Key Laboratory of Southern Medicine Utilization, Kunming, China
- College of Pharmacy, Heilongjiang University of Chinese Medicine, Harbin, China
| | - Yun Luo
- Institute of Medicinal Plant Development, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China
- Beijing Key Laboratory of Innovative Drug Discovery of Traditional Chinese Medicine (Natural Medicine) and Translational Medicine, Beijing, China
- Key Laboratory of Bioactive Substances and Resource Utilization of Chinese Herbal Medicine, Ministry of Education, Beijing, China
- *Correspondence: Yun Luo, ; Xiaobo Sun , ; Guang Li,
| | - Xiaobo Sun
- Institute of Medicinal Plant Development, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China
- Beijing Key Laboratory of Innovative Drug Discovery of Traditional Chinese Medicine (Natural Medicine) and Translational Medicine, Beijing, China
- Key Laboratory of Bioactive Substances and Resource Utilization of Chinese Herbal Medicine, Ministry of Education, Beijing, China
- *Correspondence: Yun Luo, ; Xiaobo Sun , ; Guang Li,
| | - Guang Li
- Institute of Medicinal Plant Development, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China
- Yunnan Branch, Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences and Peking Union Medical College, Jinghong, China
- Yunnan Key Laboratory of Southern Medicine Utilization, Kunming, China
- *Correspondence: Yun Luo, ; Xiaobo Sun , ; Guang Li,
| |
Collapse
|
|
29
|
Epremyan KK, Goleva TN, Zvyagilskaya RA. Effect of Tau Protein on Mitochondrial Functions. BIOCHEMISTRY. BIOKHIMIIA 2022; 87:689-701. [PMID: 36171651 DOI: 10.1134/s0006297922080028] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/27/2022] [Revised: 07/04/2022] [Accepted: 07/06/2022] [Indexed: 06/16/2023]
Abstract
Alzheimer's disease is the most common age-related progressive neurodegenerative disorder of brain cortex and hippocampus leading to cognitive impairment. Accumulation of extracellular amyloid plaques and intraneuronal neurofibrillary tangles are believed to be the main hallmarks of the disease. Origin of Alzheimer's disease is not totally clear, multiple initiator factors are likely to exist. Intracellular impacts of Alzheimer's disease include mitochondrial dysfunction, oxidative stress, ER-stress, disruption of autophagy, severe metabolic challenges leading to massive neuronal apoptosis. Mitochondria are the key players in all these processes. This formed the basis for the so-called mitochondrial cascade hypothesis. This review provides current data on the molecular mechanisms of the development of Alzheimer's disease associated with mitochondria. Special attention was paid to the interaction between Tau protein and mitochondria, as well as to the promising therapeutic approaches aimed at preventing development of neurodegeneration.
Collapse
Affiliation(s)
- Khoren K Epremyan
- Bach Institute of Biochemistry, Federal Research Center of Biotechnology, Russian Academy of Sciences, Moscow, 119071, Russia.
| | - Tatyana N Goleva
- Bach Institute of Biochemistry, Federal Research Center of Biotechnology, Russian Academy of Sciences, Moscow, 119071, Russia
| | - Renata A Zvyagilskaya
- Bach Institute of Biochemistry, Federal Research Center of Biotechnology, Russian Academy of Sciences, Moscow, 119071, Russia
| |
Collapse
|
|
30
|
Novel bifluorescent Zn(II)–cryptolepine–cyclen complexes trigger apoptosis induced by nuclear and mitochondrial DNA damage in cisplatin-resistant lung tumor cells. Eur J Med Chem 2022; 238:114418. [DOI: 10.1016/j.ejmech.2022.114418] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2022] [Revised: 04/20/2022] [Accepted: 04/26/2022] [Indexed: 12/15/2022]
|
|
31
|
Jungbauer G, Stähli A, Zhu X, Auber Alberi L, Sculean A, Eick S. Periodontal microorganisms and Alzheimer disease - A causative relationship? Periodontol 2000 2022; 89:59-82. [PMID: 35244967 PMCID: PMC9314828 DOI: 10.1111/prd.12429] [Citation(s) in RCA: 61] [Impact Index Per Article: 20.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2021] [Revised: 12/07/2021] [Accepted: 12/21/2021] [Indexed: 01/10/2023]
Abstract
In the initiation or exacerbation of Alzheimer disease, the dissemination of oral microorganisms into the brain tissue or the low‐level systemic inflammation have been speculated to play a role. However, the impact of oral microorganisms, such as Porphyromonas gingivalis, on the pathogenesis of Alzheimer disease and the potential causative relationship is still unclear. The present review has critically reviewed the literature by examining the following aspects: (a) the oral microbiome and the immune response in the elderly population, (b) human studies on the association between periodontal and gut microorganisms and Alzheimer disease, (c) animal and in vitro studies on microorganisms and Alzheimer disease, and (d) preventive and therapeutic approaches. Factors contributing to microbial dysbiosis seem to be aging, local inflammation, systemic diseases, wearing of dentures, living in nursing homes and no access to adequate oral hygiene measures. Porphyromonas gingivalis was detectable in post‐mortem brain samples. Microbiome analyses of saliva samples or oral biofilms showed a decreased microbial diversity and a different composition in Alzheimer disease compared to cognitively healthy subjects. Many in‐vitro and animal studies underline the potential of P gingivalis to induce Alzheimer disease‐related alterations. In animal models, recurring applications of P gingivalis or its components increased pro‐inflammatory mediators and β‐amyloid in the brain and deteriorated the animals' cognitive performance. Since periodontitis is the result of a disturbed microbial homoeostasis, an effect of periodontal therapy on the oral microbiome and host response related to cognitive parameters may be suggested and should be elucidated in further clinical trials.
Collapse
Affiliation(s)
- Gert Jungbauer
- Department of Periodontology, School of Dental Medicine, University of Bern, Bern, Switzerland.,Private Dental Practice, Straubing, Germany
| | - Alexandra Stähli
- Department of Periodontology, School of Dental Medicine, University of Bern, Bern, Switzerland
| | - Xilei Zhu
- Department of Periodontology, School of Dental Medicine, University of Bern, Bern, Switzerland
| | | | - Anton Sculean
- Department of Periodontology, School of Dental Medicine, University of Bern, Bern, Switzerland
| | - Sigrun Eick
- Department of Periodontology, School of Dental Medicine, University of Bern, Bern, Switzerland
| |
Collapse
|
|
32
|
Pitale PM, Gorbatyuk MS. Diabetic Retinopathy: From Animal Models to Cellular Signaling. Int J Mol Sci 2022; 23:ijms23031487. [PMID: 35163410 PMCID: PMC8835767 DOI: 10.3390/ijms23031487] [Citation(s) in RCA: 29] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2021] [Revised: 01/24/2022] [Accepted: 01/26/2022] [Indexed: 12/24/2022] Open
Abstract
Diabetic retinopathy (DR) is an ocular complication of diabetes mellitus (DM), a metabolic disorder characterized by elevation in blood glucose level. The pathogenesis of DR includes vascular, neuronal, and inflammatory components leading to activation of complex cellular molecular signaling. If untreated, the disease can culminate in vision loss that eventually leads to blindness. Animal models mimicking different aspects of DM complications have been developed to study the development and progression of DR. Despite the significant contribution of the developed DR models to discovering the mechanisms of DR and the recent achievements in the research field, the sequence of cellular events in diabetic retinas is still under investigation. Partially, this is due to the complexity of molecular mechanisms, although the lack of availability of models that adequately mimic all the neurovascular pathobiological features observed in patients has also contributed to the delay in determining a precise molecular trigger. In this review, we provide an update on the status of animal models of DR to help investigators choose an appropriate system to validate their hypothesis. We also discuss the key cellular and physiological events of DR in these models.
