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Hashemi P, Mardani P, Eghbali Raz Z, Saedi A, Fatahi E, Izapanah E, Ahmadi S. Alpha-Pinene Decreases the Elevated Levels of Astrogliosis, Pyroptosis, and Autophagy Markers in the Hippocampus Triggered by Kainate in a Rat Model of Temporal Lobe Epilepsy. Mol Neurobiol 2025; 62:2264-2276. [PMID: 39096444 DOI: 10.1007/s12035-024-04407-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2024] [Accepted: 07/28/2024] [Indexed: 08/05/2024]
Abstract
The development and progression of temporal lobe epilepsy (TLE) are heavily influenced by inflammation, excessive activation of glial cells, and neuronal cell death. This study aimed to investigate the effects of treatment with alpha-pinene (APN) on pro-and anti-inflammatory cytokine levels, astrogliosis, pyroptosis, and autophagy markers in the hippocampus in a rat model of TLE induced by kainic acid (KA). Male Wistar rats were employed, and TLE was induced by intracerebroventricular injection of KA. APN (50 mg/kg) was intraperitoneally administered for 19 days, including two weeks before and five days after the administration of KA. After full recovery from anesthesia and KA injection, the seizure-related behavioral expressions were evaluated. On day 19, the hippocampal levels of IL-1β, TNF-α, progranulin, IL-10, ERK1/2, phospho-ERK1/2, NF-κB, GFAP, S100-B, NLRP1, NLRP3, caspase-1, and becline-1 were examined. The results revealed that treatment with APN significantly diminished the heightened levels of IL-1β, TNF-α, progranulin, ERK1/2, and NF-κB and reversed the reduced levels of the anti-inflammatory cytokine, IL-10, in the hippocampus caused by KA. Furthermore, administration of APN significantly reduced the levels of astrogliosis, pyroptosis, and autophagy markers in the hippocampus that were elevated by KA. It can be concluded that treatment with APN for 19 days alleviated neuroinflammation by inhibiting ERK1/2 and NF-κB signaling pathways and prevented increases in astrogliosis, pyroptosis, and autophagy markers in the hippocampus in a rat model of TLE.
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Affiliation(s)
- Paria Hashemi
- Department of Biological Science, Faculty of Science, University of Kurdistan, P.O. Box 416, Sanandaj, Iran
| | | | - Zabihollah Eghbali Raz
- Department of Biological Science, Faculty of Science, University of Kurdistan, P.O. Box 416, Sanandaj, Iran
| | - Ali Saedi
- Department of Biological Science, Faculty of Science, University of Kurdistan, P.O. Box 416, Sanandaj, Iran
| | - Ehsan Fatahi
- Department of Biological Science, Faculty of Science, University of Kurdistan, P.O. Box 416, Sanandaj, Iran
| | - Esmael Izapanah
- Cellular and Molecular Research Center, Research Institute for Health Development, Kurdistan University of Medical Sciences, Sanandaj, Iran
| | - Shamseddin Ahmadi
- Department of Biological Science, Faculty of Science, University of Kurdistan, P.O. Box 416, Sanandaj, Iran.
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Wang M, Guo S, Yi L, Li Z, Shi X, Fan Y, Luo M, He Y, Song W, Du Y, Dong Z. KIF9 Ameliorates Neuropathology and Cognitive Dysfunction by Promoting Macroautophagy in a Mouse Model of Alzheimer's Disease. Aging Cell 2025:e14490. [PMID: 39829171 DOI: 10.1111/acel.14490] [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: 08/15/2024] [Revised: 12/27/2024] [Accepted: 12/30/2024] [Indexed: 01/22/2025] Open
Abstract
Alzheimer's disease (AD) is a prevalent neurodegenerative disorder affecting the elderly. The imbalance of protein production and degradation processes leads to the accumulation of misfolded and abnormally aggregated amyloid-beta (Aβ) in the extracellular space and forms senile plaques, which constitute one of the most critical pathological hallmarks of AD. KIF9, a member of the kinesin protein superfamily, mediates the anterograde transport of intracellular cargo along microtubules. However, the exact role of KIF9 in AD pathogenesis remains largely elusive. In this study, we reported that the expression of kinesin family member 9 (KIF9) in the hippocampus of APP23/PS45 double-transgenic AD model mice declined in an age-dependent manner, concurrent with macroautophagy dysfunction. Furthermore, we found that KIF9 mediated the transport of lysosomes through kinesin light chain 1 (KLC1), thereby participating in the degradation of amyloidogenic pathway-related proteins of Aβ precursor protein (APP) in AD model cells through promoting the macroautophagy pathway. Importantly, genetic upregulation of KIF9 via adeno-associated virus (AAV) diminished Aβ deposition and alleviated cognitive impairments in AD model mice by enhancing macroautophagy function. Collectively, our findings underscore the ability of KIF9 to promote macroautophagy through KLC1-mediated anterograde transport of lysosomes, effectively ameliorating cognitive dysfunction in AD model mice. These discoveries suggest that KIF9 may represent a novel therapeutic target for the treatment of AD.
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Affiliation(s)
- Maoju Wang
- Growth, Development, and Mental Health of Children and Adolescence Center, Pediatric Research Institute, Ministry of Education Key Laboratory of Child Development and Disorders, National Clinical Research Center for Child Health and Disorders, Chongqing Key Laboratory of Child Neurodevelopment and Cognitive Disorders, Children's Hospital of Chongqing Medical University, Chongqing, China
| | - Song Guo
- Growth, Development, and Mental Health of Children and Adolescence Center, Pediatric Research Institute, Ministry of Education Key Laboratory of Child Development and Disorders, National Clinical Research Center for Child Health and Disorders, Chongqing Key Laboratory of Child Neurodevelopment and Cognitive Disorders, Children's Hospital of Chongqing Medical University, Chongqing, China
| | - Lilin Yi
- Growth, Development, and Mental Health of Children and Adolescence Center, Pediatric Research Institute, Ministry of Education Key Laboratory of Child Development and Disorders, National Clinical Research Center for Child Health and Disorders, Chongqing Key Laboratory of Child Neurodevelopment and Cognitive Disorders, Children's Hospital of Chongqing Medical University, Chongqing, China
| | - Zhaolun Li
- Growth, Development, and Mental Health of Children and Adolescence Center, Pediatric Research Institute, Ministry of Education Key Laboratory of Child Development and Disorders, National Clinical Research Center for Child Health and Disorders, Chongqing Key Laboratory of Child Neurodevelopment and Cognitive Disorders, Children's Hospital of Chongqing Medical University, Chongqing, China
| | - Xiuyu Shi
- Growth, Development, and Mental Health of Children and Adolescence Center, Pediatric Research Institute, Ministry of Education Key Laboratory of Child Development and Disorders, National Clinical Research Center for Child Health and Disorders, Chongqing Key Laboratory of Child Neurodevelopment and Cognitive Disorders, Children's Hospital of Chongqing Medical University, Chongqing, China
| | - YePeng Fan
- Growth, Development, and Mental Health of Children and Adolescence Center, Pediatric Research Institute, Ministry of Education Key Laboratory of Child Development and Disorders, National Clinical Research Center for Child Health and Disorders, Chongqing Key Laboratory of Child Neurodevelopment and Cognitive Disorders, Children's Hospital of Chongqing Medical University, Chongqing, China
| | - Man Luo
- Growth, Development, and Mental Health of Children and Adolescence Center, Pediatric Research Institute, Ministry of Education Key Laboratory of Child Development and Disorders, National Clinical Research Center for Child Health and Disorders, Chongqing Key Laboratory of Child Neurodevelopment and Cognitive Disorders, Children's Hospital of Chongqing Medical University, Chongqing, China
| | - Yan He
- Growth, Development, and Mental Health of Children and Adolescence Center, Pediatric Research Institute, Ministry of Education Key Laboratory of Child Development and Disorders, National Clinical Research Center for Child Health and Disorders, Chongqing Key Laboratory of Child Neurodevelopment and Cognitive Disorders, Children's Hospital of Chongqing Medical University, Chongqing, China
| | - Weihong Song
- Growth, Development, and Mental Health of Children and Adolescence Center, Pediatric Research Institute, Ministry of Education Key Laboratory of Child Development and Disorders, National Clinical Research Center for Child Health and Disorders, Chongqing Key Laboratory of Child Neurodevelopment and Cognitive Disorders, Children's Hospital of Chongqing Medical University, Chongqing, China
- Townsend Family Laboratories, Department of Psychiatry, University of British Columbia, Vancouver, British Columbia, Canada
- Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision and Brain Health), Institute of Aging, Key Laboratory of Alzheimer's Disease of Zhejiang Province, Zhejiang Clinical Research Center for Mental Disorders, School of Mental Health and the Affiliated Kangning Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Yehong Du
- Growth, Development, and Mental Health of Children and Adolescence Center, Pediatric Research Institute, Ministry of Education Key Laboratory of Child Development and Disorders, National Clinical Research Center for Child Health and Disorders, Chongqing Key Laboratory of Child Neurodevelopment and Cognitive Disorders, Children's Hospital of Chongqing Medical University, Chongqing, China
| | - Zhifang Dong
- Growth, Development, and Mental Health of Children and Adolescence Center, Pediatric Research Institute, Ministry of Education Key Laboratory of Child Development and Disorders, National Clinical Research Center for Child Health and Disorders, Chongqing Key Laboratory of Child Neurodevelopment and Cognitive Disorders, Children's Hospital of Chongqing Medical University, Chongqing, China
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3
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Zhang C, Huang Z, Huang X, Ma Y, Cao Y, Zhang Z, Wang R, Ren H, Zheng L, Liu CF, Wang G. PLK2 disrupts autophagic flux to promote SNCA/α-synuclein pathology. Autophagy 2025:1-21. [PMID: 39773002 DOI: 10.1080/15548627.2024.2448914] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2024] [Revised: 12/23/2024] [Accepted: 12/27/2024] [Indexed: 01/11/2025] Open
Abstract
The aggregation and transmission of SNCA/α-synuclein (synuclein, alpha) is a hallmark pathology of Parkinson disease (PD). PLK2 (polo like kinase 2) is an evolutionarily conserved serine/threonine kinase that is more abundant in the brains of all family members, is highly expressed in PD, and is linked to SNCA deposition. However, in addition to its role in phosphorylating SNCA, the role of PLK2 in PD and the mechanisms involved in triggering neurodegeneration remain unclear. Here, we found that PLK2 regulated SNCA pathology independently of S129. Overexpression of PLK2 promoted SNCA preformed fibril (PFF)-induced aggregation of wild-type SNCA and mutant SNCAS129A. Genetic or pharmacological inhibition of PLK2 attenuated SNCA deposition and neurotoxicity. Mechanistically, PLK2 exacerbated the propagation of SNCA pathology by impeding the clearance of SNCA aggregates by blocking macroautophagic/autophagic flux. We further showed that PLK2 phosphorylated S1098 of DCTN1 (dynactin 1), a protein that controls the movement of organelles, leading to impaired autophagosome-lysosome fusion. Furthermore, genetic suppression of PLK2 alleviated SNCA aggregation and motor dysfunction in vivo. Our findings suggest that PLK2 negatively regulates autophagy, promoting SNCA pathology, suggesting a role for PLK2 in PD.Abbreviation: AD: Alzheimer disease; AMPK: AMP-activated protein kinase; CASP3: caspase 3; DCTN1: dynactin 1; LBs: lewy bodies; LDH: lactate dehydrogenase; LAMP1: lysosomal associated membrane protein 1; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; MAP2: microtubule associated protein 2; MTOR: mechanistic target of rapamycin kinase; NH4Cl: ammonium chloride; p-SNCA: phosphorylation of SNCA at S129; PD: Parkinson disease; PFF: preformed fibril; PI: propidium iodide; PLK2: polo like kinase 2; PRKAA/AMPK: protein kinase AMP-activated catalytic subunit alpha; shRNA: short hairpin RNA; SNCA: synuclein, alpha; SQSTM1/p62: sequestosome 1; TH: tyrosine hydroxylase; TX: Triton X-100; ULK1: unc-51 like autophagy activating kinase 1.
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Affiliation(s)
- Chuang Zhang
- Laboratory of Molecular Neuropathology, Department of Pharmacology, Jiangsu Key Laboratory of Neuropsychiatric Diseases and College of Pharmaceutical Sciences, Soochow University, Suzhou, Jiangsu, China
| | - Zhanpeng Huang
- Laboratory of Molecular Neuropathology, Department of Pharmacology, Jiangsu Key Laboratory of Neuropsychiatric Diseases and College of Pharmaceutical Sciences, Soochow University, Suzhou, Jiangsu, China
| | - Xinyue Huang
- Laboratory of Molecular Neuropathology, Department of Pharmacology, Jiangsu Key Laboratory of Neuropsychiatric Diseases and College of Pharmaceutical Sciences, Soochow University, Suzhou, Jiangsu, China
| | - Yanni Ma
- Laboratory of Molecular Neuropathology, Department of Pharmacology, Jiangsu Key Laboratory of Neuropsychiatric Diseases and College of Pharmaceutical Sciences, Soochow University, Suzhou, Jiangsu, China
| | - Yifan Cao
- Laboratory of Molecular Neuropathology, Department of Pharmacology, Jiangsu Key Laboratory of Neuropsychiatric Diseases and College of Pharmaceutical Sciences, Soochow University, Suzhou, Jiangsu, China
| | - Zhixiong Zhang
- Laboratory of Molecular Neuropathology, Department of Pharmacology, Jiangsu Key Laboratory of Neuropsychiatric Diseases and College of Pharmaceutical Sciences, Soochow University, Suzhou, Jiangsu, China
| | - Rui Wang
- Laboratory of Molecular Neuropathology, Department of Pharmacology, Jiangsu Key Laboratory of Neuropsychiatric Diseases and College of Pharmaceutical Sciences, Soochow University, Suzhou, Jiangsu, China
| | - Haigang Ren
- Laboratory of Molecular Neuropathology, Department of Pharmacology, Jiangsu Key Laboratory of Neuropsychiatric Diseases and College of Pharmaceutical Sciences, Soochow University, Suzhou, Jiangsu, China
- Department of Pharmacy, The Affiliated Zhangjiagang Hospital of Soochow University, Suzhou, Jiangsu, China
- MOE Key Laboratory of Geriatric Diseases and Immunology, Soochow University, Suzhou, Jiangsu, China
- Jiangsu Provincial Medical Innovation Center of Trauma Medicine, Institute of Trauma Medicine, Suzhou, Jiangsu, China
| | - Longtai Zheng
- Laboratory of Molecular Neuropathology, Department of Pharmacology, Jiangsu Key Laboratory of Neuropsychiatric Diseases and College of Pharmaceutical Sciences, Soochow University, Suzhou, Jiangsu, China
| | - Chun-Feng Liu
- Department of Neurology and Clinical Research Center of Neurological Disease, the Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China
| | - Guanghui Wang
- Laboratory of Molecular Neuropathology, Department of Pharmacology, Jiangsu Key Laboratory of Neuropsychiatric Diseases and College of Pharmaceutical Sciences, Soochow University, Suzhou, Jiangsu, China
- MOE Key Laboratory of Geriatric Diseases and Immunology, Soochow University, Suzhou, Jiangsu, China
- Suzhou Key Laboratory of Geriatric Neurological Disorders, Center of Translational Medicine, the First People's Hospital of Taicang, Taicang Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China
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Ma Y, Xu D, Gan Y, Chen Z, Chen Y, Han X. Adverse outcome pathway of Alzheimer's disease-like changes resulting from autophagy flux blockade after MC-LR exposure. ENVIRONMENTAL POLLUTION (BARKING, ESSEX : 1987) 2025; 364:125322. [PMID: 39549990 DOI: 10.1016/j.envpol.2024.125322] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/08/2024] [Revised: 11/08/2024] [Accepted: 11/14/2024] [Indexed: 11/18/2024]
Abstract
Microcystins (MCs) pollution is a worldwide environmental issue concerning about human health. Microcystin-leucine-arginine (MC-LR), the most common type of MCs produced by cyanobacteria, could enter the brain and bring about damage to the nervous system. Up to date, it is not clear about the mechanism of MC-LR-induced neurotoxicity. Amyloid-β (Aβ) deposits are hallmark of Alzheimer's disease (AD). In this study, we revealed that MC-LR exposure at environment-related doses (1, 7.5, 15 μg/L) could promote Aβ accumulation in mouse brain. Mechanically, we firstly found that Aβ accumulation is closely associated with abnormal Aβ degradation due to autophagy flux blockade and lysosome dysfunctions in neurons after MC-LR exposure. Moreover, an adverse outcome pathway (AOP) framework oriented to neurotoxicity of MC-LR was conducted in this study. MC-LR inhibited the activity of protein phosphatase 2A (PP2A) in neurons, which is regarded as a molecular initiating event (MIE). In addition, the abnormalities in autophagy were observed after MC-LR exposure. The hindered autophagosome-lysosome fusion and disrupted lysosomal function were key events (KEs) after MC-LR exposure, which contributed to proteostasis dysregulation, ultimately leading to Aβ abnormal degradation and learning deficits as adverse outcomes (AO) of neurotoxicity. This study provided novel information about MC-LR neurotoxicity and new insights into understanding the mechanisms underlying the environmental chemicals-induced neurodegeneration diseases, which has deep implications for public health.