Collapse
Affiliation(s)
- Priyamvada M. Pitale
- Department of Ophthalmology, Baylor College of Medicine, Houston, TX 77030, USA;
| | - Marina S. Gorbatyuk
- Department of Optometry and Vision Science, School of Optometry, University of Alabama at Birmingham, Birmingham, AL 35294, USA
- Correspondence: ; Tel.: +1-205-934-6762; Fax: +1-205-934-3425
| |
Collapse
|
|
33
|
Little K, Llorián-Salvador M, Scullion S, Hernández C, Simó-Servat O, Del Marco A, Bosma E, Vargas-Soria M, Carranza-Naval MJ, Van Bergen T, Galbiati S, Viganò I, Musi CA, Schlingemann R, Feyen J, Borsello T, Zerbini G, Klaassen I, Garcia-Alloza M, Simó R, Stitt AW. Common pathways in dementia and diabetic retinopathy: understanding the mechanisms of diabetes-related cognitive decline. Trends Endocrinol Metab 2022; 33:50-71. [PMID: 34794851 DOI: 10.1016/j.tem.2021.10.008] [Citation(s) in RCA: 54] [Impact Index Per Article: 18.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/23/2021] [Revised: 09/06/2021] [Accepted: 10/29/2021] [Indexed: 12/14/2022]
Abstract
Type 2 diabetes (T2D) is associated with multiple comorbidities, including diabetic retinopathy (DR) and cognitive decline, and T2D patients have a significantly higher risk of developing Alzheimer's disease (AD). Both DR and AD are characterized by a number of pathological mechanisms that coalesce around the neurovascular unit, including neuroinflammation and degeneration, vascular degeneration, and glial activation. Chronic hyperglycemia and insulin resistance also play a significant role, leading to activation of pathological mechanisms such as increased oxidative stress and the accumulation of advanced glycation end-products (AGEs). Understanding these common pathways and the degree to which they occur simultaneously in the brain and retina during diabetes will provide avenues to identify T2D patients at risk of cognitive decline.
Collapse
Affiliation(s)
- Karis Little
- Wellcome-Wolfson Institute for Experimental Medicine, Queen's University Belfast, Belfast, UK
| | - María Llorián-Salvador
- Wellcome-Wolfson Institute for Experimental Medicine, Queen's University Belfast, Belfast, UK
| | - Sarah Scullion
- Wellcome-Wolfson Institute for Experimental Medicine, Queen's University Belfast, Belfast, UK
| | - Cristina Hernández
- Vall d'Hebron Research Institute and CIBERDEM (ISCIII), Barcelona, Spain
| | - Olga Simó-Servat
- Vall d'Hebron Research Institute and CIBERDEM (ISCIII), Barcelona, Spain
| | - Angel Del Marco
- Division of Physiology, School of Medicine, Instituto de Investigacion Biomedica de Cadiz (INIBICA), Universidad de Cadiz, Cadiz, Spain
| | - Esmeralda Bosma
- Ocular Angiogenesis Group, University of Amsterdam, Amsterdam, The Netherlands
| | - Maria Vargas-Soria
- Division of Physiology, School of Medicine, Instituto de Investigacion Biomedica de Cadiz (INIBICA), Universidad de Cadiz, Cadiz, Spain
| | - Maria Jose Carranza-Naval
- Division of Physiology, School of Medicine, Instituto de Investigacion Biomedica de Cadiz (INIBICA), Universidad de Cadiz, Cadiz, Spain
| | | | - Silvia Galbiati
- Complications of Diabetes Unit, Diabetes Research Institute, IRCCS Ospedale San Raffaele, Milano, Italy
| | - Ilaria Viganò
- Complications of Diabetes Unit, Diabetes Research Institute, IRCCS Ospedale San Raffaele, Milano, Italy
| | - Clara Alice Musi
- Università Degli Studi di Milano and Istituto di Ricerche Farmacologiche Mario Negri- IRCCS, Milano, Italy
| | - Reiner Schlingemann
- Ocular Angiogenesis Group, University of Amsterdam, Amsterdam, The Netherlands; Department of Ophthalmology, University of Lausanne, Jules Gonin Eye Hospital, Lausanne, Switzerland
| | | | - Tiziana Borsello
- Università Degli Studi di Milano and Istituto di Ricerche Farmacologiche Mario Negri- IRCCS, Milano, Italy
| | - Gianpaolo Zerbini
- Complications of Diabetes Unit, Diabetes Research Institute, IRCCS Ospedale San Raffaele, Milano, Italy
| | - Ingeborg Klaassen
- Ocular Angiogenesis Group, University of Amsterdam, Amsterdam, The Netherlands
| | - Monica Garcia-Alloza
- Division of Physiology, School of Medicine, Instituto de Investigacion Biomedica de Cadiz (INIBICA), Universidad de Cadiz, Cadiz, Spain
| | - Rafael Simó
- Vall d'Hebron Research Institute and CIBERDEM (ISCIII), Barcelona, Spain.
| | - Alan W Stitt
- Wellcome-Wolfson Institute for Experimental Medicine, Queen's University Belfast, Belfast, UK.
| | | |
Collapse
|
|
34
|
Abstract
PURPOSE OF REVIEW Diabetic retinopathy (DR), the leading cause of blindness in working-aged adults, remains clinically defined and staged by its vascular manifestations. However, early retinal neurodegeneration may precede vascular pathology, suggesting that this neuronal damage may contribute to disease pathogenesis and represent an independent target for intervention. This review will discuss the evidence and implications for diabetic retinal neurodegeneration. RECENT FINDINGS A growing body of literature has identified progressive retinal thinning and visual dysfunction in patients with diabetes even prior to the onset of DR, though advances in retinal vascular imaging suggest that vascular remodeling and choroidal changes occur during these early stages as well. Animal models of diabetes and in vitro studies have also suggested that diabetes may directly affect the retinal neural and glial tissue, providing support to the concept that diabetic retinal neurodegeneration occurs early in the disease and suggesting potentially relevant molecular pathways. Diabetic retinal neurodegeneration may represent a "preclinical" manifestation of diabetic retinal disease and remains an active area of investigation. As the natural history and molecular mechanisms become increasingly understood, it may lead to upcoming developments in not only the treatment options but also the clinical definition of DR.
Collapse
Affiliation(s)
- Mira M Sachdeva
- Wilmer Eye Institute, Johns Hopkins University School of Medicine, 600 North Wolfe Street, Maumenee 748, Baltimore, MD, 21287 MD, USA.
| |
Collapse
|
|
35
|
Shi R, Lu Y, Liu D, Guo Z. Association of serum apolipoprotein B with retinal neurovascular structural alterations in patients with type 2 diabetes: an optical coherence tomography angiography study. Acta Diabetol 2021; 58:1673-1681. [PMID: 34292395 DOI: 10.1007/s00592-021-01775-x] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/21/2021] [Accepted: 07/13/2021] [Indexed: 01/14/2023]
Abstract
PURPOSE To investigate the association of serum apoB concentrations with retinal neurovascular structural alterations in type 2 diabetes patients without clinically visible retinopathy. METHODS Eyes with no clinically visible diabetic retinopathy (DR) from diabetic patients with or without dyslipidemia were included. Changes in retinal neural structures, including the ganglion cell layer (GCL) and peripapillary retinal nerve fiber layer (RNFL) thicknesses, and microvascular metrics, including macular vessel density (VD) and perfusion density (PD) of the superficial capillary plexus, were measured with optical coherence tomography angiography (OCTA). Correlations between inner retinal layer thickness and OCTA metrics were analyzed. The association of serum apoB and diabetic retinal neurovascular structures was identified with regression analysis. RESULTS A total of 148 eyes in the diabetes group (n = 74) and dyslipidemia group (n = 74) were enrolled. GCL and RNFL thicknesses in patients in the dyslipidemia group were significantly thinner than those in the diabetes group (all p < 0.025). The total area of the VD and PD in the dyslipidemia group was also decreased compared to that of the diabetes group (p < 0.05) and was found to correlate with GCL and RNFL (all p < 0.01) thicknesses in all diabetic patients. Serum apoB levels were positively related to low-density lipoprotein (LDL) and total cholesterol (TC). Moreover, the average GCL thickness was significantly associated with serum apoB levels (all p < 0.05). CONCLUSIONS GCL and RNFL thinning was significantly correlated with decreased retinal blood flow in diabetic patients with dyslipidemia. Strictly controlling serum lipids, especially apoB levels, might be an effective strategy for DR treatment.