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Affiliation(s)
- Yuhan Ma
- State Key Laboratory of Analytical Chemistry for Life Science, Division of Anatomy and Histo-Embryology, Medical School, Nanjing University, Nanjing, Jiangsu, 210093, China; Jiangsu Key Laboratory of Molecular Medicine, Nanjing University, Nanjing, Jiangsu, 210093, China
| | - Dihui Xu
- State Key Laboratory of Analytical Chemistry for Life Science, Division of Anatomy and Histo-Embryology, Medical School, Nanjing University, Nanjing, Jiangsu, 210093, China; Jiangsu Key Laboratory of Molecular Medicine, Nanjing University, Nanjing, Jiangsu, 210093, China
| | - Yibin Gan
- State Key Laboratory of Analytical Chemistry for Life Science, Division of Anatomy and Histo-Embryology, Medical School, Nanjing University, Nanjing, Jiangsu, 210093, China; Jiangsu Key Laboratory of Molecular Medicine, Nanjing University, Nanjing, Jiangsu, 210093, China
| | - Zining Chen
- State Key Laboratory of Analytical Chemistry for Life Science, Division of Anatomy and Histo-Embryology, Medical School, Nanjing University, Nanjing, Jiangsu, 210093, China; Jiangsu Key Laboratory of Molecular Medicine, Nanjing University, Nanjing, Jiangsu, 210093, China
| | - Yabing Chen
- State Key Laboratory of Analytical Chemistry for Life Science, Division of Anatomy and Histo-Embryology, Medical School, Nanjing University, Nanjing, Jiangsu, 210093, China; Jiangsu Key Laboratory of Molecular Medicine, Nanjing University, Nanjing, Jiangsu, 210093, China.
| | - Xiaodong Han
- State Key Laboratory of Analytical Chemistry for Life Science, Division of Anatomy and Histo-Embryology, Medical School, Nanjing University, Nanjing, Jiangsu, 210093, China; Jiangsu Key Laboratory of Molecular Medicine, Nanjing University, Nanjing, Jiangsu, 210093, China.
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5
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Luo Y, Liu R, Zhang H, Wang H, Yin H, Tian G, Wang B, Yan Y, Ding Z, Dai J, Niu L, Yuan G, Pan Y. Amantadine against glioma via ROS-mediated apoptosis and autophagy arrest. Cell Death Dis 2024; 15:834. [PMID: 39548081 PMCID: PMC11568115 DOI: 10.1038/s41419-024-07228-x] [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: 05/07/2024] [Revised: 10/29/2024] [Accepted: 11/06/2024] [Indexed: 11/17/2024]
Abstract
Glioma is a common primary nervous system malignant tumor with poor overall cure rate and low survival rate, yet successful treatment still remains a challenge. Here, we demonstrated that amantadine (AMT) exhibits the powerful anti-glioma effect by promoting apoptosis and autophagy in vivo and in vitro. Mechanistically, amantadine induces a large amount of reactive oxygen species (ROS) accumulation in glioma cells, and then triggers apoptosis by destroying mitochondria. In addition, amantadine induces the initiation of autophagy and inhibits the fusion of autophagosome and lysosome, consequently performing an anti-glioma role. Taken together, our findings suggest that amantadine could be a promising anti-glioma drug that inhibits glioma cells by inducing apoptosis and autophagy, which may provide a novel potential treatment option for patients.
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Affiliation(s)
- Yusong Luo
- Department of Neurosurgery, the Second Hospital & Clinical Medical School, Lanzhou University, Lanzhou, China
- Gansu Provincial Clinical Research Center for Neurological Diseases, the Second Hospital & Clinical Medical School, Lanzhou University, Lanzhou, China
| | - Ruolan Liu
- Department of Neurosurgery, the Second Hospital & Clinical Medical School, Lanzhou University, Lanzhou, China
- Gansu Provincial Clinical Research Center for Neurological Diseases, the Second Hospital & Clinical Medical School, Lanzhou University, Lanzhou, China
| | - He Zhang
- Department of Neurosurgery, the Second Hospital & Clinical Medical School, Lanzhou University, Lanzhou, China
- Gansu Provincial Clinical Research Center for Neurological Diseases, the Second Hospital & Clinical Medical School, Lanzhou University, Lanzhou, China
| | - Hongyu Wang
- Department of Neurosurgery, the Second Hospital & Clinical Medical School, Lanzhou University, Lanzhou, China
- Gansu Provincial Clinical Research Center for Neurological Diseases, the Second Hospital & Clinical Medical School, Lanzhou University, Lanzhou, China
| | - Hang Yin
- Department of Neurosurgery, the Second Hospital & Clinical Medical School, Lanzhou University, Lanzhou, China
- Gansu Provincial Clinical Research Center for Neurological Diseases, the Second Hospital & Clinical Medical School, Lanzhou University, Lanzhou, China
| | - Guopeng Tian
- Department of Neurosurgery, the Second Hospital & Clinical Medical School, Lanzhou University, Lanzhou, China
- Gansu Provincial Clinical Research Center for Neurological Diseases, the Second Hospital & Clinical Medical School, Lanzhou University, Lanzhou, China
| | - Bo Wang
- Department of Neurosurgery, the Second Hospital & Clinical Medical School, Lanzhou University, Lanzhou, China
- Gansu Provincial Clinical Research Center for Neurological Diseases, the Second Hospital & Clinical Medical School, Lanzhou University, Lanzhou, China
| | - Yunji Yan
- Department of Neurosurgery, the Second Hospital & Clinical Medical School, Lanzhou University, Lanzhou, China
- Gansu Provincial Clinical Research Center for Neurological Diseases, the Second Hospital & Clinical Medical School, Lanzhou University, Lanzhou, China
| | - Zilin Ding
- Department of Neurosurgery, the Second Hospital & Clinical Medical School, Lanzhou University, Lanzhou, China
- Gansu Provincial Clinical Research Center for Neurological Diseases, the Second Hospital & Clinical Medical School, Lanzhou University, Lanzhou, China
| | - Junqiang Dai
- Department of Neurosurgery, the Second Hospital & Clinical Medical School, Lanzhou University, Lanzhou, China
- Gansu Provincial Clinical Research Center for Neurological Diseases, the Second Hospital & Clinical Medical School, Lanzhou University, Lanzhou, China
| | - Liang Niu
- Department of Neurosurgery, the Second Hospital & Clinical Medical School, Lanzhou University, Lanzhou, China
- Gansu Provincial Clinical Research Center for Neurological Diseases, the Second Hospital & Clinical Medical School, Lanzhou University, Lanzhou, China
| | - Guoqiang Yuan
- Department of Neurosurgery, the Second Hospital & Clinical Medical School, Lanzhou University, Lanzhou, China.
- Gansu Provincial Clinical Research Center for Neurological Diseases, the Second Hospital & Clinical Medical School, Lanzhou University, Lanzhou, China.
| | - Yawen Pan
- Department of Neurosurgery, the Second Hospital & Clinical Medical School, Lanzhou University, Lanzhou, China.
- Gansu Provincial Clinical Research Center for Neurological Diseases, the Second Hospital & Clinical Medical School, Lanzhou University, Lanzhou, China.
- Academician Workstation, the Second Hospital & Clinical Medical School, Lanzhou University, Lanzhou, China.
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6
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Akbar M, Toppo P, Nazir A. Ageing, proteostasis, and the gut: Insights into neurological health and disease. Ageing Res Rev 2024; 101:102504. [PMID: 39284418 DOI: 10.1016/j.arr.2024.102504] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2024] [Revised: 08/28/2024] [Accepted: 09/09/2024] [Indexed: 09/22/2024]
Abstract
Recent research has illuminated the profound bidirectional communication between the gastrointestinal tract and the brain, furthering our understanding of neurological ailments facilitating possible therapeutic strategies. Technological advancements in high-throughput sequencing and multi-omics have unveiled significant alterations in gut microbiota and their metabolites in various neurological disorders. This review provides a thorough analysis of the role of microbiome-gut-brain axis in neurodegenerative disease pathology, linking it to reduced age-associated proteostasis. We discuss evidences that substantiate the existence of a gut-brain cross talk ranging from early clinical accounts of James Parkinson to Braak's hypothesis. In addition to understanding of microbes, the review particularly entails specific metabolites which are altered in neurodegenerative diseases. The regulatory effects of microbial metabolites on protein clearance mechanisms, proposing their potential therapeutic implications, are also discussed. By integrating this information, we advocate for a combinatory therapeutic strategy that targets early intervention, aiming to restore proteostasis and ameliorate disease progression. This approach not only provides a new perspective on the pathogenesis of neurodegenerative diseases but also highlights innovative strategies to combat the increasing burden of these age-related disorders.
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Affiliation(s)
- Mahmood Akbar
- Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, India; Division of Toxicology and Experimental Medicine, CSIR-Central Drug Research Institute, Lucknow 226031, India
| | - Pranoy Toppo
- Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, India; Division of Toxicology and Experimental Medicine, CSIR-Central Drug Research Institute, Lucknow 226031, India
| | - Aamir Nazir
- Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, India; Division of Toxicology and Experimental Medicine, CSIR-Central Drug Research Institute, Lucknow 226031, India.
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7
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Sanjari-Pour M, Faridi N, Wang P, Bathaie SZ. Protective effect of saffron carotenoids against amyloid beta-induced neurotoxicity in differentiated PC12 cells via the unfolded protein response and autophagy. Phytother Res 2024; 38:4923-4939. [PMID: 36794286 DOI: 10.1002/ptr.7773] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2022] [Revised: 01/12/2023] [Accepted: 01/29/2023] [Indexed: 02/17/2023]
Abstract
The preventive effect of saffron against Alzheimer's disease (AD) has been reported. Herein, we studied the effect of Cro and Crt, saffron carotenoids, on the cellular model of AD. The MTT assay, flow cytometry, and elevated p-JNK, p-Bcl-2, and c-PARP indicated the AβOs-induced apoptosis in differentiated PC12 cells. Then, the protective effects of Cro/Crt on dPC12 cells against AβOs were investigated in preventive and therapeutic modalities. Starvation was used as a positive control. RT-PCR and Western blot results revealed the reduced eIF2α phosphorylation and increased spliced-XBP1, Beclin1, LC3II, and p62, which indicate the AβOs-induced autophagic flux defect, autophagosome accumulation, and apoptosis. Cro and Crt inhibited the JNK-Bcl-2-Beclin1 pathway. They altered Beclin1 and LC3II and decreased p62 expressions, leading cells to survival. Cro and Crt altered the autophagic flux by different mechanisms. So, Cro increased the rate of autophagosome degradation more than Crt, while Crt increased the rate of autophagosome formation more than Cro. The application of 4μ8C and chloroquine as the inhibitors of XBP1 and autophagy, respectively, confirmed these results. So, augmentation of the survival branches of UPR and autophagy is involved and may serve as an effective strategy to prevent the progression of AβOs toxicity.
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Affiliation(s)
- Mariam Sanjari-Pour
- Department of Clinical Biochemistry, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
| | - Nassim Faridi
- Department of Clinical Biochemistry, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
| | - Ping Wang
- College of Pharmaceutical Sciences, Zhejiang University of Technology, Hangzhou, China
| | - S Zahra Bathaie
- Institute for Natural Products and Medicinal Plants, Tarbiat Modares University, Tehran, Iran
- UCLA-DOE Institute, University of California Los Angeles (UCLA), Los Angeles, California, USA
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8
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Pramanik S, Devi M H, Chakrabarty S, Paylar B, Pradhan A, Thaker M, Ayyadhury S, Manavalan A, Olsson PE, Pramanik G, Heese K. Microglia signaling in health and disease - Implications in sex-specific brain development and plasticity. Neurosci Biobehav Rev 2024; 165:105834. [PMID: 39084583 DOI: 10.1016/j.neubiorev.2024.105834] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2024] [Revised: 07/21/2024] [Accepted: 07/27/2024] [Indexed: 08/02/2024]
Abstract
Microglia, the intrinsic neuroimmune cells residing in the central nervous system (CNS), exert a pivotal influence on brain development, homeostasis, and functionality, encompassing critical roles during both aging and pathological states. Recent advancements in comprehending brain plasticity and functions have spotlighted conspicuous variances between male and female brains, notably in neurogenesis, neuronal myelination, axon fasciculation, and synaptogenesis. Nevertheless, the precise impact of microglia on sex-specific brain cell plasticity, sculpting diverse neural network architectures and circuits, remains largely unexplored. This article seeks to unravel the present understanding of microglial involvement in brain development, plasticity, and function, with a specific emphasis on microglial signaling in brain sex polymorphism. Commencing with an overview of microglia in the CNS and their associated signaling cascades, we subsequently probe recent revelations regarding molecular signaling by microglia in sex-dependent brain developmental plasticity, functions, and diseases. Notably, C-X3-C motif chemokine receptor 1 (CX3CR1), triggering receptors expressed on myeloid cells 2 (TREM2), calcium (Ca2+), and apolipoprotein E (APOE) emerge as molecular candidates significantly contributing to sex-dependent brain development and plasticity. In conclusion, we address burgeoning inquiries surrounding microglia's pivotal role in the functional diversity of developing and aging brains, contemplating their potential implications for gender-tailored therapeutic strategies in neurodegenerative diseases.
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Affiliation(s)
- Subrata Pramanik
- Jyoti and Bhupat Mehta School of Health Sciences and Technology, Indian Institute of Technology Guwahati, Guwahati 781039, Assam, India.
| | - Harini Devi M
- Jyoti and Bhupat Mehta School of Health Sciences and Technology, Indian Institute of Technology Guwahati, Guwahati 781039, Assam, India
| | - Saswata Chakrabarty
- Jyoti and Bhupat Mehta School of Health Sciences and Technology, Indian Institute of Technology Guwahati, Guwahati 781039, Assam, India
| | - Berkay Paylar
- Biology, The Life Science Center, School of Science and Technology, Örebro University, Örebro 70182, Sweden
| | - Ajay Pradhan
- Biology, The Life Science Center, School of Science and Technology, Örebro University, Örebro 70182, Sweden
| | - Manisha Thaker
- Eurofins Lancaster Laboratories, Inc., 2425 New Holland Pike, Lancaster, PA 17601, USA
| | - Shamini Ayyadhury
- The Donnelly Centre, University of Toronto, Toronto, Ontario M5S 3E1, Canada
| | - Arulmani Manavalan
- Department of Cariology, Saveetha Dental College and Hospitals, Saveetha Institute of Medical and Technical Sciences, Chennai, Tamil Nadu 600077, India
| | - Per-Erik Olsson
- Biology, The Life Science Center, School of Science and Technology, Örebro University, Örebro 70182, Sweden
| | - Gopal Pramanik
- Department of Pharmaceutical Sciences and Technology, Birla Institute of Technology, Mesra, Ranchi, Jharkhand 835215, India.
| | - Klaus Heese
- Graduate School of Biomedical Science and Engineering, Hanyang University, 222 Wangsimni-ro, Seongdong-gu, Seoul 133791, the Republic of Korea.
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9
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Wu N, Zheng W, Zhou Y, Tian Y, Tang M, Feng X, Ashrafizadeh M, Wang Y, Niu X, Tambuwala M, Wang L, Tergaonkar V, Sethi G, Klionsky D, Huang L, Gu M. Autophagy in aging-related diseases and cancer: Principles, regulatory mechanisms and therapeutic potential. Ageing Res Rev 2024; 100:102428. [PMID: 39038742 DOI: 10.1016/j.arr.2024.102428] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2024] [Revised: 07/05/2024] [Accepted: 07/15/2024] [Indexed: 07/24/2024]
Abstract
Macroautophagy/autophagy is primarily accountable for the degradation of damaged organelles and toxic macromolecules in the cells. Regarding the essential function of autophagy for preserving cellular homeostasis, changes in, or dysfunction of, autophagy flux can lead to disease development. In the current paper, the complicated function of autophagy in aging-associated pathologies and cancer is evaluated, highlighting the underlying molecular mechanisms that can affect longevity and disease pathogenesis. As a natural biological process, a reduction in autophagy is observed with aging, resulting in an accumulation of cell damage and the development of different diseases, including neurological disorders, cardiovascular diseases, and cancer. The MTOR, AMPK, and ATG proteins demonstrate changes during aging, and they are promising therapeutic targets. Insulin/IGF1, TOR, PKA, AKT/PKB, caloric restriction and mitochondrial respiration are vital for lifespan regulation and can modulate or have an interaction with autophagy. The specific types of autophagy, such as mitophagy that degrades mitochondria, can regulate aging by affecting these organelles and eliminating those mitochondria with genomic mutations. Autophagy and its specific types contribute to the regulation of carcinogenesis and they are able to dually enhance or decrease cancer progression. Cancer hallmarks, including proliferation, metastasis, therapy resistance and immune reactions, are tightly regulated by autophagy, supporting the conclusion that autophagy is a promising target in cancer therapy.
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Affiliation(s)
- Na Wu
- Department of Infectious Diseases, The First Hospital of China Medical University, Shenyang, Liaoning 110001, China
| | - Wenhui Zheng
- Department of Anesthesiology, The Shengjing Hospital of China Medical University, Shenyang, Liaoning 110001, China
| | - Yundong Zhou
- Department of Thoracic Surgery, Ningbo Medical Center Lihuili Hospital, Ningbo University, Ningbo, Zhejiang 315040, China
| | - Yu Tian
- School of Public Health, Benedictine University, No.5700 College Road, Lisle, IL 60532, USA; Research Center, the Huizhou Central People's Hospital, Guangdong Medical University, Huizhou, Guangdong, China
| | - Min Tang
- Department of Oncology, Chongqing General Hospital, Chongqing University, Chongqing 401120, China
| | - Xiaoqiang Feng
- Center of Stem Cell and Regenerative Medicine, Gaozhou People's Hospital, Gaozhou, Guangdong 525200, China
| | - Milad Ashrafizadeh
- Department of Radiation Oncology, Shandong Provincial Key Laboratory of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University, Shandong Academy of Medical Sciences, Jinan, Shandong 250000, China; Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, Shanghai, 200032, China
| | - Yuzhuo Wang
- Department of Urologic Sciences and Vancouver Prostate Centre, University of British Columbia, Vancouver, BC V6H3Z6, Canada
| | - Xiaojia Niu
- Department of Urologic Sciences and Vancouver Prostate Centre, University of British Columbia, Vancouver, BC V6H3Z6, Canada
| | - Murtaza Tambuwala
- Lincoln Medical School, University of Lincoln, Brayford Pool Campus, Lincoln LN6 7TS, UK
| | - Lingzhi Wang
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, 16 Medical Drive, Singapore 117600, Singapore
| | - Vinay Tergaonkar
- Laboratory of NF-κB Signalling, Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A⁎STAR), 61 Biopolis Drive, Proteos, Singapore 138673, Singapore
| | - Gautam Sethi
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, 16 Medical Drive, Singapore 117600, Singapore; NUS Centre for Cancer Research (N2CR), Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117599, Singapore.
| | - Daniel Klionsky
- Life Sciences Institute and Department of Molecular, Cellular and Developmental Biology, University of Michigan, Ann Arbor, MI, USA.
| | - Li Huang
- Center of Stem Cell and Regenerative Medicine, Gaozhou People's Hospital, Gaozhou, Guangdong 525200, China.
| | - Ming Gu
- Department of Breast Surgery, The First Hospital of China Medical University, Shenyang, Liaoning 110001, China.
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10
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Xu L, Wu X, Zhao S, Hu H, Wang S, Zhang Y, Chen J, Zhang X, Zhao Y, Ma R, Huang F, Shi L. Harnessing Nanochaperone-Mediated Autophagy for Selective Clearance of Pathogenic Tau Protein in Alzheimer's Disease. ADVANCED MATERIALS (DEERFIELD BEACH, FLA.) 2024; 36:e2313869. [PMID: 38688523 DOI: 10.1002/adma.202313869] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/19/2023] [Revised: 04/27/2024] [Indexed: 05/02/2024]
Abstract
Accumulation of pathological tau is a hallmark of Alzheimer's disease (AD), which correlates more closely with cognitive impairment than does the amyloid-β (Aβ) burden. Autophagy is a powerful process for the clearance of toxic proteins including aberrant tau. However, compromised autophagy is demonstrated in neurodegeneration including AD, and current autophagy inducers remain enormously challenging due to inability of restoring autophagy pathway and lack of targeting specificity. Here, pathogenic tau-specific autophagy based on customized nanochaperone is developed for AD treatment. In this strategy, the nanochaperone can selectively bind to pathogenic tau and maintain tau homeostasis, thereby ensuring microtubule stability which is important for autophagy pathway. Meanwhile, the bound pathogenic tau can be sequestered in autophagosomes by in situ autophagy activation of nanochaperone. Consequently, autophagosomes wrapping with pathogenic tau are able to be trafficked along the stabilized microtubule to achieve successful fusion with lysosomes, resulting in the enhancement of autophagic flux and pathologic tau clearance. After treatment with this nanochaperone-mediated autophagy strategy, the tau burden, neuron damages, and cognitive deficits of AD mice are significantly alleviated in the brain. Therefore, this work represents a promising candidate for AD-targeted therapy and provides new insights into future design of anti-neurodegeneration drugs.
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Affiliation(s)
- Linlin Xu
- State Key Laboratory of Medicinal Chemical Biology, Key Laboratory of Functional Polymer Materials of Ministry of Education, College of Chemistry, Nankai University, Tianjin, 300071, P. R. China
| | - Xiaohui Wu
- State Key Laboratory of Medicinal Chemical Biology, Key Laboratory of Functional Polymer Materials of Ministry of Education, College of Chemistry, Nankai University, Tianjin, 300071, P. R. China
| | - Shuyue Zhao
- State Key Laboratory of Medicinal Chemical Biology, Key Laboratory of Functional Polymer Materials of Ministry of Education, College of Chemistry, Nankai University, Tianjin, 300071, P. R. China
| | - Haodong Hu
- State Key Laboratory of Medicinal Chemical Biology, Key Laboratory of Functional Polymer Materials of Ministry of Education, College of Chemistry, Nankai University, Tianjin, 300071, P. R. China
| | - Silei Wang
- State Key Laboratory of Medicinal Chemical Biology, Key Laboratory of Functional Polymer Materials of Ministry of Education, College of Chemistry, Nankai University, Tianjin, 300071, P. R. China
| | - Yongxin Zhang
- State Key Laboratory of Medicinal Chemical Biology, Key Laboratory of Functional Polymer Materials of Ministry of Education, College of Chemistry, Nankai University, Tianjin, 300071, P. R. China
| | - Jiajing Chen
- State Key Laboratory of Medicinal Chemical Biology, Key Laboratory of Functional Polymer Materials of Ministry of Education, College of Chemistry, Nankai University, Tianjin, 300071, P. R. China
| | - Xiaochen Zhang
- State Key Laboratory of Medicinal Chemical Biology, Key Laboratory of Functional Polymer Materials of Ministry of Education, College of Chemistry, Nankai University, Tianjin, 300071, P. R. China
| | - Yu Zhao
- State Key Laboratory of Medicinal Chemical Biology, Key Laboratory of Functional Polymer Materials of Ministry of Education, College of Chemistry, Nankai University, Tianjin, 300071, P. R. China
| | - Rujiang Ma
- State Key Laboratory of Medicinal Chemical Biology, Key Laboratory of Functional Polymer Materials of Ministry of Education, College of Chemistry, Nankai University, Tianjin, 300071, P. R. China
| | - Fan Huang
- State Key Laboratory of Advanced Medical Materials and Devices, Tianjin Key Laboratory of Radiation Medicine and Molecular Nuclear Medicine, Institute of Radiation Medicine, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, 300192, P.R. China
| | - Linqi Shi
- State Key Laboratory of Medicinal Chemical Biology, Key Laboratory of Functional Polymer Materials of Ministry of Education, College of Chemistry, Nankai University, Tianjin, 300071, P. R. China
- Haihe Laboratory of Sustainable Chemical Transformations, Tianjin, 300090, P. R. China
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11
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Du Z, Lessard S, Iyyanki T, Chao M, Hammond T, Ofengeim D, Klinger K, de Rinaldis E, Shameer K, Chatelain C. Genetic analyses of inflammatory polyneuropathy and chronic inflammatory demyelinating polyradiculoneuropathy identified candidate genes. HGG ADVANCES 2024; 5:100317. [PMID: 38851890 PMCID: PMC11259940 DOI: 10.1016/j.xhgg.2024.100317] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2024] [Revised: 06/04/2024] [Accepted: 06/05/2024] [Indexed: 06/10/2024] Open
Abstract
Chronic inflammatory demyelinating polyneuropathy (CIDP) is a rare, immune-mediated disorder in which an aberrant immune response causes demyelination and axonal damage of the peripheral nerves. Genetic contribution to CIDP is unclear and no genome-wide association study (GWAS) has been reported so far. In this study, we aimed to identify CIDP-related risk loci, genes, and pathways. We first focused on CIDP, and 516 CIDP cases and 403,545 controls were included in the GWAS analysis. We also investigated genetic risk for inflammatory polyneuropathy (IP), in which we performed a GWAS study using FinnGen data and combined the results with GWAS from the UK Biobank using a fixed-effect meta-analysis. A total of 1,261 IP cases and 823,730 controls were included in the analysis. Stratified analyses by gender were performed. Mendelian randomization (MR), colocalization, and transcriptome-wide association study (TWAS) analyses were performed to identify associated genes. Gene-set analyses were conducted to identify associated pathways. We identified one genome-wide significant locus at 20q13.33 for CIDP risk among women, the top variant located at the intron region of gene CDH4. Sex-combined MR, colocalization, and TWAS analyses identified three candidate pathogenic genes for CIDP and five genes for IP. MAGMA gene-set analyses identified a total of 18 pathways related to IP or CIDP. Sex-stratified analyses identified three genes for IP among males and two genes for IP among females. Our study identified suggestive risk genes and pathways for CIDP and IP. Functional analyses should be conducted to further confirm these associations.
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Affiliation(s)
- Zhaohui Du
- Precision Medicine & Computational Biology, Sanofi, Cambridge, MA, USA
| | - Samuel Lessard
- Precision Medicine & Computational Biology, Sanofi, Cambridge, MA, USA
| | - Tejaswi Iyyanki
- Precision Medicine & Computational Biology, Sanofi, Cambridge, MA, USA
| | - Michael Chao
- Precision Medicine & Computational Biology, Sanofi, Cambridge, MA, USA
| | | | | | | | | | - Khader Shameer
- Precision Medicine & Computational Biology, Sanofi, Cambridge, MA, USA
| | - Clément Chatelain
- Precision Medicine & Computational Biology, Sanofi, Cambridge, MA, USA.
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12
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Singh MK, Shin Y, Ju S, Han S, Kim SS, Kang I. Comprehensive Overview of Alzheimer's Disease: Etiological Insights and Degradation Strategies. Int J Mol Sci 2024; 25:6901. [PMID: 39000011 PMCID: PMC11241648 DOI: 10.3390/ijms25136901] [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: 05/21/2024] [Revised: 06/19/2024] [Accepted: 06/21/2024] [Indexed: 07/14/2024] Open
Abstract
Alzheimer's disease (AD) is the most prevalent neurodegenerative disorder and affects millions of individuals globally. AD is associated with cognitive decline and memory loss that worsens with aging. A statistical report using U.S. data on AD estimates that approximately 6.9 million individuals suffer from AD, a number projected to surge to 13.8 million by 2060. Thus, there is a critical imperative to pinpoint and address AD and its hallmark tau protein aggregation early to prevent and manage its debilitating effects. Amyloid-β and tau proteins are primarily associated with the formation of plaques and neurofibril tangles in the brain. Current research efforts focus on degrading amyloid-β and tau or inhibiting their synthesis, particularly targeting APP processing and tau hyperphosphorylation, aiming to develop effective clinical interventions. However, navigating this intricate landscape requires ongoing studies and clinical trials to develop treatments that truly make a difference. Genome-wide association studies (GWASs) across various cohorts identified 40 loci and over 300 genes associated with AD. Despite this wealth of genetic data, much remains to be understood about the functions of these genes and their role in the disease process, prompting continued investigation. By delving deeper into these genetic associations, novel targets such as kinases, proteases, cytokines, and degradation pathways, offer new directions for drug discovery and therapeutic intervention in AD. This review delves into the intricate biological pathways disrupted in AD and identifies how genetic variations within these pathways could serve as potential targets for drug discovery and treatment strategies. Through a comprehensive understanding of the molecular underpinnings of AD, researchers aim to pave the way for more effective therapies that can alleviate the burden of this devastating disease.
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Affiliation(s)
- Manish Kumar Singh
- Department of Biochemistry and Molecular Biology, School of Medicine, Kyung Hee University, Seoul 02447, Republic of Korea
- Biomedical Science Institute, Kyung Hee University, Seoul 02447, Republic of Korea
| | - Yoonhwa Shin
- Department of Biochemistry and Molecular Biology, School of Medicine, Kyung Hee University, Seoul 02447, Republic of Korea
- Biomedical Science Institute, Kyung Hee University, Seoul 02447, Republic of Korea
| | - Songhyun Ju
- Department of Biochemistry and Molecular Biology, School of Medicine, Kyung Hee University, Seoul 02447, Republic of Korea
- Biomedical Science Institute, Kyung Hee University, Seoul 02447, Republic of Korea
- Department of Biomedical Science, Graduate School, Kyung Hee University, Seoul 02447, Republic of Korea
| | - Sunhee Han
- Department of Biochemistry and Molecular Biology, School of Medicine, Kyung Hee University, Seoul 02447, Republic of Korea
- Biomedical Science Institute, Kyung Hee University, Seoul 02447, Republic of Korea
- Department of Biomedical Science, Graduate School, Kyung Hee University, Seoul 02447, Republic of Korea
| | - Sung Soo Kim
- Department of Biochemistry and Molecular Biology, School of Medicine, Kyung Hee University, Seoul 02447, Republic of Korea
- Biomedical Science Institute, Kyung Hee University, Seoul 02447, Republic of Korea
- Department of Biomedical Science, Graduate School, Kyung Hee University, Seoul 02447, Republic of Korea
| | - Insug Kang
- Department of Biochemistry and Molecular Biology, School of Medicine, Kyung Hee University, Seoul 02447, Republic of Korea
- Biomedical Science Institute, Kyung Hee University, Seoul 02447, Republic of Korea
- Department of Biomedical Science, Graduate School, Kyung Hee University, Seoul 02447, Republic of Korea
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13
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Polini B, Zallocco L, Gado F, Ferrisi R, Ricardi C, Zuccarini M, Carnicelli V, Manera C, Ronci M, Lucacchini A, Zucchi R, Giusti L, Chiellini G. A Proteomic Approach Identified TFEB as a Key Player in the Protective Action of Novel CB2R Bitopic Ligand FD22a against the Deleterious Effects Induced by β-Amyloid in Glial Cells. Cells 2024; 13:875. [PMID: 38786097 PMCID: PMC11119469 DOI: 10.3390/cells13100875] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2024] [Revised: 05/11/2024] [Accepted: 05/16/2024] [Indexed: 05/25/2024] Open
Abstract
Neurodegenerative diseases (NDDs) are progressive multifactorial disorders of the nervous system sharing common pathogenic features, including intracellular misfolded protein aggregation, mitochondrial deficit, and inflammation. Taking into consideration the multifaceted nature of NDDs, development of multitarget-directed ligands (MTDLs) has evolved as an attractive therapeutic strategy. Compounds that target the cannabinoid receptor type II (CB2R) are rapidly emerging as novel effective MTDLs against common NDDs, such as Alzheimer's disease (AD). We recently developed the first CB2R bitopic/dualsteric ligand, namely FD22a, which revealed the ability to induce neuroprotection with fewer side effects. To explore the potential of FD22a as a multitarget drug for the treatment of NDDs, we investigated here its ability to prevent the toxic effect of β-amyloid (Aβ25-35 peptide) on human cellular models of neurodegeneration, such as microglia (HMC3) and glioblastoma (U87-MG) cell lines. Our results displayed that FD22a efficiently prevented Aβ25-35 cytotoxic and proinflammatory effects in both cell lines and counteracted β-amyloid-induced depression of autophagy in U87-MG cells. Notably, a quantitative proteomic analysis of U87-MG cells revealed that FD22a was able to potently stimulate the autophagy-lysosomal pathway (ALP) by activating its master transcriptional regulator TFEB, ultimately increasing the potential of this novel CB2R bitopic/dualsteric ligand as a multitarget drug for the treatment of NDDs.
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Affiliation(s)
- Beatrice Polini
- Department of Pathology, University of Pisa, 56100 Pisa, Italy; (B.P.); (C.R.); (V.C.); (R.Z.)
| | - Lorenzo Zallocco
- Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, 56126 Pisa, Italy;
| | - Francesca Gado
- Department of Pharmaceutical Sciences, University of Milan, 20133 Milano, Italy; (F.G.); (R.F.)
- Department of Pharmacy, University of Pisa, 56126 Pisa, Italy;
| | - Rebecca Ferrisi
- Department of Pharmaceutical Sciences, University of Milan, 20133 Milano, Italy; (F.G.); (R.F.)
- Department of Pharmacy, University of Pisa, 56126 Pisa, Italy;
| | - Caterina Ricardi
- Department of Pathology, University of Pisa, 56100 Pisa, Italy; (B.P.); (C.R.); (V.C.); (R.Z.)
| | - Mariachiara Zuccarini
- Department of Medical, Oral and Biotechnological Sciences, University G. D’Annunzio of Chieti-Pescara, 66100 Chieti, Italy; (M.Z.); (M.R.)
| | - Vittoria Carnicelli
- Department of Pathology, University of Pisa, 56100 Pisa, Italy; (B.P.); (C.R.); (V.C.); (R.Z.)
| | | | - Maurizio Ronci
- Department of Medical, Oral and Biotechnological Sciences, University G. D’Annunzio of Chieti-Pescara, 66100 Chieti, Italy; (M.Z.); (M.R.)