Collapse
Affiliation(s)
- Rui Shi
- Department of Ophthalmology, Shaanxi Provincial People's Hospital, Xi'an, 710068, China.
| | - Yao Lu
- Department of Ophthalmology, Shaanxi Provincial People's Hospital, Xi'an, 710068, China
| | - DanDan Liu
- Department of Ophthalmology, Shaanxi Provincial People's Hospital, Xi'an, 710068, China
| | - ZhongLan Guo
- Department of Ophthalmology, Shaanxi Provincial People's Hospital, Xi'an, 710068, China
| |
Collapse
|
|
36
|
Liu Y, Zhang H, Dai X, Zhu R, Chen B, Xia B, Ye Z, Zhao D, Gao S, Orekhov AN, Zhang D, Wang L, Guo S. A comprehensive review on the phytochemistry, pharmacokinetics, and antidiabetic effect of Ginseng. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2021; 92:153717. [PMID: 34583224 DOI: 10.1016/j.phymed.2021.153717] [Citation(s) in RCA: 34] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/17/2021] [Revised: 08/08/2021] [Accepted: 08/15/2021] [Indexed: 06/13/2023]
Abstract
BACKGROUND Radix Ginseng, one of the well-known medicinal herbs, has been used in the management of diabetes and its complications for more than 1000 years. PURPOSE The aim of this review is devoted to summarize the phytochemistry and pharmacokinetics of Ginseng, and provide evidence for the antidiabetic effects of Ginseng and its ingredients as well as the underlying mechanisms involved. METHODS For the purpose of this review, the following databases were consulted: the PubMed Database (https://pubmed.ncbi.nlm.nih.gov), Chinese National Knowledge Infrastructure (http://www.cnki.net), National Science and Technology Library (http://www.nstl.gov.cn/), Wanfang Data (http://www.wanfangdata.com.cn/) and the Web of Science Database (http://apps.webofknowledge.com/). RESULTS Ginseng exhibits glucose-lowering effects in different diabetic animal models. In addition, Ginseng may prevent the development of diabetic complications, including liver, pancreas, adipose tissue, skeletal muscle, nephropathy, cardiomyopathy, retinopathy, atherosclerosis and others. The main ingredients of Ginseng include ginsenosides and polysaccharides. The underlying mechanisms whereby this herb exerts antidiabetic activities may be attributed to the regulation of multiple signaling pathways, including IRS1/PI3K/AKT, LKB1/AMPK/FoxO1, AGEs/RAGE, MAPK/ERK, NF-κB, PPARδ/STAT3, cAMP/PKA/CERB and HIF-1α/VEGF, etc. The pharmacokinetic profiles of ginsenosides provide valuable information on therapeutic efficacy of Ginseng in diabetes. Although Ginseng is well-tolerated, dietary consumption of this herb should follow the doctors' advice. CONCLUSION Ginseng may offer an alternative strategy in protection against diabetes and its complications through the regulations of the multi-targets via various signaling pathways. Efforts to understand the underlying mechanisms with strictly-controlled animal models, combined with well-designed clinical trials and pharmacokinetic evaluation, will be important subjects of the further investigations and weigh in translational value of this herb in diabetes management.
Collapse
Affiliation(s)
- Yage Liu
- Diabetes Research Center, School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing 100029, China
| | - Hao Zhang
- Diabetes Research Center, School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing 100029, China
| | - Xuan Dai
- Diabetes Research Center, School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing 100029, China
| | - Ruyuan Zhu
- Diabetes Research Center, School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing 100029, China
| | - Beibei Chen
- Diabetes Research Center, School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing 100029, China
| | - Bingke Xia
- Diabetes Research Center, School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing 100029, China
| | - Zimengwei Ye
- Diabetes Research Center, School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing 100029, China
| | - Dandan Zhao
- Diabetes Research Center, School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing 100029, China
| | - Sihua Gao
- Diabetes Research Center, School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing 100029, China
| | - Alexander N Orekhov
- Laboratory of Angiopathology, Institute of General Pathology and Pathophysiology, Russian Academy of Medical Sciences, Moscow 125315, Russia
| | - Dongwei Zhang
- Diabetes Research Center, School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing 100029, China.
| | - Lili Wang
- Department of TCM Pharmacology, School of Chinese Material Medica, Beijing University of Chinese Medicine, Beijing 100029, China.
| | - Shuzhen Guo
- Department of Scientific Research Center, School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing 100029, China.
| |
Collapse
|
|
37
|
Modulation of the Wound Healing through Noncoding RNA Interplay and GSK-3 β/NF- κB Signaling Interaction. Int J Genomics 2021; 2021:9709290. [PMID: 34485505 PMCID: PMC8413067 DOI: 10.1155/2021/9709290] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2021] [Accepted: 08/10/2021] [Indexed: 12/30/2022] Open
Abstract
Diabetic foot ulcers are seriously endangering the physical and mental health of patients. Due to the long duration of inflammation, the treatment of nonhealing wounds in diabetes is one of the most prominent healthcare problems in the world. The nuclear factor kappa B (NF-κB) signaling pathway, a classical pathway that triggers inflammatory response, is regulated by many regulators, such as glycogen synthase kinase 3 beta (GSK-3β). Noncoding RNAs, a large class of molecules that regulate gene expression at the posttranscriptional or posttranslational level, play an important role in various stages of wound healing, especially in the stage of inflammation. Herein, we summarized the roles of noncoding RNAs in the NF-κB/GSK-3β signaling, which might provide new ideas for the treatment of diabetic wound healing.
Collapse
|
|
38
|
Evidence for a dysfunction and disease-promoting role of the circadian clock in the diabetic retina. Exp Eye Res 2021; 211:108751. [PMID: 34478739 DOI: 10.1016/j.exer.2021.108751] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2021] [Revised: 08/12/2021] [Accepted: 08/25/2021] [Indexed: 11/21/2022]
Abstract
Diabetic retinopathy is a major complication of chronic hyperglycemia and a leading cause of blindness in developed countries. In the present study the interaction between diabetes and retinal clocks was investigated in mice. It was seen that in the db/db mouse - a widely used animal model of diabetic retinopathy - clock function and circadian regulation of gene expression was disturbed in the retina. Remarkably, elimination of clock function by Bmal1-deficiency mitigates the progression of pathophysiology of the diabetic retina. Thus high-fat diet was seen to induce histopathology and molecular markers associated with diabetic retinopathy in wild type but not in Bmal1-deficient mice. The data of the present study suggest that Bmal1/the retinal clock system is both, a target and an effector of diabetes mellitus in the retina and hence represents a putative therapeutic target in the pathogenesis of diabetic retinopathy.