- Interuniversitary Consortium for Engineering and Medicine (COIIM), 86100 Campobasso, Italy
| | - Antonio Lucacchini
- Department of Clinical and Experimental Medicine, University of Pisa, 56126 Pisa, Italy;
| | - Riccardo Zucchi
- Department of Pathology, University of Pisa, 56100 Pisa, Italy; (B.P.); (C.R.); (V.C.); (R.Z.)
| | - Laura Giusti
- School of Pharmacy, University of Camerino, 62032 Camerino, Italy
| | - Grazia Chiellini
- Department of Pathology, University of Pisa, 56100 Pisa, Italy; (B.P.); (C.R.); (V.C.); (R.Z.)
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14
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Afjadi MN, Dabirmanesh B, Uversky VN. Therapeutic approaches in proteinopathies. PROGRESS IN MOLECULAR BIOLOGY AND TRANSLATIONAL SCIENCE 2024; 206:341-388. [PMID: 38811085 DOI: 10.1016/bs.pmbts.2024.03.008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/31/2024]
Abstract
A family of maladies known as amyloid disorders, proteinopathy, or amyloidosis, are characterized by the accumulation of abnormal protein aggregates containing cross-β-sheet amyloid fibrils in many organs and tissues. Often, proteins that have been improperly formed or folded make up these fibrils. Nowadays, most treatments for amyloid illness focus on managing symptoms rather than curing or preventing the underlying disease process. However, recent advances in our understanding of the biology of amyloid diseases have led to the development of innovative therapies that target the emergence and accumulation of amyloid fibrils. Examples of these treatments include the use of small compounds, monoclonal antibodies, gene therapy, and others. In the end, even if the majority of therapies for amyloid diseases are symptomatic, greater research into the biology behind these disorders is identifying new targets for potential therapy and paving the way for the development of more effective treatments in the future.
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Affiliation(s)
- Mohsen Nabi Afjadi
- Department of Biochemistry, Faculty of Biological Sciences, Tarbiat Modares University, Tehran, Iran
| | - Bahareh Dabirmanesh
- Department of Biochemistry, Faculty of Biological Sciences, Tarbiat Modares University, Tehran, Iran
| | - Vladimir N Uversky
- Pushchino Scientific Center for Biological Research of the Russian Academy of Sciences, Institute for Biological Instrumentation, Pushchino, Moscow, Russia; Department of Molecular Medicine and USF Health Byrd Alzheimer's Research Institute, Morsani College of Medicine, University of South Florida, Tampa, FL, United States.
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15
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Davoody S, Asgari Taei A, Khodabakhsh P, Dargahi L. mTOR signaling and Alzheimer's disease: What we know and where we are? CNS Neurosci Ther 2024; 30:e14463. [PMID: 37721413 PMCID: PMC11017461 DOI: 10.1111/cns.14463] [Citation(s) in RCA: 10] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2022] [Revised: 08/28/2023] [Accepted: 08/29/2023] [Indexed: 09/19/2023] Open
Abstract
Despite the great body of research done on Alzheimer's disease, the underlying mechanisms have not been vividly investigated. To date, the accumulation of amyloid-beta plaques and tau tangles constitutes the hallmark of the disease; however, dysregulation of the mammalian target of rapamycin (mTOR) seems to be significantly involved in the pathogenesis of the disease as well. mTOR, as a serine-threonine protein kinase, was previously known for controlling many cellular functions such as cell size, autophagy, and metabolism. In this regard, mammalian target of rapamycin complex 1 (mTORC1) may leave anti-aging impacts by robustly inhibiting autophagy, a mechanism that inhibits the accumulation of damaged protein aggregate and dysfunctional organelles. Formation and aggregation of neurofibrillary tangles and amyloid-beta plaques seem to be significantly regulated by mTOR signaling. Understanding the underlying mechanisms and connection between mTOR signaling and AD may suggest conducting clinical trials assessing the efficacy of rapamycin, as an mTOR inhibitor drug, in managing AD or may help develop other medications. In this literature review, we aim to elaborate mTOR signaling network mainly in the brain, point to gaps of knowledge, and define how and in which ways mTOR signaling can be connected with AD pathogenesis and symptoms.
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Affiliation(s)
- Samin Davoody
- Student Research Committee, School of MedicineShahid Beheshti University of Medical SciencesTehranIran
| | - Afsaneh Asgari Taei
- Neuroscience Research CenterShahid Beheshti University of Medical SciencesTehranIran
| | - Pariya Khodabakhsh
- Department of NeurophysiologyInstitute of Physiology, Eberhard Karls University of TübingenTübingenGermany
| | - Leila Dargahi
- Neurobiology Research CenterShahid Beheshti University of Medical SciencesTehranIran
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16
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Li W, Ali T, He K, Zheng C, Li N, Yu Z, Li S. ApoE4 dysregulation incites depressive symptoms and mitochondrial impairments in mice. J Cell Mol Med 2024; 28:e18160. [PMID: 38506067 PMCID: PMC10951871 DOI: 10.1111/jcmm.18160] [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: 07/10/2023] [Revised: 01/12/2024] [Accepted: 01/18/2024] [Indexed: 03/21/2024] Open
Abstract
Apolipoprotein E4 (ApoE4) is involved in the stress-response processes and is hypothesized to be a risk factor for depression by means of mitochondrial dysfunction. However, their exact roles and underlying mechanisms are largely unknown. ApoE4 transgenic mice (B6. Cg-ApoEtm1Unc Cdh18Tg( GFAP-APOE i4)1Hol /J) were subjected to stress (lipopolysaccharides, LPS) to elucidate the aetiology of ApoE4-induced depression. LPS treatment significantly aggravated depression-like behaviours, concurrent with neuroinflammation and impaired mitochondrial changes, and melatonin/Urolithin A (UA) + 5-aminoimidazole-4-carboxamide 1-β-D-ribofuranoside (AICAR) reversed these effects in ApoE4 mice. Concurrently, ApoE4 mice exhibited mitophagy deficits, which could be further exacerbated by LPS stimulation, as demonstrated by reduced Atg5, Beclin-1 and Parkin levels, while PINK1 levels were increased. However, these changes were reversed by melatonin treatment. Additionally, proteomic profiling suggested mitochondria-related signalling and network changes in ApoE4 mice, which may underlie the exaggerated response to LPS. Furthermore, HEK 293T cells transfected with ApoE4 showed mitochondria-associated protein and mitophagy defects, including PGC-1α, TFAM, p-AMPKα, PINK1 and LC3B impairments. Additionally, it aggravates mitochondrial impairment (particularly mitophagy), which can be attenuated by triggering autophagy. Collectively, ApoE4 dysregulation enhanced depressive behaviour upon LPS stimulation.
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Affiliation(s)
- Weifen Li
- Department of Infectious Diseases, Huazhong University of Science and Technology Union Shenzhen HospitalShenzhen University School of MedicineShenzhenChina
- State Key Laboratory of Oncogenomics, School of Chemical Biology and BiotechnologyPeking University Shenzhen Graduate SchoolShenzhenChina
| | - Tahir Ali
- State Key Laboratory of Oncogenomics, School of Chemical Biology and BiotechnologyPeking University Shenzhen Graduate SchoolShenzhenChina
- Shenzhen Bay LaboratoryShenzhenChina
| | - Kaiwu He
- State Key Laboratory of Oncogenomics, School of Chemical Biology and BiotechnologyPeking University Shenzhen Graduate SchoolShenzhenChina
| | - Chengyou Zheng
- State Key Laboratory of Oncogenomics, School of Chemical Biology and BiotechnologyPeking University Shenzhen Graduate SchoolShenzhenChina
| | - Ningning Li
- Tomas Lindahl Nobel Laureate Laboratory, Precision Medicine Research CentreThe Seventh Affiliated Hospital of Sun Yat‐sen UniversityShenzhenChina
| | - Zhi‐Jian Yu
- Department of Infectious Diseases, Huazhong University of Science and Technology Union Shenzhen HospitalShenzhen University School of MedicineShenzhenChina
| | - Shupeng Li
- State Key Laboratory of Oncogenomics, School of Chemical Biology and BiotechnologyPeking University Shenzhen Graduate SchoolShenzhenChina
- Shenzhen Bay LaboratoryShenzhenChina
- Campbell Research Institute, Centre for Addiction and Mental HealthTorontoOntarioCanada
- Department of PsychiatryUniversity of TorontoTorontoOntarioCanada
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17
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Ni H, Kan X, Rui Q, Zhang Y, Zhai W, Zhang B, Yu Z. RACK1 promotes autophagy via the PERK signaling pathway to protect against traumatic brain injury in rats. CNS Neurosci Ther 2024; 30:e14691. [PMID: 38532543 PMCID: PMC10966134 DOI: 10.1111/cns.14691] [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: 10/29/2023] [Revised: 02/29/2024] [Accepted: 03/03/2024] [Indexed: 03/28/2024] Open
Abstract
AIMS Neuronal cell death is a primary factor that determines the outcome after traumatic brain injury (TBI). We previously revealed the importance of receptor for activated C kinase (RACK1), a multifunctional scaffold protein, in maintaining neuronal survival after TBI, but the specific mechanism remains unclear. The aim of this study was to explore the mechanism underlying RACK1-mediated neuroprotection in TBI. METHODS TBI model was established using controlled cortical impact injury in Sprague-Dawley rats. Genetic intervention and pharmacological inhibition of RACK1 and PERK-autophagy signaling were administrated by intracerebroventricular injection. Western blotting, coimmunoprecipitation, transmission electron microscopy, real-time PCR, immunofluorescence, TUNEL staining, Nissl staining, neurobehavioral tests, and contusion volume assessment were performed. RESULTS Endogenous RACK1 was upregulated and correlated with autophagy induction after TBI. RACK1 knockdown markedly inhibited TBI-induced autophagy, whereas RACK1 overexpression exerted the opposite effects. Moreover, RACK1 overexpression ameliorated neuronal apoptosis, neurological deficits, and cortical tissue loss after TBI, and these effects were abrogated by the autophagy inhibitor 3-methyladenine or siRNAs targeting Beclin1 and Atg5. Mechanistically, RACK1 interacted with PERK and activated PERK signaling. Pharmacological and genetic inhibition of the PERK pathway abolished RACK1-induced autophagy after TBI. CONCLUSION Our findings indicate that RACK1 protected against TBI-induced neuronal damage partly through autophagy induction by regulating the PERK signaling pathway.
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Affiliation(s)
- Haibo Ni
- Department of Neurosurgery & Brain and Nerve Research LaboratoryThe First Affiliated Hospital of Soochow UniversitySuzhouChina
- Department of NeurosurgeryThe Fourth Affiliated Hospital of Soochow UniversitySuzhouChina
| | - Xugang Kan
- Department of Neurobiology and Cell Biology, Xuzhou Key Laboratory of NeurobiologyXuzhou Medical UniversityXuzhouChina
| | - Qin Rui
- Department of Center of Clinical LaboratoryThe Fourth Affiliated Hospital of Soochow UniversitySuzhouChina
| | - Yang Zhang
- Department of Neurobiology and Cell Biology, Xuzhou Key Laboratory of NeurobiologyXuzhou Medical UniversityXuzhouChina
| | - Weiwei Zhai
- Department of Neurosurgery & Brain and Nerve Research LaboratoryThe First Affiliated Hospital of Soochow UniversitySuzhouChina
| | - Baole Zhang
- Department of Neurobiology and Cell Biology, Xuzhou Key Laboratory of NeurobiologyXuzhou Medical UniversityXuzhouChina
| | - Zhengquan Yu
- Department of Neurosurgery & Brain and Nerve Research LaboratoryThe First Affiliated Hospital of Soochow UniversitySuzhouChina
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18
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Bai I, Keyser C, Zhang Z, Rosolia B, Hwang JY, Zukin RS, Yan J. Epigenetic regulation of autophagy in neuroinflammation and synaptic plasticity. Front Immunol 2024; 15:1322842. [PMID: 38455054 PMCID: PMC10918468 DOI: 10.3389/fimmu.2024.1322842] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2023] [Accepted: 02/02/2024] [Indexed: 03/09/2024] Open
Abstract
Autophagy is a conserved cellular mechanism that enables the degradation and recycling of cellular organelles and proteins via the lysosomal pathway. In neurodevelopment and maintenance of neuronal homeostasis, autophagy is required to regulate presynaptic functions, synapse remodeling, and synaptic plasticity. Deficiency of autophagy has been shown to underlie the synaptic and behavioral deficits of many neurological diseases such as autism, psychiatric diseases, and neurodegenerative disorders. Recent evidence reveals that dysregulated autophagy plays an important role in the initiation and progression of neuroinflammation, a common pathological feature in many neurological disorders leading to defective synaptic morphology and plasticity. In this review, we will discuss the regulation of autophagy and its effects on synapses and neuroinflammation, with emphasis on how autophagy is regulated by epigenetic mechanisms under healthy and diseased conditions.
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Affiliation(s)
- Isaac Bai
- Center for Gene Regulation in Health and Disease, Department of Biological, Geological, and Environmental Sciences, Cleveland State University, Cleveland, OH, United States
| | - Cameron Keyser
- Center for Gene Regulation in Health and Disease, Department of Biological, Geological, and Environmental Sciences, Cleveland State University, Cleveland, OH, United States
| | - Ziyan Zhang
- Center for Gene Regulation in Health and Disease, Department of Biological, Geological, and Environmental Sciences, Cleveland State University, Cleveland, OH, United States
| | - Breandan Rosolia
- Center for Gene Regulation in Health and Disease, Department of Biological, Geological, and Environmental Sciences, Cleveland State University, Cleveland, OH, United States
| | - Jee-Yeon Hwang
- Department of Pharmacology and Neuroscience, Creighton University School of Medicine, Omaha, NE, United States
| | - R. Suzanne Zukin
- Dominick P. Purpura Department of Neuroscience, Albert Einstein College of Medicine, New York, NY, United States
| | - Jingqi Yan
- Center for Gene Regulation in Health and Disease, Department of Biological, Geological, and Environmental Sciences, Cleveland State University, Cleveland, OH, United States
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19
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Cano-Cano F, Martín-Loro F, Gallardo-Orihuela A, González-Montelongo MDC, Ortuño-Miquel S, Hervás-Corpión I, de la Villa P, Ramón-Marco L, Navarro-Calvo J, Gómez-Jaramillo L, Arroba AI, Valor LM. Retinal dysfunction in Huntington's disease mouse models concurs with local gliosis and microglia activation. Sci Rep 2024; 14:4176. [PMID: 38378796 PMCID: PMC10879138 DOI: 10.1038/s41598-024-54347-8] [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: 10/24/2023] [Accepted: 02/12/2024] [Indexed: 02/22/2024] Open
Abstract
Huntington's disease (HD) is caused by an aberrant expansion of CAG repeats in the HTT gene that mainly affects basal ganglia. Although striatal dysfunction has been widely studied in HD mouse models, other brain areas can also be relevant to the pathology. In this sense, we have special interest on the retina as this is the most exposed part of the central nervous system that enable health monitoring of patients using noninvasive techniques. To establish the retina as an appropriate tissue for HD studies, we need to correlate the retinal alterations with those in the inner brain, i.e., striatum. We confirmed the malfunction of the transgenic R6/1 retinas, which underwent a rearrangement of their transcriptome as extensive as in the striatum. Although tissue-enriched genes were downregulated in both areas, a neuroinflammation signature was only clearly induced in the R6/1 retina in which the observed glial activation was reminiscent of the situation in HD patient's brains. The retinal neuroinflammation was confirmed in the slow progressive knock-in zQ175 strain. Overall, these results demonstrated the suitability of the mouse retina as a research model for HD and its associated glial activation.