Collapse
|
|
39
|
Simó R, Simó-Servat O, Bogdanov P, Hernández C. Neurovascular Unit: A New Target for Treating Early Stages of Diabetic Retinopathy. Pharmaceutics 2021; 13:pharmaceutics13081320. [PMID: 34452281 PMCID: PMC8399715 DOI: 10.3390/pharmaceutics13081320] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2021] [Revised: 08/18/2021] [Accepted: 08/19/2021] [Indexed: 01/02/2023] Open
Abstract
The concept of diabetic retinopathy as a microvascular disease has evolved and is now considered a more complex diabetic complication in which neurovascular unit impairment plays an essential role and, therefore, can be considered as a main therapeutic target in the early stages of the disease. However, neurodegeneration is not always the apparent primary event in the natural story of diabetic retinopathy, and a phenotyping characterization is recommendable to identify those patients in whom neuroprotective treatment might be of benefit. In recent years, a myriad of treatments based on neuroprotection have been tested in experimental models, but more interestingly, there are drugs with a dual activity (neuroprotective and vasculotropic). In this review, the recent evidence concerning the therapeutic approaches targeting neurovascular unit impairment will be presented, along with a critical review of the scientific gaps and problems which remain to be overcome before our knowledge can be transferred to clinical practice.
Collapse
Affiliation(s)
- Rafael Simó
- Diabetes and Metabolism Research Unit, Vall d’Hebron Research Institute (VHIR), 08035 Barcelona, Spain; (O.S.-S.); (P.B.); (C.H.)
- Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Instituto de Salud Carlos III (ICSIII), 28029 Madrid, Spain
- Correspondence:
| | - Olga Simó-Servat
- Diabetes and Metabolism Research Unit, Vall d’Hebron Research Institute (VHIR), 08035 Barcelona, Spain; (O.S.-S.); (P.B.); (C.H.)
- Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Instituto de Salud Carlos III (ICSIII), 28029 Madrid, Spain
| | - Patricia Bogdanov
- Diabetes and Metabolism Research Unit, Vall d’Hebron Research Institute (VHIR), 08035 Barcelona, Spain; (O.S.-S.); (P.B.); (C.H.)
- Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Instituto de Salud Carlos III (ICSIII), 28029 Madrid, Spain
| | - Cristina Hernández
- Diabetes and Metabolism Research Unit, Vall d’Hebron Research Institute (VHIR), 08035 Barcelona, Spain; (O.S.-S.); (P.B.); (C.H.)
- Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Instituto de Salud Carlos III (ICSIII), 28029 Madrid, Spain
| |
Collapse
|
|
40
|
The Pathogenesis and Therapeutic Approaches of Diabetic Neuropathy in the Retina. Int J Mol Sci 2021; 22:ijms22169050. [PMID: 34445756 PMCID: PMC8396448 DOI: 10.3390/ijms22169050] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2021] [Revised: 08/19/2021] [Accepted: 08/19/2021] [Indexed: 02/07/2023] Open
Abstract
Diabetic retinopathy is a major retinal disease and a leading cause of blindness in the world. Diabetic retinopathy is a neurovascular disease that is associated with disturbances of the interdependent relationship of cells composed of the neurovascular units, i.e., neurons, glial cells, and vascular cells. An impairment of these neurovascular units causes both neuronal and vascular abnormalities in diabetic retinopathy. More specifically, neuronal abnormalities including neuronal cell death and axon degeneration are irreversible changes that are directly related to the vision reduction in diabetic patients. Thus, establishment of neuroprotective and regenerative therapies for diabetic neuropathy in the retina is an emergent task for preventing the blindness of patients with diabetic retinopathy. This review focuses on the pathogenesis of the neuronal abnormalities in diabetic retina including glial abnormalities, neuronal cell death, and axon degeneration. The possible molecular cell death pathways and intrinsic survival and regenerative pathways are also described. In addition, therapeutic approaches for diabetic neuropathy in the retina both in vitro and in vivo are presented. This review should be helpful for providing clues to overcome the barriers for establishing neuroprotection and regeneration of diabetic neuropathy in the retina.
Collapse
|
|
41
|
Wang WZ, Li MW, Chen Y, Liu LY, Xu Y, Xia ZH, Yu Y, Wang XD, Chen W, Zhang F, Xu XY, Gao YF, Zhang JG, Qin SC, Wang H. 3×Tg-AD Mice Overexpressing Phospholipid Transfer Protein Improves Cognition Through Decreasing Amyloid-β Production and Tau Hyperphosphorylation. J Alzheimers Dis 2021; 82:1635-1649. [PMID: 34219730 DOI: 10.3233/jad-210463] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Abstract
BACKGROUND Phospholipid transfer protein (PLTP) belongs to the lipid transfer glycoprotein family. Studies have shown that it is closely related to Alzheimer's disease (AD); however, the exact effect and mechanism remain unknown. OBJECTIVE To observe the effect of PLTP overexpression on behavioral dysfunction and the related mechanisms in APP/PS1/Tau triple transgenic (3×Tg-AD) mice. METHODS AAV-PLTP-EGFP was injected into the lateral ventricle to induce PLTP overexpression. The memory of 3×Tg-AD mice and wild type (WT) mice aged 10 months were assessed using Morris water maze (MWM) and shuttle-box passive avoidance test (PAT). Western blotting and ELISA assays were used to quantify the protein contents. Hematoxylin and eosin, Nissl, and immunochemistry staining were utilized in observing the pathological changes in the brain. RESULTS 3×Tg-AD mice displayed cognitive impairment in WMW and PAT, which was ameliorated by PLTP overexpression. The histopathological hallmarks of AD, senile plaques and neurofibrillary tangles, were observed in 3×Tg-AD mice and were improved by PLTP overexpression. Besides, the increase of amyloid-β42 (Aβ42) and Aβ40 were found in the cerebral cortex and hippocampus of 3×Tg-AD mice and reversed by PLTP overexpression through inhibiting APP and PS1. PLTP overexpression also reversed tau phosphorylation at the Ser404, Thr231 and Ser199 of the hippocampus in 3×Tg-AD mice. Furthermore, PLTP overexpression induced the glycogen synthase kinase 3β (GSK3β) inactivation via upregulating GSK3β (pSer9). CONCLUSION These results suggest that PLTP overexpression has neuroprotective effects. These effects are possibly achieved through the inhibition of the Aβ production and tau phosphorylation, which is related to GSK3β inactivation.
Collapse
Affiliation(s)
- Wen-Zhi Wang
- Institute of Pharmacology, Shandong First Medical University & Shandong Academy of Medical Sciences, Tai'an, China
| | - Ming-Wei Li
- Institute of Pharmacology, Shandong First Medical University & Shandong Academy of Medical Sciences, Tai'an, China
| | - Ying Chen
- Institute of Pharmacology, Shandong First Medical University & Shandong Academy of Medical Sciences, Tai'an, China
| | - Li-Yuan Liu
- Institute of Pharmacology, Shandong First Medical University & Shandong Academy of Medical Sciences, Tai'an, China
| | - Yong Xu
- Institute of Pharmacology, Shandong First Medical University & Shandong Academy of Medical Sciences, Tai'an, China
| | - Zeng-Hui Xia
- Institute of Pharmacology, Shandong First Medical University & Shandong Academy of Medical Sciences, Tai'an, China
| | - Yang Yu
- Key Laboratory of Atherosclerosis, University of Shandong, Jinan, China.,Institute of Artherosclerosis, Shandong First Medical University & Shandong Academy of Medical Sciences, Tai'an, China
| | - Xiao-Dan Wang
- Institute of Pharmacology, Shandong First Medical University & Shandong Academy of Medical Sciences, Tai'an, China
| | - Wei Chen
- Institute of Pharmacology, Shandong First Medical University & Shandong Academy of Medical Sciences, Tai'an, China
| | - Feng Zhang
- Institute of Pharmacology, Shandong First Medical University & Shandong Academy of Medical Sciences, Tai'an, China
| | - Xiao-Yan Xu
- Institute of Pharmacology, Shandong First Medical University & Shandong Academy of Medical Sciences, Tai'an, China
| | - Yong-Feng Gao
- Institute of Pharmacology, Shandong First Medical University & Shandong Academy of Medical Sciences, Tai'an, China
| | - Ji-Guo Zhang
- Institute of Pharmacology, Shandong First Medical University & Shandong Academy of Medical Sciences, Tai'an, China
| | - Shu-Cun Qin
- Key Laboratory of Atherosclerosis, University of Shandong, Jinan, China.,Institute of Artherosclerosis, Shandong First Medical University & Shandong Academy of Medical Sciences, Tai'an, China
| | - Hao Wang
- Institute of Pharmacology, Shandong First Medical University & Shandong Academy of Medical Sciences, Tai'an, China
| |
Collapse
|
|
42
|
Wang X, Liu Q, Li XG, Zhou QZ, Wu DQ, Li SH, Liu YC, Wang JZ. T217-Phosphorylation Exacerbates Tau Pathologies and Tau-Induced Cognitive Impairment. J Alzheimers Dis 2021; 81:1403-1418. [PMID: 33935099 DOI: 10.3233/jad-210297] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
BACKGROUND Recent studies show that an increased T217-phosphorylation of tau in plasma could diagnose AD at an early stage with high accuracy and high specificity, while the potential toxic role of tau T217-phosphorylation is not known. OBJECTIVE To study the potential toxic role of tau T217-phosphorylation. METHODS We performed stereotactic brain injection, behavioral testing, immunohistochemistry and immunofluorescence, western blotting, Golgi staining, in vitro recombinant tau polymerization, and other measurements. RESULTS We first constructed tau T217-wild-type (T217), T217-phospho-mimic (T217E), and T217-non-phospho-mimic (T217A) plasmids or their virus vectors on the basis of wild-type tau. We found that expressing tau-T217E induced a significantly increased tau phosphorylation at multiple AD-associated sites with inhibited proteolysis and increased cleavage/fibrillization of tau, while expressing tau-T217A abolished the above changes of tau both in vitro and in vivo. By mutating T217E on tau-P301L, a dominant mutation identified in patients with frontotemporal dementia, we did not observe significant exacerbation of tau-P301L phosphorylation and cognitive impairment although the increased tau cleavage and propagation were shown. CONCLUSION T217-phosphorylation exacerbates wild-type tau hyperphosphorylation with aggravated tau cleavage/fibrillization and cognitive impairments, while overexpressing T217E on the basis P301L does not exacerbate tau phosphorylation or the P301L-induced cognitive deficits, although it aggravates tau cleavage and propagation.
Collapse
Affiliation(s)
- Xin Wang
- Department of Pathophysiology, School of Basic Medicine, Key Laboratory of Education Ministry of China/Hubei Province for Neurological Disorders, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Qian Liu
- Department of Pathophysiology, School of Basic Medicine, Key Laboratory of Education Ministry of China/Hubei Province for Neurological Disorders, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Xiao-Guang Li
- Clinic Center of Human Gene Research, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Qiu-Zhi Zhou
- Department of Pathophysiology, School of Basic Medicine, Key Laboratory of Education Ministry of China/Hubei Province for Neurological Disorders, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Dong-Qin Wu
- Department of Pathophysiology, School of Basic Medicine, Key Laboratory of Education Ministry of China/Hubei Province for Neurological Disorders, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Shi-Hong Li
- Department of Pathophysiology, School of Basic Medicine, Key Laboratory of Education Ministry of China/Hubei Province for Neurological Disorders, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yan-Chao Liu
- Department of Pathophysiology, School of Basic Medicine, Key Laboratory of Education Ministry of China/Hubei Province for Neurological Disorders, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.,Department of Neurosurgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Jian-Zhi Wang
- Department of Pathophysiology, School of Basic Medicine, Key Laboratory of Education Ministry of China/Hubei Province for Neurological Disorders, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.,Co-innovation Center of Neuroregeneration, Nantong University, Nantong, China
| |
Collapse
|
|
43
|
Latina V, Giacovazzo G, Cordella F, Balzamino BO, Micera A, Varano M, Marchetti C, Malerba F, Florio R, Ercole BB, La Regina F, Atlante A, Coccurello R, Di Angelantonio S, Calissano P, Amadoro G. Systemic delivery of a specific antibody targeting the pathological N-terminal truncated tau peptide reduces retinal degeneration in a mouse model of Alzheimer's Disease. Acta Neuropathol Commun 2021; 9:38. [PMID: 33750467 PMCID: PMC7942014 DOI: 10.1186/s40478-021-01138-1] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2020] [Accepted: 02/26/2021] [Indexed: 12/28/2022] Open
Abstract
Retina and optic nerve are sites of extra-cerebral manifestations of Alzheimer's Disease (AD). Amyloid-β (Aβ) plaques and neurofibrillary tangles of hyperphosphorylated tau protein are detected in eyes from AD patients and transgenic animals in correlation with inflammation, reduction of synapses, visual deficits, loss of retinal cells and nerve fiber. However, neither the pathological relevance of other post-translational tau modifications-such as truncation with generation of toxic fragments-nor the potential neuroprotective action induced by their in vivo clearance have been investigated in the context of AD retinal degeneration. We have recently developed a monoclonal tau antibody (12A12mAb) which selectively targets the neurotoxic 20-22 kDa NH2-derived peptide generated from pathological truncation at the N-terminal domain of tau without cross-reacting with its full-length normal protein. Previous studies have shown that 12A12mAb, when intravenously (i.v.)-injected into 6-month-old Tg2576 animals, markedly improves their AD-like, behavioural and neuropathological syndrome. By taking advantage of this well-established tau-directed immunization regimen, we found that 12A12mAb administration also exerts a beneficial action on biochemical, morphological and metabolic parameters (i.e. APP/Aβ processing, tau hyperphosphorylation, neuroinflammation, synaptic proteins, microtubule stability, mitochondria-based energy production, neuronal death) associated with ocular injury in the AD phenotype. These findings prospect translational implications in the AD field by: (1) showing for the first time that cleavage of tau takes part in several pathological changes occurring in vivo in affected retinas and vitreous bodies and that its deleterious effects are successfully antagonized by administration of the specific 12A12mAb; (2) shedding further insights on the tight connections between neurosensory retina and brain, in particular following tau-based immunotherapy. In our view, the parallel response we detected in this preclinical animal model, both in the eye and in the hippocampus, following i.v. 12A12mAb injection opens novel diagnostic and therapeutic avenues for the clinical management of cerebral and extracerebral AD signs in human beings.