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Affiliation(s)
- Fátima Cano-Cano
- Instituto de Investigación e Innovación Biomédica de Cádiz (INiBICA), Unidad de Investigación, Hospital Universitario Puerta del Mar, Av. Ana de Viya 21, 11009, Cádiz, Spain
| | - Francisco Martín-Loro
- Instituto de Investigación e Innovación Biomédica de Cádiz (INiBICA), Unidad de Investigación, Hospital Universitario Puerta del Mar, Av. Ana de Viya 21, 11009, Cádiz, Spain
| | - Andrea Gallardo-Orihuela
- Instituto de Investigación e Innovación Biomédica de Cádiz (INiBICA), Unidad de Investigación, Hospital Universitario Puerta del Mar, Av. Ana de Viya 21, 11009, Cádiz, Spain
| | - María Del Carmen González-Montelongo
- Instituto de Investigación e Innovación Biomédica de Cádiz (INiBICA), Unidad de Investigación, Hospital Universitario Puerta del Mar, Av. Ana de Viya 21, 11009, Cádiz, Spain
| | - Samanta Ortuño-Miquel
- Instituto de Investigación Sanitaria y Biomédica de Alicante (ISABIAL), Unidad de Bioinformática, Hospital General Universitario Dr. Balmis, 03010, Alicante, Spain
| | - Irati Hervás-Corpión
- Instituto de Investigación e Innovación Biomédica de Cádiz (INiBICA), Unidad de Investigación, Hospital Universitario Puerta del Mar, Av. Ana de Viya 21, 11009, Cádiz, Spain
- Programa de Tumores Sólidos, Centro de Investigación Médica Aplicada (CIMA), Departamento de Pediatría, Clínica Universidad de Navarra, Instituto de Investigación Sanitaria de Navarra (IdiSNA), 31008, Pamplona, Spain
| | - Pedro de la Villa
- Departamento de Biología de Sistemas, Universidad de Alcalá de Henares, 28871, Alcalá de Henares, Spain
- Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), 28034, Madrid, Spain
| | - Lucía Ramón-Marco
- Laboratorio de Investigación, Diagnostics Building, Instituto de Investigación Sanitaria y Biomédica de Alicante (ISABIAL), Hospital General Universitario Dr. Balmis, Av. Pintor Baeza 12, 03010, Alicante, Spain
| | - Jorge Navarro-Calvo
- Laboratorio de Investigación, Diagnostics Building, Instituto de Investigación Sanitaria y Biomédica de Alicante (ISABIAL), Hospital General Universitario Dr. Balmis, Av. Pintor Baeza 12, 03010, Alicante, Spain
| | - Laura Gómez-Jaramillo
- Instituto de Investigación e Innovación Biomédica de Cádiz (INiBICA), Unidad de Investigación, Hospital Universitario Puerta del Mar, Av. Ana de Viya 21, 11009, Cádiz, Spain
| | - Ana I Arroba
- Instituto de Investigación e Innovación Biomédica de Cádiz (INiBICA), Unidad de Investigación, Hospital Universitario Puerta del Mar, Av. Ana de Viya 21, 11009, Cádiz, Spain.
| | - Luis M Valor
- Laboratorio de Investigación, Diagnostics Building, Instituto de Investigación Sanitaria y Biomédica de Alicante (ISABIAL), Hospital General Universitario Dr. Balmis, Av. Pintor Baeza 12, 03010, Alicante, Spain.
- Instituto de Investigación, Desarrollo e Innovación en Biotecnología Sanitaria de Elche (IDiBE), 03202, Elche, Spain.
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20
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Trinh VH, Nguyen Huu T, Sah DK, Choi JM, Yoon HJ, Park SC, Jung YS, Lee SR. Redox Regulation of PTEN by Reactive Oxygen Species: Its Role in Physiological Processes. Antioxidants (Basel) 2024; 13:199. [PMID: 38397797 PMCID: PMC10886030 DOI: 10.3390/antiox13020199] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2024] [Revised: 01/25/2024] [Accepted: 01/27/2024] [Indexed: 02/25/2024] Open
Abstract
Phosphatase and tensin homolog (PTEN) is a tumor suppressor due to its ability to regulate cell survival, growth, and proliferation by downregulating the PI3K/AKT signaling pathway. In addition, PTEN plays an essential role in other physiological events associated with cell growth demands, such as ischemia-reperfusion, nerve injury, and immune responsiveness. Therefore, recently, PTEN inhibition has emerged as a potential therapeutic intervention in these situations. Increasing evidence demonstrates that reactive oxygen species (ROS), especially hydrogen peroxide (H2O2), are produced and required for the signaling in many important cellular processes under such physiological conditions. ROS have been shown to oxidize PTEN at the cysteine residue of its active site, consequently inhibiting its function. Herein, we provide an overview of studies that highlight the role of the oxidative inhibition of PTEN in physiological processes.
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Affiliation(s)
- Vu Hoang Trinh
- Department of Biochemistry, Department of Biomedical Sciences, Chonnam National University Medical School, Gwangju 501190, Republic of Korea; (V.H.T.); (T.N.H.); (D.K.S.); (J.M.C.); (H.J.Y.)
- Department of Oncology, Department of Medical Sciences, Pham Ngoc Thach University of Medicine, Ho Chi Minh City 700000, Vietnam
| | - Thang Nguyen Huu
- Department of Biochemistry, Department of Biomedical Sciences, Chonnam National University Medical School, Gwangju 501190, Republic of Korea; (V.H.T.); (T.N.H.); (D.K.S.); (J.M.C.); (H.J.Y.)
| | - Dhiraj Kumar Sah
- Department of Biochemistry, Department of Biomedical Sciences, Chonnam National University Medical School, Gwangju 501190, Republic of Korea; (V.H.T.); (T.N.H.); (D.K.S.); (J.M.C.); (H.J.Y.)
| | - Jin Myung Choi
- Department of Biochemistry, Department of Biomedical Sciences, Chonnam National University Medical School, Gwangju 501190, Republic of Korea; (V.H.T.); (T.N.H.); (D.K.S.); (J.M.C.); (H.J.Y.)
| | - Hyun Joong Yoon
- Department of Biochemistry, Department of Biomedical Sciences, Chonnam National University Medical School, Gwangju 501190, Republic of Korea; (V.H.T.); (T.N.H.); (D.K.S.); (J.M.C.); (H.J.Y.)
| | - Sang Chul Park
- The Future Life & Society Research Center, Advanced Institute of Aging Science, Chonnam National University, Gwangju 61469, Republic of Korea;
| | - Yu Seok Jung
- Chonnam National University Medical School, Gwangju 501190, Republic of Korea;
| | - Seung-Rock Lee
- Department of Biochemistry, Department of Biomedical Sciences, Chonnam National University Medical School, Gwangju 501190, Republic of Korea; (V.H.T.); (T.N.H.); (D.K.S.); (J.M.C.); (H.J.Y.)
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21
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Wang X, Song Y, Cong P, Wang Z, Liu Y, Xu J, Xue C. Docosahexaenoic Acid-Acylated Astaxanthin Monoester Ameliorates Amyloid-β Pathology and Neuronal Damage by Restoring Autophagy in Alzheimer's Disease Models. Mol Nutr Food Res 2024; 68:e2300414. [PMID: 37991232 DOI: 10.1002/mnfr.202300414] [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: 06/16/2023] [Revised: 08/29/2023] [Indexed: 11/23/2023]
Abstract
SCOPE Astaxanthin (AST) is ubiquitous in aquatic foods and microorganisms. The study previously finds that docosahexaenoic acid-acylated AST monoester (AST-DHA) improves cognitive function in Alzheimer's disease (AD), although the underlying mechanism remains unclear. Moreover, autophagy is reportedly involved in amyloid-β (Aβ) clearance and AD pathogenesis. Therefore, this study aims to evaluate the preventive effect of AST-DHA and elucidates the mechanism of autophagy modulation in Aβ pathology. METHODS AND RESULTS In the cellular AD model, AST-DHA significantly reduces toxic Aβ1-42 levels and alleviated the accumulation of autophagic markers (LC3II/I and p62) in Aβ25-35 -induced SH-SY5Y cells. Notably, AST-DHA restores the autophagic flux in SH-SY5YmRFP-GFP-LC3 cells. In APP/PS1 mice, a 3-month dietary supplementation of AST-DHA exceeded free-astaxanthin (F-AST) capacity to increase hippocampal and cortical autophagy. Mechanistically, AST-DHA restores autophagy by activating the ULK1 signaling pathway and restoring autophagy-lysosome fusion. Moreover, AST-DHA relieves ROS production and mitochondrial stress affecting autophagy in AD. As a favorable outcome of restored autophagy, AST-DHA mitigates cerebral Aβ and p-Tau deposition, ultimately improving neuronal function. CONCLUSION The findings demonstrate that AST-DHA can rectify autophagic impairment in AD, and confer neuroprotection in Aβ-related pathology, which supports the future application of AST as an autophagic inducer for maintaining brain health.
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Affiliation(s)
- Xiaoxu Wang
- A State Key Laboratory of Marine Food Processing & Safety Control, College of Food Science and Engineering, Ocean University of China, No. 1299, Sansha Road, Qingdao, Shandong Province, 266235, China
- College of Marine Life Sciences, Ocean University of China, 5 Yushan Road, Qingdao, Shandong Province, 266003, China
| | - Yu Song
- A State Key Laboratory of Marine Food Processing & Safety Control, College of Food Science and Engineering, Ocean University of China, No. 1299, Sansha Road, Qingdao, Shandong Province, 266235, China
| | - Peixu Cong
- A State Key Laboratory of Marine Food Processing & Safety Control, College of Food Science and Engineering, Ocean University of China, No. 1299, Sansha Road, Qingdao, Shandong Province, 266235, China
| | - Zhigao Wang
- A State Key Laboratory of Marine Food Processing & Safety Control, College of Food Science and Engineering, Ocean University of China, No. 1299, Sansha Road, Qingdao, Shandong Province, 266235, China
| | - Yanjun Liu
- A State Key Laboratory of Marine Food Processing & Safety Control, College of Food Science and Engineering, Ocean University of China, No. 1299, Sansha Road, Qingdao, Shandong Province, 266235, China
- School of Food Science and Technology, Jiangnan University, 1800 Lihu Road, Wuxi, Jiangsu Province, 214122, China
| | - Jie Xu
- A State Key Laboratory of Marine Food Processing & Safety Control, College of Food Science and Engineering, Ocean University of China, No. 1299, Sansha Road, Qingdao, Shandong Province, 266235, China
| | - Changhu Xue
- A State Key Laboratory of Marine Food Processing & Safety Control, College of Food Science and Engineering, Ocean University of China, No. 1299, Sansha Road, Qingdao, Shandong Province, 266235, China
- Qingdao Marine Science and Technology Center, Qingdao, Shandong Province, 266235, China
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22
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Gopar-Cuevas Y, Saucedo-Cardenas O, Loera-Arias MJ, Montes-de-Oca-Luna R, Rodriguez-Rocha H, Garcia-Garcia A. Metformin and Trehalose-Modulated Autophagy Exerts a Neurotherapeutic Effect on Parkinson's Disease. Mol Neurobiol 2023; 60:7253-7273. [PMID: 37542649 DOI: 10.1007/s12035-023-03530-5] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2023] [Accepted: 07/20/2023] [Indexed: 08/07/2023]
Abstract
Since the number of aged people will increase in the next years, neurodegenerative diseases, including Parkinson's Disease (PD), will also rise. Recently, we demonstrated that autophagy stimulation with rapamycin decreases dopaminergic neuronal death mediated by oxidative stress in the paraquat (PQ)-induced PD model. Assessing the neurotherapeutic efficacy of autophagy-inducing molecules is critical for preventing or delaying neurodegeneration. Therefore, we evaluated the autophagy inducers metformin and trehalose effect in a PD model. Autophagy induced by both molecules was confirmed in the SH-SY5Y dopaminergic cells by detecting increased LC3-II marker and autophagosome number compared to the control by western blot and transmission electron microscopy. Both autophagy inducers showed an antioxidant effect, improved mitochondrial activity, and decreased dopaminergic cell death induced by PQ. Next, we evaluated the effect of both inducers in vivo. C57BL6 mice were pretreated with metformin or trehalose before PQ administration. Cognitive and motor deteriorated functions in the PD model were evaluated through the nest building and the gait tests and were prevented by metformin and trehalose. Both autophagy inducers significantly reduced the dopaminergic neuronal loss, astrocytosis, and microgliosis induced by PQ. Also, cell death mediated by PQ was prevented by metformin and trehalose, assessed by TUNEL assay. Metformin and trehalose induced autophagy through AMPK phosphorylation and decreased α-synuclein accumulation. Therefore, metformin and trehalose are promising neurotherapeutic autophagy inducers with great potential for treating neurodegenerative diseases such as PD.
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Affiliation(s)
- Yareth Gopar-Cuevas
- Departamento de Histologia, Facultad de Medicina, Universidad Autonoma de Nuevo Leon, Francisco I. Madero S/N, 64460, Monterrey, Nuevo Leon, Mexico
| | - Odila Saucedo-Cardenas
- Departamento de Histologia, Facultad de Medicina, Universidad Autonoma de Nuevo Leon, Francisco I. Madero S/N, 64460, Monterrey, Nuevo Leon, Mexico
| | - Maria J Loera-Arias
- Departamento de Histologia, Facultad de Medicina, Universidad Autonoma de Nuevo Leon, Francisco I. Madero S/N, 64460, Monterrey, Nuevo Leon, Mexico
| | - Roberto Montes-de-Oca-Luna
- Departamento de Histologia, Facultad de Medicina, Universidad Autonoma de Nuevo Leon, Francisco I. Madero S/N, 64460, Monterrey, Nuevo Leon, Mexico
| | - Humberto Rodriguez-Rocha
- Departamento de Histologia, Facultad de Medicina, Universidad Autonoma de Nuevo Leon, Francisco I. Madero S/N, 64460, Monterrey, Nuevo Leon, Mexico.
| | - Aracely Garcia-Garcia
- Departamento de Histologia, Facultad de Medicina, Universidad Autonoma de Nuevo Leon, Francisco I. Madero S/N, 64460, Monterrey, Nuevo Leon, Mexico.
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23
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Xiang H, Zhou M, Li Y, Zhou L, Wang R. Drug discovery by targeting the protein-protein interactions involved in autophagy. Acta Pharm Sin B 2023; 13:4373-4390. [PMID: 37969735 PMCID: PMC10638514 DOI: 10.1016/j.apsb.2023.07.016] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2023] [Revised: 05/31/2023] [Accepted: 07/10/2023] [Indexed: 11/17/2023] Open
Abstract
Autophagy is a cellular process in which proteins and organelles are engulfed in autophagosomal vesicles and transported to the lysosome/vacuole for degradation. Protein-protein interactions (PPIs) play a crucial role at many stages of autophagy, which present formidable but attainable targets for autophagy regulation. Moreover, selective regulation of PPIs tends to have a lower risk in causing undesired off-target effects in the context of a complicated biological network. Thus, small-molecule regulators, including peptides and peptidomimetics, targeting the critical PPIs involved in autophagy provide a new opportunity for innovative drug discovery. This article provides general background knowledge of the critical PPIs involved in autophagy and reviews a range of successful attempts on discovering regulators targeting those PPIs. Successful strategies and existing limitations in this field are also discussed.
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Affiliation(s)
- Honggang Xiang
- Department of Medicinal Chemistry, School of Pharmacy, Fudan University, Shanghai 201203, China
| | - Mi Zhou
- Department of Medicinal Chemistry, School of Pharmacy, Fudan University, Shanghai 201203, China
| | - Yan Li
- Department of Medicinal Chemistry, School of Pharmacy, Fudan University, Shanghai 201203, China
| | - Lu Zhou
- Department of Medicinal Chemistry, School of Pharmacy, Fudan University, Shanghai 201203, China
| | - Renxiao Wang
- Department of Medicinal Chemistry, School of Pharmacy, Fudan University, Shanghai 201203, China
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24
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Shang R, Miao J. Mechanisms and effects of metformin on skeletal muscle disorders. Front Neurol 2023; 14:1275266. [PMID: 37928155 PMCID: PMC10621799 DOI: 10.3389/fneur.2023.1275266] [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: 08/10/2023] [Accepted: 10/09/2023] [Indexed: 11/07/2023] Open
Abstract
Skeletal muscle disorders are mostly genetic and include several rare diseases. With disease progression, muscle fibrosis and adiposis occur, resulting in limited mobility. The long course of these diseases combined with limited treatment options affect patients both psychologically and economically, hence the development of novel treatments for neuromuscular diseases is crucial to obtain a better quality of life. As a widely used hypoglycemic drug in clinical practice, metformin not only has anti-inflammatory, autophagy-regulating, and mitochondrial biogenesis-regulating effects, but it has also been reported to improve the symptoms of neuromuscular diseases, delay hypokinesia, and regulate skeletal muscle mass. However, metformin's specific mechanism of action in neuromuscular diseases requires further elucidation. This review summarizes the evidence showing that metformin can regulate inflammation, autophagy, and mitochondrial biogenesis through different pathways, and further explores its mechanism of action in Duchenne muscular dystrophy, statin-associated muscle disorders, and age-related sarcopenia. This review clarifies the directions of future research on therapy for neuromuscular diseases.
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Affiliation(s)
| | - Jing Miao
- Department of Neurology, The First Hospital of Jilin University, Changchun, China
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25
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Yang Z, Shi H, Cai G, Jiang S, Hu Z, Wang Z. A Reactive Oxygen Species-Responsive Targeted Nanoscavenger to Promote Mitophagy for the Treatment of Alzheimer's Disease. SMALL (WEINHEIM AN DER BERGSTRASSE, GERMANY) 2023; 19:e2302284. [PMID: 37322535 DOI: 10.1002/smll.202302284] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/17/2023] [Revised: 06/02/2023] [Indexed: 06/17/2023]
Abstract
Mitophagy modulators are proposed as potential therapeutic intervention that enhance neuronal health and brain homeostasis in Alzheimer's disease (AD). Nevertheless, the lack of specific mitophagy inducers, low efficacies, and the severe side effects of nonselective autophagy during AD treatment have hindered their application. In this study, the P@NB nanoscavenger is designed with a reactive-oxygen-species-responsive (ROS-responsive) poly(l-lactide-co-glycolide) core and a surface modified with the Beclin1 and angiopoietin-2 peptides. Notably, nicotinamide adenine dinucleotide (NAD+ ) and Beclin1, which act as mitophagy promoters, are quickly released from P@NB in the presence of high ROS levels in lesions to restore mitochondrial homeostasis and induce microglia polarization toward the M2-type, thereby enabling it to phagocytose amyloid-peptide (Aβ). These studies demonstrate that P@NB accelerates Aβ degradation and alleviates excessive inflammatory responses by restoring autophagic flux, which ameliorates cognitive impairment in AD mice. This multitarget strategy induces autophagy/mitophagy through synergy, thereby normalizing mitochondrial dysfunction. Therefore, the developed method provides a promising AD-therapy strategy.
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Affiliation(s)
- Zhimin Yang
- Fujian Provincial Key Laboratory of Brain Aging and Neurodegenerative Diseases, School of Basic Medical Sciences, Fujian Medical University, Fuzhou, Fujian, 350122, China
- CAS Key Laboratory of Standardization and Measurement for Nanotechnology, CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety, CAS Center for Excellence in Nanoscience, National Center for Nanoscience and Technology, Beijing, 100190, China
| | - Haoyuan Shi
- Fujian Provincial Key Laboratory of Brain Aging and Neurodegenerative Diseases, School of Basic Medical Sciences, Fujian Medical University, Fuzhou, Fujian, 350122, China
- CAS Key Laboratory of Standardization and Measurement for Nanotechnology, CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety, CAS Center for Excellence in Nanoscience, National Center for Nanoscience and Technology, Beijing, 100190, China
| | - Guoen Cai
- Department of Neurology, Fujian Medical University Union Hospital, Fuzhou, 350001, China
| | - Sujun Jiang
- Fujian Provincial Key Laboratory of Brain Aging and Neurodegenerative Diseases, School of Basic Medical Sciences, Fujian Medical University, Fuzhou, Fujian, 350122, China
- CAS Key Laboratory of Standardization and Measurement for Nanotechnology, CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety, CAS Center for Excellence in Nanoscience, National Center for Nanoscience and Technology, Beijing, 100190, China
| | - Zhiyuan Hu
- Fujian Provincial Key Laboratory of Brain Aging and Neurodegenerative Diseases, School of Basic Medical Sciences, Fujian Medical University, Fuzhou, Fujian, 350122, China
- CAS Key Laboratory of Standardization and Measurement for Nanotechnology, CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety, CAS Center for Excellence in Nanoscience, National Center for Nanoscience and Technology, Beijing, 100190, China
- School of Nanoscience and Technology, Sino-Danish College, University of Chinese Academy of Sciences, Beijing, 100049, China
- School of Chemical Engineering and Pharmacy, Wuhan Institute of Technology, Wuhan, 430205, China
| | - Zihua Wang
- Fujian Provincial Key Laboratory of Brain Aging and Neurodegenerative Diseases, School of Basic Medical Sciences, Fujian Medical University, Fuzhou, Fujian, 350122, China
- CAS Key Laboratory of Standardization and Measurement for Nanotechnology, CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety, CAS Center for Excellence in Nanoscience, National Center for Nanoscience and Technology, Beijing, 100190, China
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He X, Li X, Tian W, Li C, Li P, Zhao J, Yang S, Li S. The role of redox-mediated lysosomal dysfunction and therapeutic strategies. Biomed Pharmacother 2023; 165:115121. [PMID: 37418979 DOI: 10.1016/j.biopha.2023.115121] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2023] [Revised: 06/30/2023] [Accepted: 07/01/2023] [Indexed: 07/09/2023] Open
Abstract
Redox homeostasis refers to the dynamic equilibrium between oxidant and reducing agent in the body which plays a crucial role in maintaining normal physiological activities of the body. The imbalance of redox homeostasis can lead to the development of various human diseases. Lysosomes regulate the degradation of cellular proteins and play an important role in influencing cell function and fate, and lysosomal dysfunction is closely associated with the development of various diseases. In addition, several studies have shown that redox homeostasis plays a direct or indirect role in regulating lysosomes. Therefore, this paper systematically reviews the role and mechanisms of redox homeostasis in the regulation of lysosomal function. Therapeutic strategies based on the regulation of redox exerted to disrupt or restore lysosomal function are further discussed. Uncovering the role of redox in the regulation of lysosomes helps to point new directions for the treatment of many human diseases.
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Affiliation(s)
- Xiaomeng He
- Department of Pharmacy, The First Affiliated Hospital of Dalian Medical University, Dalian, China
| | - Xuening Li
- Institute of Clinical Pharmacology, Central South University, Changsha, China
| | - Wei Tian
- The First Affiliated Hospital of Dalian Medical University, Dalian, China
| | - Chenyu Li
- The First Affiliated Hospital of Dalian Medical University, Dalian, China
| | - Pengfei Li
- The First Affiliated Hospital of Dalian Medical University, Dalian, China
| | - Jingyuan Zhao
- The First Affiliated Hospital of Dalian Medical University, Dalian, China.
| | - Shilei Yang
- Department of Pharmacy, The First Affiliated Hospital of Dalian Medical University, Dalian, China.
| | - Shuai Li
- Department of Pharmacy, The First Affiliated Hospital of Dalian Medical University, Dalian, China.
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Wu M, Li Y, Miao Y, Qiao H, Wang Y. Exploring the efficient natural products for Alzheimer's disease therapy via Drosophila melanogaster (fruit fly) models. J Drug Target 2023; 31:817-831. [PMID: 37545435 DOI: 10.1080/1061186x.2023.2245582] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2023] [Revised: 07/11/2023] [Accepted: 07/31/2023] [Indexed: 08/08/2023]
Abstract
Alzheimer's disease (AD) is a grievous neurodegenerative disorder and a major form of senile dementia, which is partially caused by abnormal amyloid-beta peptide deposition and Tau protein phosphorylation. But until now, the exact pathogenesis of AD and its treatment strategy still need to investigate. Fortunately, natural products have shown potential as therapeutic agents for treating symptoms of AD due to their neuroprotective activity. To identify the excellent lead compounds for AD control from natural products of herbal medicines, as well as, detect their modes of action, suitable animal models are required. Drosophila melanogaster (fruit fly) is an important model for studying genetic and cellular biological pathways in complex biological processes. Various Drosophila AD models were broadly used for AD research, especially for the discovery of neuroprotective natural products. This review focused on the research progress of natural products in AD disease based on the fruit fly AD model, which provides a reference for using the invertebrate model in developing novel anti-AD drugs.
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Affiliation(s)
- Mengdi Wu
- School of Pharmaceutical Science and Technology, Tianjin University, Tianjin, China
| | - Ying Li
- School of Pharmaceutical Science and Technology, Tianjin University, Tianjin, China
| | - Yaodong Miao
- Second Affiliated Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Huanhuan Qiao
- Academy of Medical Engineering and Translational Medicine, Tianjin University, Tianjin, China
| | - Yiwen Wang
- School of Pharmaceutical Science and Technology, Tianjin University, Tianjin, China
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Suresh K, Mattern M, Goldberg MS, Butt TR. The Ubiquitin Proteasome System as a Therapeutic Area in Parkinson's Disease. Neuromolecular Med 2023; 25:313-329. [PMID: 36739586 DOI: 10.1007/s12017-023-08738-1] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2022] [Accepted: 01/28/2023] [Indexed: 02/06/2023]
Abstract
Parkinson's disease (PD) is the most common neurodegenerative movement disorder. There are no available therapeutics that slow or halt the progressive loss of dopamine-producing neurons, which underlies the primary clinical symptoms. Currently approved PD drugs can provide symptomatic relief by increasing brain dopamine content or activity; however, the alleviation is temporary, and the effectiveness diminishes with the inevitable progression of neurodegeneration. Discovery and development of disease-modifying neuroprotective therapies has been hampered by insufficient understanding of the root cause of PD-related neurodegeneration. The etiology of PD involves a combination of genetic and environmental factors. Although a single cause has yet to emerge, genetic, cell biological and neuropathological evidence implicates mitochondrial dysfunction and protein aggregation. Postmortem PD brains show pathognomonic Lewy body intraneuronal inclusions composed of aggregated α-synuclein, indicative of failure to degrade misfolded protein. Mutations in the genes that code for α-synuclein, as well as the E3 ubiquitin ligase Parkin, cause rare inherited forms of PD. While many ubiquitin ligases label proteins with ubiquitin chains to mark proteins for degradation by the proteasome, Parkin has been shown to mark dysfunctional mitochondria for degradation by mitophagy. The ubiquitin proteasome system participates in several aspects of the cell's response to mitochondrial damage, affording numerous therapeutic opportunities to augment mitophagy and potentially stop PD progression. This review examines the role and therapeutic potential of such UPS modulators, exemplified by both ubiquitinating and deubiquitinating enzymes.
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Affiliation(s)
- Kumar Suresh
- Progenra Inc., 271A Great Valley Parkway, Malvern, PA, 19355, USA.
| | - Michael Mattern
- Progenra Inc., 271A Great Valley Parkway, Malvern, PA, 19355, USA
| | - Matthew S Goldberg
- Department of Neurology, The University of Alabama at Birmingham, Birmingham, AL, USA
- Center for Neurodegeneration and Experimental Therapeutics, The University of Alabama at Birmingham, Birmingham, AL, USA
- Department of Neurobiology, The University of Alabama at Birmingham, Birmingham, AL, USA
| | - Tauseef R Butt
- Progenra Inc., 271A Great Valley Parkway, Malvern, PA, 19355, USA
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Yu H, Zhong H, Sun J, Li N, Chen J, Shen B, Huang P, Shen X, Huang S, Zhong Y. Molecular signaling from microglia impacts macroglia autophagy and neurons survival in glaucoma. iScience 2023; 26:106839. [PMID: 37250793 PMCID: PMC10213002 DOI: 10.1016/j.isci.2023.106839] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2022] [Revised: 02/01/2023] [Accepted: 05/04/2023] [Indexed: 05/31/2023] Open
Abstract
Interactions between microglia and macroglia play important roles in the neurodegeneration of the central nervous system and so is the situation between microglia and Müller cells in retina neurodegenerations like glaucoma. This study focuses on the roles of microglia-derived osteopontin (OPN) in impacting Müller cells and retinal ganglion cells (RGCs). Rat model and cell pressurization culture were used to simulate glaucoma scenarios. Animals were differently treated with anti-OPN, suppressors of OPN receptors (Itgαvβ3/CD44) or microglia inhibitor minocycline, while isolated retinal Müller cells were accordingly treated with conditioned media from microglia culture pretreated with pressuring, overexpression-OPN, SiR-OPN, or minocycline. SB203580 was introduced to explore the role of p38 MAPK signaling pathway. Results revealed microglia may secret OPN to impact Müller cells' autophagy and RGCs survival via binding to Itgαvβ3/CD44 receptors in glaucomatous neurodegeneration with involvement of p38 MAPK pathway. This discovery may benefit understanding neurodegenerative disorders and exploring therapeutics.
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Affiliation(s)
- Huan Yu
- Department of Ophthalmology, Ruijin Hospital Affiliated Medical School, Shanghai Jiaotong University, 197 Ruijin Er Road, Shanghai 200025, China
| | - Huimin Zhong
- Department of Ophthalmology, Shanghai General Hospital (Shanghai First People’s Hospital), Shanghai Jiao Tong University School of Medicine, Shanghai 200080, China
| | - Jun Sun
- Department of Ophthalmology, Ruijin Hospital Affiliated Medical School, Shanghai Jiaotong University, 197 Ruijin Er Road, Shanghai 200025, China
| | - Na Li
- Department of Ophthalmology, Ruijin Hospital Affiliated Medical School, Shanghai Jiaotong University, 197 Ruijin Er Road, Shanghai 200025, China
| | - Junjue Chen
- Department of Ophthalmology, Ruijin Hospital Affiliated Medical School, Shanghai Jiaotong University, 197 Ruijin Er Road, Shanghai 200025, China
| | - Bingqiao Shen
- Department of Ophthalmology, Ruijin Hospital Affiliated Medical School, Shanghai Jiaotong University, 197 Ruijin Er Road, Shanghai 200025, China
| | - Ping Huang
- Department of Orthopaedics, Shanghai Key Laboratory for Bone and Joint Diseases, Shanghai Institute of Traumatology and Orthopaedics, Ruijin Hospital Affiliated Medical School, Shanghai Jiaotong University, 197 Ruijin Er Road, Shanghai 200025, China
| | - Xi Shen
- Department of Ophthalmology, Ruijin Hospital Affiliated Medical School, Shanghai Jiaotong University, 197 Ruijin Er Road, Shanghai 200025, China
| | - Shouyue Huang
- Department of Ophthalmology, Ruijin Hospital Affiliated Medical School, Shanghai Jiaotong University, 197 Ruijin Er Road, Shanghai 200025, China
| | - Yisheng Zhong
- Department of Ophthalmology, Ruijin Hospital Affiliated Medical School, Shanghai Jiaotong University, 197 Ruijin Er Road, Shanghai 200025, China
- Department of Ophthalmology, Zhoushan Branch of Ruijin Hospital Affiliated Medical School, Shanghai Jiaotong University, Zhoushan, China
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Mubariz F, Saadin A, Lingenfelter N, Sarkar C, Banerjee A, Lipinski MM, Awad O. Deregulation of mTORC1-TFEB axis in human iPSC model of GBA1-associated Parkinson's disease. Front Neurosci 2023; 17:1152503. [PMID: 37332877 PMCID: PMC10272450 DOI: 10.3389/fnins.2023.1152503] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2023] [Accepted: 05/02/2023] [Indexed: 06/20/2023] Open
Abstract
Mutations in the GBA1 gene are the single most frequent genetic risk factor for Parkinson's disease (PD). Neurodegenerative changes in GBA1-associated PD have been linked to the defective lysosomal clearance of autophagic substrates and aggregate-prone proteins. To elucidate novel mechanisms contributing to proteinopathy in PD, we investigated the effect of GBA1 mutations on the transcription factor EB (TFEB), the master regulator of the autophagy-lysosomal pathway (ALP). Using PD patients' induced-pluripotent stem cells (iPSCs), we examined TFEB activity and regulation of the ALP in dopaminergic neuronal cultures generated from iPSC lines harboring heterozygous GBA1 mutations and the CRISPR/Cas9-corrected isogenic controls. Our data showed a significant decrease in TFEB transcriptional activity and attenuated expression of many genes in the CLEAR network in GBA1 mutant neurons, but not in the isogenic gene-corrected cells. In PD neurons, we also detected increased activity of the mammalian target of rapamycin complex1 (mTORC1), the main upstream negative regulator of TFEB. Increased mTORC1 activity resulted in excess TFEB phosphorylation and decreased nuclear translocation. Pharmacological mTOR inhibition restored TFEB activity, decreased ER stress and reduced α-synuclein accumulation, indicating improvement of neuronal protiostasis. Moreover, treatment with the lipid substrate reducing compound Genz-123346, decreased mTORC1 activity and increased TFEB expression in the mutant neurons, suggesting that mTORC1-TFEB alterations are linked to the lipid substrate accumulation. Our study unveils a new mechanism contributing to PD susceptibility by GBA1 mutations in which deregulation of the mTORC1-TFEB axis mediates ALP dysfunction and subsequent proteinopathy. It also indicates that pharmacological restoration of TFEB activity could be a promising therapeutic approach in GBA1-associated neurodegeneration.
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Affiliation(s)
- Fahad Mubariz
- Department of Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, MD, United States
| | - Afsoon Saadin
- Department of Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, MD, United States
| | - Nicholas Lingenfelter
- Department of Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, MD, United States
| | - Chinmoy Sarkar
- Department of Anesthesiology, University of Maryland School of Medicine, Baltimore, MD, United States
| | - Aditi Banerjee
- Department of Pediatrics, University of Maryland School of Medicine, Baltimore, MD, United States
| | - Marta M. Lipinski
- Department of Anesthesiology, University of Maryland School of Medicine, Baltimore, MD, United States
- Department of Anatomy and Neurobiology, University of Maryland School of Medicine, Baltimore, MD, United States
| | - Ola Awad
- Department of Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, MD, United States
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Liu C, Shi R, Liu Y, Zhao X, Zhang X, Wang H, Wu L, Shang X. Low-frequency transcranial magnetic stimulation protects cognition in mice with chronic unpredictable mild stress through autophagy regulation. Behav Brain Res 2023; 444:114366. [PMID: 36854362 DOI: 10.1016/j.bbr.2023.114366] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2022] [Revised: 01/29/2023] [Accepted: 02/25/2023] [Indexed: 02/27/2023]
Abstract
Although transcranial magnetic stimulation (TMS) has been approved for the treatment of major depression, few studies have analyzed the ability of low-frequency TMS (LF-TMS) to treat depressive symptoms. Our study confirmed that LF-TMS protects the cognitive function,which can play a certain reference role in the future clinical treatment. The effectiveness of high-frequency TMS therapy has been well documented. However, the use of low-frequency TMS (LF-TMS) in the treatment of depression is rarely reported. This study aims to evaluate whether LF-TMS can reverse depression-induced cognitive impairment. We created a mouse model of depression using the chronic unpredictable mild stress (CUMS) paradigm. Male C57BL/6J mice,6-8 weeks old,were randomly divided into four groups: a CON (control) group, a CUMS group, a CUMS+LF-TMS group, and a CUMS+LF-TMS+RAP (rapamycin) group. The CUMS was maintained for 28 days. LF-TMS (1 Hz) and Rap were administered for 28 days from the first day of CUMS. The mice in all groups except the control demonstrated evidence of anhedonia, anxiety, and cognitive decline on behavioral tests during the four weeks of CUMS.All the experiments were carried out under a 12-h light/dark cycle (lights on at 7 a.m.) except for the dark/light cycle reversal stimulation of CUMS. LF-TMS at 20 Mt, 1 Hz for 1 min alleviated damage to spatial cognition and synaptic plasticity in the hippocampus. Western blot analysis showed that LF-TMS reduced the down-regulation of autophagy signals in the CUMS+LF-TMS group, and enhanced the expression of synaptic plasticity-related factors, thereby improving the spatial cognitive impairment resulting from the CUMS. We concluded that LF-TMS can effectively relieve depressive behavior and cognitive dysfunction in mice subjected to CUMS by regulating autophagy signals and synaptic proteins.