Collapse
Affiliation(s)
- Valentina Latina
- European Brain Research Institute (EBRI), Viale Regina Elena 295, 00161 Rome, Italy
| | - Giacomo Giacovazzo
- IRCSS Santa Lucia Foundation, Via Fosso del Fiorano 64-65, 00143 Rome, Italy
| | - Federica Cordella
- Department of Physiology and Pharmacology, University of Rome La Sapienza, Piazzale Aldo Moro 5, 00185 Rome, Italy
- Center for Life Nanoscience, Istituto Italiano Di Tecnologia, Viale Regina Elena 291, 00161 Rome, Italy
| | - Bijorn Omar Balzamino
- Research Laboratories in Ophthalmology, IRCCS - Fondazione Bietti, Via Santo Stefano Rotondo, 6, 00184 Rome, Italy
| | - Alessandra Micera
- Research Laboratories in Ophthalmology, IRCCS - Fondazione Bietti, Via Santo Stefano Rotondo, 6, 00184 Rome, Italy
| | - Monica Varano
- Research Laboratories in Ophthalmology, IRCCS - Fondazione Bietti, Via Santo Stefano Rotondo, 6, 00184 Rome, Italy
| | - Cristina Marchetti
- European Brain Research Institute (EBRI), Viale Regina Elena 295, 00161 Rome, Italy
| | - Francesca Malerba
- European Brain Research Institute (EBRI), Viale Regina Elena 295, 00161 Rome, Italy
| | - Rita Florio
- European Brain Research Institute (EBRI), Viale Regina Elena 295, 00161 Rome, Italy
| | - Bruno Bruni Ercole
- European Brain Research Institute (EBRI), Viale Regina Elena 295, 00161 Rome, Italy
| | - Federico La Regina
- European Brain Research Institute (EBRI), Viale Regina Elena 295, 00161 Rome, Italy
| | - Anna Atlante
- Institute of Biomembranes, Bioenergetics and Molecular Biotechnologies (IBIOM)-CNR, Via Amendola 122/O, 70126 Bari, Italy
| | - Roberto Coccurello
- IRCSS Santa Lucia Foundation, Via Fosso del Fiorano 64-65, 00143 Rome, Italy
- Institute for Complex System (ISC)-CNR, Via dei Taurini 19, 00185 Rome, Italy
| | - Silvia Di Angelantonio
- Department of Physiology and Pharmacology, University of Rome La Sapienza, Piazzale Aldo Moro 5, 00185 Rome, Italy
- Center for Life Nanoscience, Istituto Italiano Di Tecnologia, Viale Regina Elena 291, 00161 Rome, Italy
| | - Pietro Calissano
- European Brain Research Institute (EBRI), Viale Regina Elena 295, 00161 Rome, Italy
| | - Giuseppina Amadoro
- European Brain Research Institute (EBRI), Viale Regina Elena 295, 00161 Rome, Italy
- Institute of Translational Pharmacology (IFT), National Research Council (CNR), Via Fosso del Cavaliere 100, 00133 Rome, Italy
| |
Collapse
|
|
44
|
Clarkson-Townsend DA, Douglass AJ, Singh A, Allen RS, Uwaifo IN, Pardue MT. Impacts of high fat diet on ocular outcomes in rodent models of visual disease. Exp Eye Res 2021; 204:108440. [PMID: 33444582 PMCID: PMC7946735 DOI: 10.1016/j.exer.2021.108440] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2020] [Revised: 12/23/2020] [Accepted: 01/05/2021] [Indexed: 02/08/2023]
Abstract
High fat diets (HFD) have been utilized in rodent models of visual disease for over 50 years to model the effects of lipids, metabolic dysfunction, and diet-induced obesity on vision and ocular health. HFD treatment can recapitulate the pathologies of some of the leading causes of blindness, such as age-related macular degeneration (AMD) and diabetic retinopathy (DR) in rodent models of visual disease. However, there are many important factors to consider when using and interpreting these models. To synthesize our current understanding of the importance of lipid signaling, metabolism, and inflammation in HFD-driven visual disease processes, we systematically review the use of HFD in mouse and rat models of visual disease. The resulting literature is grouped into three clusters: models that solely focus on HFD treatment, models of diabetes that utilize both HFD and streptozotocin (STZ), and models of AMD that utilize both HFD and genetic models and/or other exposures. Our findings show that HFD profoundly affects vision, retinal function, many different ocular tissues, and multiple cell types through a variety of mechanisms. We delineate how HFD affects the cornea, lens, uvea, vitreous humor, retina, retinal pigmented epithelium (RPE), and Bruch's membrane (BM). Furthermore, we highlight how HFD impairs several retinal cell types, including glia (microglia), retinal ganglion cells, bipolar cells, photoreceptors, and vascular support cells (endothelial cells and pericytes). However, there are a number of gaps, limitations, and biases in the current literature. We highlight these gaps and discuss experimental design to help guide future studies. Very little is known about how HFD impacts the lens, ciliary bodies, and specific neuronal populations, such as rods, cones, bipolar cells, amacrine cells, and retinal ganglion cells. Additionally, sex bias is an important limitation in the current literature, with few HFD studies utilizing female rodents. Future studies should use ingredient-matched control diets (IMCD), include both sexes in experiments to evaluate sex-specific outcomes, conduct longitudinal metabolic and visual measurements, and capture acute outcomes. In conclusion, HFD is a systemic exposure with profound systemic effects, and rodent models are invaluable in understanding the impacts on visual and ocular disease.
Collapse
Affiliation(s)
- Danielle A Clarkson-Townsend
- Gangarosa Department of Environmental Health, Emory University, Atlanta, GA, USA; Center for Visual and Neurocognitive Rehabilitation, Atlanta VA Healthcare System, Decatur, GA, USA
| | - Amber J Douglass
- Center for Visual and Neurocognitive Rehabilitation, Atlanta VA Healthcare System, Decatur, GA, USA
| | - Anayesha Singh
- Center for Visual and Neurocognitive Rehabilitation, Atlanta VA Healthcare System, Decatur, GA, USA; Emory Center for Ethics, Emory University, Atlanta, GA, USA
| | - Rachael S Allen
- Center for Visual and Neurocognitive Rehabilitation, Atlanta VA Healthcare System, Decatur, GA, USA; Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, Atlanta, GA, USA
| | - Ivie N Uwaifo
- Center for Visual and Neurocognitive Rehabilitation, Atlanta VA Healthcare System, Decatur, GA, USA; Department of Neuroscience, Emory University, Atlanta, GA, USA
| | - Machelle T Pardue
- Center for Visual and Neurocognitive Rehabilitation, Atlanta VA Healthcare System, Decatur, GA, USA; Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, Atlanta, GA, USA.
| |
Collapse
|
|
45
|
Targeted pharmacotherapy against neurodegeneration and neuroinflammation in early diabetic retinopathy. Neuropharmacology 2021; 187:108498. [PMID: 33582150 DOI: 10.1016/j.neuropharm.2021.108498] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2020] [Revised: 01/18/2021] [Accepted: 02/06/2021] [Indexed: 02/07/2023]
Abstract
Diabetic retinopathy (DR), the most frequent complication of diabetes, is one of the leading causes of irreversible blindness in working-age adults and has traditionally been regarded as a microvascular disease. However, increasing evidence has revealed that synaptic neurodegeneration of retinal ganglion cells (RGCs) and activation of glial cells may represent some of the earliest events in the pathogenesis of DR. Upon diabetes-induced metabolic stress, abnormal glycogen synthase kinase-3β (GSK-3β) activation drives tau hyperphosphorylation and β-catenin downregulation, leading to mitochondrial impairment and synaptic neurodegeneration prior to RGC apoptosis. Moreover, glial cell activation triggers enhanced inflammation and oxidative stress, which may accelerate the deterioration of diabetic RGCs neurodegeneration. These findings have opened up opportunities for therapies, such as inhibition of GSK-3β, glial cell activation, glutamate excitotoxicity and the use of neuroprotective drugs targeting early neurodegenerative processes in the retina and halting the progression of DR before the manifestation of microvascular abnormalities. Such interventions could potentially remedy early neurodegeneration and help prevent vision loss in people suffering from DR.
Collapse
|
|
46
|
Ngolab J, Canchi S, Rasool S, Elmaarouf A, Thomas K, Sarsoza F, Grundman J, Mante M, Florio J, Nandankar N, Korouri S, Zago W, Masliah E, Rissman RA. Mutant three-repeat tau expression initiates retinal ganglion cell death through Caspase-2. Neurobiol Dis 2021; 152:105277. [PMID: 33516874 PMCID: PMC8373010 DOI: 10.1016/j.nbd.2021.105277] [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: 08/26/2020] [Revised: 01/20/2021] [Accepted: 01/24/2021] [Indexed: 12/14/2022] Open
Abstract
The microtubule-associated protein tau is implicated in multiple degenerative diseases including retinal diseases such as glaucoma; however, the way tau initiates retinopathy is unclear. Previous retinal assessments in mouse models of tauopathy suggest that mutations in four-repeat (4R) tau are associated with disease-induced retinal dysfunction, while shifting tau isoform ratio to favor three-repeat (3R) tau production enhanced photoreceptor function. To further understand how alterations in tau expression impact the retina, we analyzed the retinas of transgenic mice overexpressing mutant 3R tau (m3R tau-Tg), a model known to exhibit Pick's Disease pathology in the brain. Analysis of retinal cross-sections from young (3 month) and adult (9 month) mice detected asymmetric 3R tau immunoreactivity in m3R tau-Tg retina, concentrated in the retinal ganglion and amacrine cells of the dorsal retinal periphery. Accumulation of hyperphosphorylated tau was detected specifically in the detergent insoluble fraction of the adult m3R tau-Tg retina. RNA-seq analysis highlighted biological pathways associated with tauopathy that were uniquely altered in m3R tau-Tg retina. The upregulation of transcript encoding apoptotic protease caspase-2 coincided with increased immunostaining in predominantly 3R tau positive retinal regions. In adult m3R tau-Tg, the dorsal peripheral retina of the adult m3R tau-Tg exhibited decreased cell density in the ganglion cell layer (GCL) and reduced thickness of the inner plexiform layer (IPL) compared to the ventral peripheral retina. Together, these data indicate that mutant 3R tau may mediate toxicity in retinal ganglion cells (RGC) by promoting caspase-2 expression which results in RGC degeneration. The m3R tau-Tg line has the potential to be used to assess tau-mediated RGC degeneration and test novel therapeutics for degenerative diseases such as glaucoma.
Collapse
Affiliation(s)
- Jennifer Ngolab
- Department of Neurosciences, University of California, San Diego, School of Medicine, La Jolla, CA 92093, United States of America
| | - Saranya Canchi
- Department of Neurosciences, University of California, San Diego, School of Medicine, La Jolla, CA 92093, United States of America; Veterans Affairs San Diego Healthcare System, San Diego, CA 92161, United States of America
| | - Suhail Rasool
- Department of Neurosciences, University of California, San Diego, School of Medicine, La Jolla, CA 92093, United States of America; Amydis Inc, San Diego, CA 92121, United States of America
| | | | - Kimberly Thomas
- Prothena Biosciences, South San Francisco, CA 94080, United States of America
| | - Floyd Sarsoza
- Department of Neurosciences, University of California, San Diego, School of Medicine, La Jolla, CA 92093, United States of America; Veterans Affairs San Diego Healthcare System, San Diego, CA 92161, United States of America
| | - Jennifer Grundman
- Department of Neurosciences, University of California, San Diego, School of Medicine, La Jolla, CA 92093, United States of America
| | - Michael Mante
- Department of Neurosciences, University of California, San Diego, School of Medicine, La Jolla, CA 92093, United States of America
| | - Jazmin Florio
- Department of Neurosciences, University of California, San Diego, School of Medicine, La Jolla, CA 92093, United States of America
| | - Nimisha Nandankar
- Department of Neurosciences, University of California, San Diego, School of Medicine, La Jolla, CA 92093, United States of America
| | - Shaina Korouri
- Department of Neurosciences, University of California, San Diego, School of Medicine, La Jolla, CA 92093, United States of America
| | - Wagner Zago
- Prothena Biosciences, South San Francisco, CA 94080, United States of America
| | - Eliezer Masliah
- Division of Neuroscience and Laboratory of Neurogenetics, National Institutes on Aging, NIH, Bethesda, MD 20892, United States of America
| | - Robert A Rissman
- Department of Neurosciences, University of California, San Diego, School of Medicine, La Jolla, CA 92093, United States of America; Veterans Affairs San Diego Healthcare System, San Diego, CA 92161, United States of America.
| |
Collapse
|
|
47
|
Zhang J, Lai ZP, Chen P, Ying Y, Zhuang J, Yu KM. Glycogen synthase kinase-3β inhibitor SB216763 promotes DNA repair in ischemic retinal neurons. Neural Regen Res 2021; 16:394-400. [PMID: 32859805 PMCID: PMC7896226 DOI: 10.4103/1673-5374.290913] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
Glycogen synthase kinase-3β (GSK-3β) has been shown to attenuate DNA damage in nerve cells, thereby enhancing neuronal survival under pathological conditions; however, the underlying mechanism remains unclear. An in vitro serum-starvation retinal neuron model and in vivo ischemia/reperfusion retina injury rat model were established and treated with SB216763, a GSK-3β inhibitor. SB21673 decreased the formation of γ-H2A histone family member X foci and enhanced the viability of ischemic retinal neurons. In addition, SB216763 upregulated expression of phosphorylated-CREB1, a ligase IV transcription factor, and significantly increased the transcriptional activity of ligase IV in ischemic retinal neurons. These results were confirmed in rat retinas following ischemia/reperfusion injury. Furthermore, we found that unlike lithium chlorine (a well-known direct inhibitor of GSK-3β), SB216763 inhibited GSK-3β activity by suppressing its phosphorylation. Taken together, our results suggest that GSK-3β inhibition enhances repair of DNA double-strand breaks by upregulating ligase IV expression in ischemic retinal neurons. This study was approved by the Institutional Animal Care and Use Committee of Zhongshan Ophthalmic Center on February 18, 2018.
Collapse
Affiliation(s)
- Jing Zhang
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, Guangdong Province, China
| | - Zhi-Peng Lai
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, Guangdong Province, China
| | - Pei Chen
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, Guangdong Province, China
| | - Yang Ying
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, Guangdong Province, China
| | - Jing Zhuang
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, Guangdong Province, China
| | - Ke-Ming Yu
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, Guangdong Province, China
| |
Collapse
|
|
48
|
Yu CC, He C, Du YJ, Gao S, Lin YF, Wang SQ, Wang L, Wang J, Wang XS, Jiang T, Kong LH. Preventive electroacupuncture reduces cognitive deficits in a rat model of D-galactose-induced aging. Neural Regen Res 2021; 16:916-923. [PMID: 33229729 PMCID: PMC8178792 DOI: 10.4103/1673-5374.297090] [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] [Indexed: 11/12/2022] Open
Abstract
Acupuncture can reduce cognitive deficits in Alzheimer’s disease. However, whether electroacupuncture can prevent or alleviate the cognitive deficits in animal models of aging remains poorly understood. Studies have shown that disordered epigenetic modifications play a critical role in age-related cognitive decline. Therefore, we hypothesized that preventive electroacupuncture might improve cognitive functions during aging by regulating epigenetic modifications. A rat model of aging was produced by intraperitoneal injection of 120 mg/kg D-galactose for 8 weeks. Baihui and Shenshu acupoints were stimulated by electroacupuncture for 8 weeks from the first day of D-galactose administration. Preventive electroacupuncture alleviated memory impairment, decreased tau hyperphosphorylation, and reduced glycogen synthase kinase-3β protein and mRNA expression levels in the brainstem dorsal raphe nucleus, where intracellular neurofibrillary tangle lesions first occur. In addition, the DNA methylation level in the promoter region of the glycogen synthase kinase-3β gene was increased. The effects of preventive electroacupuncture were stronger than those of preventive acupuncture. Intraperitoneal injection of 0.4 mg/kg 5-aza-2′-deoxycytidine, an inhibitor of DNA methyltransferase that blocks epigenetic modifications, antagonized the effects of preventive electroacupuncture. Our results suggest that preventive electroacupuncture treatment alleviates cognitive impairment in aging rats probably by affecting the epigenetic modification of the glycogen synthase kinase-3β gene in the dorsal raphe nucleus. This study was approved by the Animal Ethics Committee of Hubei University of Chinese Medicine, China (approval No. HUCMS201712001) on November 28, 2017.