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Affiliation(s)
- Chuan Liu
- School of Psychology and Mental Health, North China University of Science and Technology, 21 Bohai Road, Tang'shan 063210, Hebei Province, PR China; College of Basic Medical Sciences, North China University of Science and Technology, 21 Bohai Road, Tang'shan 063210, Hebei Province, PR China
| | - Ruidie Shi
- School of Psychology and Mental Health, North China University of Science and Technology, 21 Bohai Road, Tang'shan 063210, Hebei Province, PR China
| | - Yuting Liu
- School of Psychology and Mental Health, North China University of Science and Technology, 21 Bohai Road, Tang'shan 063210, Hebei Province, PR China
| | - Xiangwei Zhao
- School of Psychology and Mental Health, North China University of Science and Technology, 21 Bohai Road, Tang'shan 063210, Hebei Province, PR China
| | - Xiujun Zhang
- School of Psychology and Mental Health, North China University of Science and Technology, 21 Bohai Road, Tang'shan 063210, Hebei Province, PR China.
| | - Haitao Wang
- School of Psychology and Mental Health, North China University of Science and Technology, 21 Bohai Road, Tang'shan 063210, Hebei Province, PR China; College of Basic Medical Sciences, North China University of Science and Technology, 21 Bohai Road, Tang'shan 063210, Hebei Province, PR China.
| | - Lei Wu
- School of Psychology and Mental Health, North China University of Science and Technology, 21 Bohai Road, Tang'shan 063210, Hebei Province, PR China.
| | - Xueliang Shang
- School of Psychology and Mental Health, North China University of Science and Technology, 21 Bohai Road, Tang'shan 063210, Hebei Province, PR China.
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Diab R, Pilotto F, Saxena S. Autophagy and neurodegeneration: Unraveling the role of C9ORF72 in the regulation of autophagy and its relationship to ALS-FTD pathology. Front Cell Neurosci 2023; 17:1086895. [PMID: 37006471 PMCID: PMC10060823 DOI: 10.3389/fncel.2023.1086895] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2022] [Accepted: 03/01/2023] [Indexed: 03/18/2023] Open
Abstract
The proper functioning of the cell clearance machinery is critical for neuronal health within the central nervous system (CNS). In normal physiological conditions, the cell clearance machinery is actively involved in the elimination of misfolded and toxic proteins throughout the lifetime of an organism. The highly conserved and regulated pathway of autophagy is one of the important processes involved in preventing and neutralizing pathogenic buildup of toxic proteins that could eventually lead to the development of neurodegenerative diseases (NDs) such as Alzheimer’s disease or Amyotrophic lateral sclerosis (ALS). The most common genetic cause of ALS and frontotemporal dementia (FTD) is a hexanucleotide expansion consisting of GGGGCC (G4C2) repeats in the chromosome 9 open reading frame 72 gene (C9ORF72). These abnormally expanded repeats have been implicated in leading to three main modes of disease pathology: loss of function of the C9ORF72 protein, the generation of RNA foci, and the production of dipeptide repeat proteins (DPRs). In this review, we discuss the normal physiological role of C9ORF72 in the autophagy-lysosome pathway (ALP), and present recent research deciphering how dysfunction of the ALP synergizes with C9ORF72 haploinsufficiency, which together with the gain of toxic mechanisms involving hexanucleotide repeat expansions and DPRs, drive the disease process. This review delves further into the interactions of C9ORF72 with RAB proteins involved in endosomal/lysosomal trafficking, and their role in regulating various steps in autophagy and lysosomal pathways. Lastly, the review aims to provide a framework for further investigations of neuronal autophagy in C9ORF72-linked ALS-FTD as well as other neurodegenerative diseases.
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Affiliation(s)
- Rim Diab
- Department of Neurology, Center for Experimental Neurology, Inselspital University Hospital, Bern, Switzerland
- Department for BioMedical Research (DBMR), University of Bern, Bern, Switzerland
| | - Federica Pilotto
- Department of Neurology, Center for Experimental Neurology, Inselspital University Hospital, Bern, Switzerland
- Department for BioMedical Research (DBMR), University of Bern, Bern, Switzerland
| | - Smita Saxena
- Department of Neurology, Center for Experimental Neurology, Inselspital University Hospital, Bern, Switzerland
- Department for BioMedical Research (DBMR), University of Bern, Bern, Switzerland
- *Correspondence: Smita Saxena,
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Rahman MM, Islam MR, Alam Tumpa MA, Shohag S, Shakil Khan Shuvo, Ferdous J, Kajol SA, Aljohani ASM, Al Abdulmonem W, Rauf A, Thiruvengadam M. Insights into the promising prospect of medicinal chemistry studies against neurodegenerative disorders. Chem Biol Interact 2023; 373:110375. [PMID: 36739931 DOI: 10.1016/j.cbi.2023.110375] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2022] [Revised: 12/06/2022] [Accepted: 01/30/2023] [Indexed: 02/05/2023]
Abstract
Medicinal chemistry is an interdisciplinary field that incorporates organic chemistry, biochemistry, physical chemistry, pharmacology, informatics, molecular biology, structural biology, cell biology, and other disciplines. Additionally, it considers molecular factors such as the mode of action of the drugs, their chemical structure-activity relationship (SAR), and pharmacokinetic aspects like absorption, distribution, metabolism, elimination, and toxicity. Neurodegenerative disorders (NDs), which are defined by the breakdown of neurons over time, are affecting an increasing number of people. Oxidative stress, particularly the increased production of Reactive Oxygen Species (ROS), plays a crucial role in the growth of various disorders, as indicated by the identification of protein, lipid, and Deoxyribonucleic acid (DNA) oxidation products in vivo. Because of their inherent nature, most biological molecules are vulnerable to ROS, even if they play a role in metabolic parameters and cell signaling. Due to their high polyunsaturated fatty acid content, low antioxidant barrier, and high oxygen uptake, neurons are particularly vulnerable to oxidation by nature. As a result, excessive ROS generation in neurons looks especially harmful, and the mechanisms associated with biomolecule oxidative destruction are several and complex. This review focuses on the formation and management of ROS, as well as their chemical characteristics (both thermodynamic and kinetic), interactions, and implications in NDs.
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Affiliation(s)
- Md Mominur Rahman
- Department of Pharmacy, Faculty of Allied Health Sciences, Daffodil International University, Dhaka, 1207, Bangladesh
| | - Md Rezaul Islam
- Department of Pharmacy, Faculty of Allied Health Sciences, Daffodil International University, Dhaka, 1207, Bangladesh
| | - Mst Afroza Alam Tumpa
- Department of Pharmacy, Faculty of Allied Health Sciences, Daffodil International University, Dhaka, 1207, Bangladesh
| | - Sheikh Shohag
- Department of Veterinary Medicine, College of Agriculture and Veterinary Medicine, Qassim University Buraydah, 52571, Saudi Arabia
| | - Shakil Khan Shuvo
- Department of Pharmacy, Faculty of Allied Health Sciences, Daffodil International University, Dhaka, 1207, Bangladesh
| | - Jannatul Ferdous
- Department of Pharmacy, Faculty of Allied Health Sciences, Daffodil International University, Dhaka, 1207, Bangladesh
| | - Saima Akter Kajol
- Department of Pharmacy, Faculty of Allied Health Sciences, Daffodil International University, Dhaka, 1207, Bangladesh
| | - Abdullah S M Aljohani
- Department of Veterinary Medicine, College of Agriculture and Veterinary Medicine, Qassim University Buraydah, 52571, Saudi Arabia
| | - Waleed Al Abdulmonem
- Department of Pathology, College of Medicine Qassim University, Buraydah, Saudi Arabia
| | - Abdur Rauf
- Department of Chemistry, University of Swabi, Swabi, Anbar, 23430, Khyber Pakhtunkhwa (KP), Pakistan.
| | - Muthu Thiruvengadam
- Department of Applied Bioscience, College of Life and Environmental Sciences, Konkuk University, Seoul, 05029, South Korea; Department of Microbiology, Saveetha Dental College and Hospitals, Saveetha Institute of Medical and Technical Sciences, Saveetha University, Chennai, 600077, Tamil Nadu, India.
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Huh S, Yu HS, Kang N, Ahn YM, Kim YS, Kim SH. Electroconvulsive Seizure Normalizes Motor Deficits and Induces Autophagy Signaling in the MPTP-Induced Parkinson Disease Mouse Model. Psychiatry Investig 2023; 20:273-283. [PMID: 36990671 PMCID: PMC10064206 DOI: 10.30773/pi.2022.0327] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/10/2022] [Accepted: 01/11/2022] [Indexed: 03/31/2023] Open
Abstract
OBJECTIVE Electroconvulsive seizure (ECS) is a potent treatment modality for various neuropsychiatric diseases, including Parkinson disease (PD). Recent animal studies showed that repeated ECS activates autophagy signaling, the impairment of which is known to be involved in PD. However, the effectiveness of ECS on PD and its therapeutic mechanisms have not yet been investigated in detail. METHODS Systemic injection of a neurotoxin 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine hydrochloride (MPTP), which destroys dopaminergic neurons in the substantia nigra compacta (SNc), in mice was utilized to induce an animal model of PD. Mice were treated with ECS 3 times per week for 2 weeks. Behavioral changes were measured with a rotarod test. Molecular changes related to autophagy signaling in midbrain including SNc, striatum, and prefrontal cortex were analyzed with immunohistochemistry and immunoblot analyses. RESULTS Repeated ECS treatments normalized the motor deficits and the loss of dopamiergic neurons in SNc of the MPTP PD mouse model. In the mouse model, LC3-II, an autophagy marker, was increased in midbrain while decreased in prefrontal cortex, both of which were reversed by repeated ECS treatments. In the prefrontal cortex, ECS-induced LC3-II increase was accompanied with AMP-activated protein kinase (AMPK)-Unc-51-like kinase 1-Beclin1 pathway activation and inhibition of mamalian target of rapamycin signaling which promotes autophagy initiation. CONCLUSION The findings revealed the therapeutic effects of repeated ECS treatments on PD, which could be attributed to the neuroprotective effect of ECS mediated by AMPK-autophagy signaling.
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Affiliation(s)
- Seonghoo Huh
- Biomedical Research Institute, Seoul National University Hospital, Seoul, Republic of Korea
| | - Hyun Sook Yu
- Biomedical Research Institute, Seoul National University Hospital, Seoul, Republic of Korea
| | - Nuree Kang
- Department of Psychiatry, Gyeongsang National University Hospital, Jinju, Republic of Korea
| | - Yong Min Ahn
- Biomedical Research Institute, Seoul National University Hospital, Seoul, Republic of Korea
- Department of Psychiatry, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Yong Sik Kim
- Department of Psychiatry, Nowon Eulji Meical Center, Eulji University, Seoul, Republic of Korea
| | - Se Hyun Kim
- Biomedical Research Institute, Seoul National University Hospital, Seoul, Republic of Korea
- Department of Psychiatry, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Republic of Korea
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Peng X, Luo R, Ran X, Guo Y, Yao YG, Qiu M. Ganoapplins A and B with an unprecedented 6/6/6/5/6-fused pentacyclic skeleton from Ganoderma inhibit Tau pathology through activating autophagy. Bioorg Chem 2023; 132:106375. [PMID: 36682148 DOI: 10.1016/j.bioorg.2023.106375] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2022] [Revised: 11/28/2022] [Accepted: 01/12/2023] [Indexed: 01/19/2023]
Abstract
Ganoapplins A and B (1 and 2) with a 6/6/6/5/6-fused pentacyclic skeleton containing an aromatic E ring, were obtained from Ganoderma applanatum. Their structures were established through extensive spectroscopic analyses, quantum chemical calculations, including calculated chemical shifts with DP4 + analysis and electronic circular dichroism (ECD). A plausible biosynthetic pathway for 1 and 2 was proposed. Furthermore, their roles in activating autophagy were investigated and the cellular assays showed that 1 and 2 can inhibit tau pathology by inducing autophagy, suggesting their potential against Alzheimer's disease (AD).
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Affiliation(s)
- Xingrong Peng
- State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Science, Kunming 650201, China; Kunming College of Life Science, University of Chinese Academy of Sciences, Kunming, Yunnan 650204, China
| | - Rongcan Luo
- Kunming College of Life Science, University of Chinese Academy of Sciences, Kunming, Yunnan 650204, China; Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences & Yunnan Province, and KIZ-CUHK Joint Laboratory of Bioresources and Molecular Research in Common Diseases, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming 650204, China
| | - Xiaoqian Ran
- Kunming College of Life Science, University of Chinese Academy of Sciences, Kunming, Yunnan 650204, China; Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences & Yunnan Province, and KIZ-CUHK Joint Laboratory of Bioresources and Molecular Research in Common Diseases, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming 650204, China
| | - Yarong Guo
- School of Life Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230026, China
| | - Yong-Gang Yao
- Kunming College of Life Science, University of Chinese Academy of Sciences, Kunming, Yunnan 650204, China; Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences & Yunnan Province, and KIZ-CUHK Joint Laboratory of Bioresources and Molecular Research in Common Diseases, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming 650204, China; CAS Center for Excellence in Brain Science and Intelligence Technology, Chinese Academy of Sciences, Shanghai 200031, China.
| | - Minghua Qiu
- State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Science, Kunming 650201, China; Kunming College of Life Science, University of Chinese Academy of Sciences, Kunming, Yunnan 650204, China.
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Roşianu F, Mihaylov SR, Eder N, Martiniuc A, Claxton S, Flynn HR, Jalal S, Domart MC, Collinson L, Skehel M, Snijders AP, Krause M, Tooze SA, Ultanir SK. Loss of NDR1/2 kinases impairs endomembrane trafficking and autophagy leading to neurodegeneration. Life Sci Alliance 2023; 6:6/2/e202201712. [PMID: 36446521 PMCID: PMC9711861 DOI: 10.26508/lsa.202201712] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2022] [Revised: 10/28/2022] [Accepted: 11/01/2022] [Indexed: 11/30/2022] Open
Abstract
Autophagy is essential for neuronal development and its deregulation contributes to neurodegenerative diseases. NDR1 and NDR2 are highly conserved kinases, implicated in neuronal development, mitochondrial health and autophagy, but how they affect mammalian brain development in vivo is not known. Using single and double Ndr1/2 knockout mouse models, we show that only dual loss of Ndr1/2 in neurons causes neurodegeneration. This phenotype was present when NDR kinases were deleted both during embryonic development, as well as in adult mice. Proteomic and phosphoproteomic comparisons between Ndr1/2 knockout and control brains revealed novel kinase substrates and indicated that endocytosis is significantly affected in the absence of NDR1/2. We validated the endocytic protein Raph1/Lpd1, as a novel NDR1/2 substrate, and showed that both NDR1/2 and Raph1 are critical for endocytosis and membrane recycling. In NDR1/2 knockout brains, we observed prominent accumulation of transferrin receptor, p62 and ubiquitinated proteins, indicative of a major impairment of protein homeostasis. Furthermore, the levels of LC3-positive autophagosomes were reduced in knockout neurons, implying that reduced autophagy efficiency mediates p62 accumulation and neurotoxicity. Mechanistically, pronounced mislocalisation of the transmembrane autophagy protein ATG9A at the neuronal periphery, impaired axonal ATG9A trafficking and increased ATG9A surface levels further confirm defects in membrane trafficking, and could underlie the impairment in autophagy. We provide novel insight into the roles of NDR1/2 kinases in maintaining neuronal health.