Collapse
Affiliation(s)
- Chao-Chao Yu
- Department of Tuina, Shenzhen Traditional Chinese Medicine Hospital; The 4th Clinical College, Guangzhou University of Chinese Medicine, Shenzhen, Guangdong Province, China
| | - Chuan He
- College of Acupuncture and Orthopedics, Hubei University of Chinese Medicine, Wuhan, Hubei Province, China
| | - Yan-Jun Du
- College of Acupuncture and Orthopedics, Hubei University of Chinese Medicine, Wuhan, Hubei Province, China
| | - Shan Gao
- Department of Acupuncture & Moxibustion, Wuhan Hospital of Integrated Chinese & Western Medicine, Tongji Medical College of Huazhong University of Science & Technology, Wuhan, Hubei Province, China
| | - Yuan-Fang Lin
- Department of Tuina, Shenzhen Traditional Chinese Medicine Hospital; The 4th Clinical College, Guangzhou University of Chinese Medicine, Shenzhen, Guangdong Province, China
| | - Shu-Qin Wang
- Department of Tuina, Shenzhen Traditional Chinese Medicine Hospital; The 4th Clinical College, Guangzhou University of Chinese Medicine, Shenzhen, Guangdong Province, China
| | - Li Wang
- College of Acupuncture and Orthopedics, Hubei University of Chinese Medicine, Wuhan, Hubei Province, China
| | - Jia Wang
- Department of Acupuncture & Moxibustion, Wuhan Hospital of Integrated Chinese & Western Medicine, Tongji Medical College of Huazhong University of Science & Technology, Wuhan, Hubei Province, China
| | - Xue-Song Wang
- College of Acupuncture and Orthopedics, Hubei University of Chinese Medicine, Wuhan, Hubei Province, China
| | - Tao Jiang
- College of Acupuncture and Orthopedics, Hubei University of Chinese Medicine, Wuhan, Hubei Province, China
| | - Li-Hong Kong
- College of Acupuncture and Orthopedics, Hubei University of Chinese Medicine, Wuhan, Hubei Province, China
| |
Collapse
|
|
49
|
Shi L, Zhang R, Li T, Han X, Yuan N, Jiang L, Zhou H, Xu S. Decreased miR-132 plays a crucial role in diabetic encephalopathy by regulating the GSK-3β/Tau pathway. Aging (Albany NY) 2020; 13:4590-4604. [PMID: 33406505 PMCID: PMC7906212 DOI: 10.18632/aging.202418] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2020] [Accepted: 11/10/2020] [Indexed: 12/12/2022]
Abstract
Diabetic encephalopathy (DE) is a global concern and Gordian knot worldwide. miRNA-132 (miR-132) is a class of negative gene regulators that promote diabetic pathologic mechanisms and its complications. However, the molecular mechanisms of miR-132 in DE are elusive, thus an alternative therapeutic strategy is urgently in demand. The present study explored the protective effect and the underlying mechanism of miR-132 on DE via the GSK-β/Tau signaling pathway. Experimentally, a type 2 DM rat model was developed by incorporating a high-fat diet and streptozotocin injection. Further, the DE model was screened via the Morris Water Maze test. Primary hippocampal neurons and HT-22 cells were used for in vitro analysis. We found that hyperglycemia exacerbates cognitive impairment in T2DM rats. When we isolated the primary hippocampus neurons, the expression of miR-132 RNA was low in both the DE hippocampus and primary neurons. GSK-3β and Tau 404 were highly expressed in injured HT-22 cells and diabetic hippocampal tissues. miR-132 downregulated the expression of GSK-3β. Besides, a binding and colocalized relationship between GSK3β and Tau was also reported. These findings suggest that miR-132 exerts protective effects from DE injury by repressing GSK-3β expression and alleviating Tau hyperphosphorylation in HT-22 cells and hippocampus tissues.
Collapse
Affiliation(s)
- Li Shi
- Department of Endocrinology, The First Hospital of Hebei Medical University, Shijiazhuang 050000, China.,Central Laboratory, The First Hospital of Hebei Medical University, Shijiazhuang 050000, China.,Department of Endocrinology, The First Affiliated Hospital of Hebei North University, Zhangjiakou 075000, China
| | - Rui Zhang
- Central Laboratory, The First Hospital of Hebei Medical University, Shijiazhuang 050000, China.,Hebei Key Laboratory of Brain Science and Psychiatric-Psychologic Disease, Shijiazhuang 075000, China.,Hebei International Joint Research Center for Brain Science, Shijiazhuang 075000, China
| | - Tian Li
- School of Basic Medicine, The Fourth Military Medical University, Xi'an 710032, China
| | - Xue Han
- Department of General Practice, Xingtai People's Hospital, Xingtai 054000, China
| | - Nannan Yuan
- Central Laboratory, The First Hospital of Hebei Medical University, Shijiazhuang 050000, China.,Hebei Key Laboratory of Brain Science and Psychiatric-Psychologic Disease, Shijiazhuang 075000, China.,Hebei International Joint Research Center for Brain Science, Shijiazhuang 075000, China
| | - Lei Jiang
- Central Laboratory, The First Hospital of Hebei Medical University, Shijiazhuang 050000, China.,Hebei Key Laboratory of Brain Science and Psychiatric-Psychologic Disease, Shijiazhuang 075000, China.,Hebei International Joint Research Center for Brain Science, Shijiazhuang 075000, China
| | - Huimin Zhou
- Department of Endocrinology, The First Hospital of Hebei Medical University, Shijiazhuang 050000, China.,Hebei Key Laboratory of Brain Science and Psychiatric-Psychologic Disease, Shijiazhuang 075000, China.,Hebei International Joint Research Center for Brain Science, Shijiazhuang 075000, China
| | - Shunjiang Xu
- Central Laboratory, The First Hospital of Hebei Medical University, Shijiazhuang 050000, China.,Hebei Key Laboratory of Brain Science and Psychiatric-Psychologic Disease, Shijiazhuang 075000, China.,Hebei International Joint Research Center for Brain Science, Shijiazhuang 075000, China
| |
Collapse
|
|
50
|
Diabetic Retinopathy: The Role of Mitochondria in the Neural Retina and Microvascular Disease. Antioxidants (Basel) 2020; 9:antiox9100905. [PMID: 32977483 PMCID: PMC7598160 DOI: 10.3390/antiox9100905] [Citation(s) in RCA: 54] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2020] [Revised: 09/17/2020] [Accepted: 09/18/2020] [Indexed: 12/11/2022] Open
Abstract
Diabetic retinopathy (DR), a common chronic complication of diabetes mellitus and the leading cause of vision loss in the working-age population, is clinically defined as a microvascular disease that involves damage of the retinal capillaries with secondary visual impairment. While its clinical diagnosis is based on vascular pathology, DR is associated with early abnormalities in the electroretinogram, indicating alterations of the neural retina and impaired visual signaling. The pathogenesis of DR is complex and likely involves the simultaneous dysregulation of multiple metabolic and signaling pathways through the retinal neurovascular unit. There is evidence that microvascular disease in DR is caused in part by altered energetic metabolism in the neural retina and specifically from signals originating in the photoreceptors. In this review, we discuss the main pathogenic mechanisms that link alterations in neural retina bioenergetics with vascular regression in DR. We focus specifically on the recent developments related to alterations in mitochondrial metabolism including energetic substrate selection, mitochondrial function, oxidation-reduction (redox) imbalance, and oxidative stress, and critically discuss the mechanisms of these changes and their consequences on retinal function. We also acknowledge implications for emerging therapeutic approaches and future research directions to find novel mitochondria-targeted therapeutic strategies to correct bioenergetics in diabetes. We conclude that retinal bioenergetics is affected in the early stages of diabetes with consequences beyond changes in ATP content, and that maintaining mitochondrial integrity may alleviate retinal disease.
Collapse
|