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Affiliation(s)
- Flavia Roşianu
- Kinases and Brain Development Laboratory, The Francis Crick Institute, London, UK
| | - Simeon R Mihaylov
- Kinases and Brain Development Laboratory, The Francis Crick Institute, London, UK
| | - Noreen Eder
- Kinases and Brain Development Laboratory, The Francis Crick Institute, London, UK
| | - Antonie Martiniuc
- Kinases and Brain Development Laboratory, The Francis Crick Institute, London, UK
| | - Suzanne Claxton
- Kinases and Brain Development Laboratory, The Francis Crick Institute, London, UK
| | - Helen R Flynn
- Mass Spectrometry Proteomics Science Technology Platform, The Francis Crick Institute, London, UK
| | - Shamsinar Jalal
- Randall Centre for Cell and Molecular Biophysics, King's College London, London, UK
| | - Marie-Charlotte Domart
- Electron Microscopy Science Technology Platform, The Francis Crick Institute, London, UK
| | - Lucy Collinson
- Electron Microscopy Science Technology Platform, The Francis Crick Institute, London, UK
| | - Mark Skehel
- Mass Spectrometry Proteomics Science Technology Platform, The Francis Crick Institute, London, UK
| | - Ambrosius P Snijders
- Mass Spectrometry Proteomics Science Technology Platform, The Francis Crick Institute, London, UK
| | - Matthias Krause
- Randall Centre for Cell and Molecular Biophysics, King's College London, London, UK
| | - Sharon A Tooze
- Molecular Cell Biology of Autophagy Laboratory, The Francis Crick Institute, London, UK
| | - Sila K Ultanir
- Kinases and Brain Development Laboratory, The Francis Crick Institute, London, UK
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37
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Fang Q, Zheng S, Chen Q, Chen L, Yang Y, Wang Y, Zhang H, Chen J. The protective effect of inhibiting mitochondrial fission on the juvenile rat brain following PTZ kindling through inhibiting the BCL2L13/LC3 mitophagy pathway. Metab Brain Dis 2023; 38:453-466. [PMID: 36094724 DOI: 10.1007/s11011-022-01077-3] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/18/2022] [Accepted: 08/30/2022] [Indexed: 02/04/2023]
Abstract
Maintaining the balance of mitochondrial fission and mitochondrial autophagy on seizures is helpful to find a solution to control seizures and reduce brain injuries. The present study is to investigate the protective effect of inhibiting mitochondrial fission on brain injury in juvenile rat epilepsy induced by pentatetrazol (PTZ) by inhibiting the BCL2L13/LC3-mediated mitophagy pathway. PTZ was injected (40 mg/kg) to induce kindling once every other day, for a total of 15 times. In the PTZ + DMSO (DMSO), PTZ + Mdivi-1 (Mdivi-1), and PTZ + WY14643 (WY14643) groups, rats were pretreated with DMSO, Mdivi-1 and WY14643 for half an hour prior to PTZ injection. The seizure attacks of young rats were observed for 30 min after model establishment. The Morris water maze (MWM) was used to test the cognition of experimental rats. After the test, the numbers of NeuN(+) neurons and GFAP(+) astrocytes were observed and counted by immunofluorescence (IF). The protein expression levels of Drp1, BCL2L13, LC3 and caspase 3 in the hippocampus of young rats were detected by immunohistochemistry (IHC) and Western blotting (WB). Compared with the PTZ and DMSO groups, the seizure latency in the Mdivi-1 group was longer (P < 0.01), and the severity degree and frequency of seizures were lower (P < 0.01). The MWM test showed that the incubation periods of crossing the platform in the Mdivi-1 group was significantly shorter. The number of platform crossings, the platform stay time, and the ratio of residence time/total stay time were significantly increased in the Mdivi-1 group (P < 0.01). The IF results showed that the number of NeuN(+) neurons in the Mdivi-1 group was greater, while the number of GFAP(+) astrocytes was lower. IHC and WB showed that the average optical density (AOD) and relative protein expression levels of Drp1, BCL2L13, LC3 and caspase 3 in the hippocampi of rats in the Mdivi-1 group were higher (P < 0.05). The above results in the WY14643 group were opposite to those in the Mdivi-1 group. Inhibition of mitochondrial fission could reduce seizure attacks, protect injured neurons, and improve cognition following PTZ-induced epilepsy by inhibiting mitochondrial autophagy mediated by the BCL2L13/LC3 mitophagy pathway.
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Affiliation(s)
- Qiong Fang
- Department of Pediatrics, Fujian Provincial Hospital, Shengli Clinical Medical College of Fujian Medical University, 134 East Street, Gulou District, Fuzhou, 350001, Fujian Province, China.
| | - Shaojuan Zheng
- Department of Pediatrics, Fujian Provincial Hospital, Shengli Clinical Medical College of Fujian Medical University, 134 East Street, Gulou District, Fuzhou, 350001, Fujian Province, China
| | - Qiaobin Chen
- Department of Pediatrics, Fujian Provincial Hospital, Shengli Clinical Medical College of Fujian Medical University, 134 East Street, Gulou District, Fuzhou, 350001, Fujian Province, China.
| | - Lang Chen
- Department of Pediatrics, Fujian Provincial Hospital, Shengli Clinical Medical College of Fujian Medical University, 134 East Street, Gulou District, Fuzhou, 350001, Fujian Province, China
| | - Yating Yang
- Department of Pediatrics, Fujian Provincial Hospital, Shengli Clinical Medical College of Fujian Medical University, 134 East Street, Gulou District, Fuzhou, 350001, Fujian Province, China
| | - Ying Wang
- Department of clinical medicine, Fujian Medical University, Fuzhou, 350001, Fujian Province, China
| | - Huixia Zhang
- Department of clinical medicine, Fujian Medical University, Fuzhou, 350001, Fujian Province, China
| | - Jiafan Chen
- Department of clinical medicine, Fujian Medical University, Fuzhou, 350001, Fujian Province, China
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38
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Dou C, Zhang Y, Zhang L, Qin C. Autophagy and autophagy-related molecules in neurodegenerative diseases. Animal Model Exp Med 2023; 6:10-17. [PMID: 35730702 PMCID: PMC9986236 DOI: 10.1002/ame2.12229] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2021] [Revised: 03/18/2022] [Accepted: 03/27/2022] [Indexed: 11/07/2022] Open
Abstract
Autophagy is one of the degradation pathways to remove proteins or damaged organelles in cells that plays an important role in neuroprotection. Different stages of autophagy are regulated by autophagy-related genes, and many molecules such as transcription factor EB (TFEB) are involved. The complete autophagy process plays an important role in maintaining the dynamic balance of autophagy and is crucial to the homeostasis of intracellular substance and energy metabolism. Autophagy balance is disrupted in neurodegenerative diseases, accounting for a variety of degeneration disorders. These impairments can be alleviated or treated by the regulation of autophagy through molecules such as TFEB.
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Affiliation(s)
- Changsong Dou
- NHC Key Laboratory of Human Disease Comparative Medicine, Key Laboratory of Human Diseases Animal Model, Institute of Laboratory Animal Sciences, Comparative Medicine Center, Peking Union Medical College (PUMC), Chinese Academy of Medical Sciences (CAMS), Beijing, China.,Beijing Engineering Research Center for Experimental Animal Models of Human Critical Diseases Beijing, Comparative Medicine Center, Peking Union Medical College (PUMC), Chinese Academy of Medical Sciences (CAMS), Beijing, China
| | - Yu Zhang
- NHC Key Laboratory of Human Disease Comparative Medicine, Key Laboratory of Human Diseases Animal Model, Institute of Laboratory Animal Sciences, Comparative Medicine Center, Peking Union Medical College (PUMC), Chinese Academy of Medical Sciences (CAMS), Beijing, China.,Beijing Engineering Research Center for Experimental Animal Models of Human Critical Diseases Beijing, Comparative Medicine Center, Peking Union Medical College (PUMC), Chinese Academy of Medical Sciences (CAMS), Beijing, China
| | - Ling Zhang
- NHC Key Laboratory of Human Disease Comparative Medicine, Key Laboratory of Human Diseases Animal Model, Institute of Laboratory Animal Sciences, Comparative Medicine Center, Peking Union Medical College (PUMC), Chinese Academy of Medical Sciences (CAMS), Beijing, China.,Beijing Engineering Research Center for Experimental Animal Models of Human Critical Diseases Beijing, Comparative Medicine Center, Peking Union Medical College (PUMC), Chinese Academy of Medical Sciences (CAMS), Beijing, China
| | - Chuan Qin
- NHC Key Laboratory of Human Disease Comparative Medicine, Key Laboratory of Human Diseases Animal Model, Institute of Laboratory Animal Sciences, Comparative Medicine Center, Peking Union Medical College (PUMC), Chinese Academy of Medical Sciences (CAMS), Beijing, China.,Beijing Engineering Research Center for Experimental Animal Models of Human Critical Diseases Beijing, Comparative Medicine Center, Peking Union Medical College (PUMC), Chinese Academy of Medical Sciences (CAMS), Beijing, China
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Ran X, Lu QY, Li YY, Pu XX, Guo Y, Yuan MR, Guan SP, Sun M, Jiao L, Yao YG, Di YT, Hao XJ, Luo R. Euphejolkinolide A, a new ent-abietane lactone from Euphorbia peplus L. with promising biological activity in activating the autophagy-lysosomal pathway. Heliyon 2023; 9:e13691. [PMID: 36852065 PMCID: PMC9958456 DOI: 10.1016/j.heliyon.2023.e13691] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2022] [Revised: 02/04/2023] [Accepted: 02/07/2023] [Indexed: 02/15/2023] Open
Abstract
A new ent-abietane diterpenoid, named Euphejolkinolide A (1), was isolated from the whole plant of Euphorbia peplus L. Its structure, including absolute configurations, was determined by spectroscopic analyses and was corroborated by single-crystal X-ray diffraction analysis. This new compound was assessed for its activity to induce lysosome biogenesis through Lyso-Tracker Red staining, in which compound 1 could significantly induce lysosome biogenesis. In addition, quantitative real-time PCR (qRT-PCR) analysis demonstrated a direct correlation between the observed lysosome biogenesis and the transcriptional activation of the lysosomal genes after treatment with the compound 1. Moreover, compound 1 promoted autophagic flux by upregulating LC3-II and downregulating SQSTM1 in both human microglia cells and U251 cells, which is required for cellular homeostasis. Further results suggested 1 induced lysosome biogenesis and autophagy which was mediated by TFEB (transcription factor EB). The structure activity relationships (SAR) analysis suggested that the carbony1 at C-7 in 1 might be a key active group. Overall, the current data suggested that 1 could be a potential compound for lysosome disorder therapy by induction of autophagy.
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Affiliation(s)
- Xiaoqian Ran
- Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences & Yunnan Province, KIZ-CUHK Joint Laboratory of Bioresources and Molecular Research in Common Diseases, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, 650204, China.,Kunming College of Life Science, University of Chinese Academy of Sciences, Kunming, Yunnan, 650204, China
| | - Qing-Yun Lu
- State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming, 650201, China
| | - Ying-Yao Li
- College of Life Sciences, Yunnan University, Kunming, 650091, China
| | - Xue-Xue Pu
- College of Traditional Medicine, Yunnan University of Chinese Medicine, Kunming, 650500, China
| | - Yarong Guo
- Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences & Yunnan Province, KIZ-CUHK Joint Laboratory of Bioresources and Molecular Research in Common Diseases, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, 650204, China.,School of Life Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, 230026, China
| | - Ming-Rui Yuan
- State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming, 650201, China
| | - Shi-Peng Guan
- College of Traditional Medicine, Yunnan University of Chinese Medicine, Kunming, 650500, China
| | - Mao Sun
- State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming, 650201, China
| | - Lijin Jiao
- Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences & Yunnan Province, KIZ-CUHK Joint Laboratory of Bioresources and Molecular Research in Common Diseases, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, 650204, China.,Kunming College of Life Science, University of Chinese Academy of Sciences, Kunming, Yunnan, 650204, China
| | - Yong-Gang Yao
- Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences & Yunnan Province, KIZ-CUHK Joint Laboratory of Bioresources and Molecular Research in Common Diseases, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, 650204, China.,Kunming College of Life Science, University of Chinese Academy of Sciences, Kunming, Yunnan, 650204, China.,CAS Center for Excellence in Brain Science and Intelligence Technology, Chinese Academy of Sciences, Shanghai, 200031, China
| | - Ying-Tong Di
- State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming, 650201, China.,Kunming College of Life Science, University of Chinese Academy of Sciences, Kunming, Yunnan, 650204, China.,College of Traditional Medicine, Yunnan University of Chinese Medicine, Kunming, 650500, China
| | - Xiao-Jiang Hao
- State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming, 650201, China.,Yunnan Key Laboratory of Natural Medicinal Chemistry, Kunming, Yunnan, 650201, China.,Guizhou Chemical Drug Research and Development Engineering Technical Center, Guizhou Medicinal University, Guiyang, 550004, China
| | - Rongcan Luo
- Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences & Yunnan Province, KIZ-CUHK Joint Laboratory of Bioresources and Molecular Research in Common Diseases, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, 650204, China.,Kunming College of Life Science, University of Chinese Academy of Sciences, Kunming, Yunnan, 650204, China
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40
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Yan Y, Ran X, Wang D, Zhang X, Peng M, Yan X, Tang L, Liang H, Qin X, Di YT, Luo R, Hao XJ, Yao YG. Munronin V with 7/7/6 tricarbocyclic framework from Munronia henryi harms inhibits tau pathology by activating autophagy. Org Biomol Chem 2023; 21:514-519. [PMID: 36594355 DOI: 10.1039/d2ob01965e] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Munronin V (1), isolated from Munronia henryi Harms, is the first example, to the best of our knowledge, of an unprecedented 7/7/6 tricarbocyclic framework featuring an unusual A,B-seco-limonoid ring. The structures of munronin V were established from extensive spectroscopic and electronic circular dichroism (ECD) analyses. The novel A,B-seco with two seven-membered lactones was formed as a result of Baeyer-Villiger oxidation. Compound 1 activated autophagy and inhibited Tau pathology as revealed by flow cytometric analyses, confocal imaging analysis and western blotting, and this effect was mediated by transcription factor EB (TFEB). These findings suggested that 1 might have potential as a compound for combating Alzheimer's disease.
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Affiliation(s)
- Ying Yan
- State Key Laboratory of Functions and Applications of Medicinal Plants & College of Pharmacy, Guizhou Provincial Engineering Technology Research Center for Chemical Drug R&D, Guizhou Medical University, Guiyang 550014, China
| | - Xiaoqian Ran
- Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences & Yunnan Province, KIZ-CUHK Joint Laboratory of Bioresources and Molecular Research in Common Diseases, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming 650204, China. .,Kunming College of Life Science, University of Chinese Academy of Sciences, Kunming, Yunnan 650204, China
| | - Dan Wang
- State Key Laboratory of Functions and Applications of Medicinal Plants & College of Pharmacy, Guizhou Provincial Engineering Technology Research Center for Chemical Drug R&D, Guizhou Medical University, Guiyang 550014, China
| | - Xiong Zhang
- State Key Laboratory of Functions and Applications of Medicinal Plants & College of Pharmacy, Guizhou Provincial Engineering Technology Research Center for Chemical Drug R&D, Guizhou Medical University, Guiyang 550014, China
| | - Mingyou Peng
- State Key Laboratory of Functions and Applications of Medicinal Plants & College of Pharmacy, Guizhou Provincial Engineering Technology Research Center for Chemical Drug R&D, Guizhou Medical University, Guiyang 550014, China
| | - Xiaoyan Yan
- State Key Laboratory of Functions and Applications of Medicinal Plants & College of Pharmacy, Guizhou Provincial Engineering Technology Research Center for Chemical Drug R&D, Guizhou Medical University, Guiyang 550014, China
| | - Lei Tang
- State Key Laboratory of Functions and Applications of Medicinal Plants & College of Pharmacy, Guizhou Provincial Engineering Technology Research Center for Chemical Drug R&D, Guizhou Medical University, Guiyang 550014, China
| | - Hong Liang
- State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming 650201, China.
| | - Xujie Qin
- State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming 650201, China.
| | - Ying-Tong Di
- State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming 650201, China.
| | - Rongcan Luo
- Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences & Yunnan Province, KIZ-CUHK Joint Laboratory of Bioresources and Molecular Research in Common Diseases, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming 650204, China. .,Kunming College of Life Science, University of Chinese Academy of Sciences, Kunming, Yunnan 650204, China
| | - Xiao-Jiang Hao
- State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming 650201, China.
| | - Yong-Gang Yao
- Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences & Yunnan Province, KIZ-CUHK Joint Laboratory of Bioresources and Molecular Research in Common Diseases, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming 650204, China. .,Kunming College of Life Science, University of Chinese Academy of Sciences, Kunming, Yunnan 650204, China.,CAS Center for Excellence in Brain Science and Intelligence Technology, Chinese Academy of Sciences, Shanghai 200031, China
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41
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Yan Y, Zhou Q, Ran X, Lu Q, Zhang C, Peng M, Tang L, Luo R, Di Y, Hao X. Jatrophane Diterpenoids from Euphorbia peplus Linn. as Activators of Autophagy and Inhibitors of Tau Pathology. Int J Mol Sci 2023; 24:ijms24021088. [PMID: 36674604 PMCID: PMC9863522 DOI: 10.3390/ijms24021088] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2022] [Revised: 12/12/2022] [Accepted: 12/26/2022] [Indexed: 01/09/2023] Open
Abstract
Ten jatrophane diterpenoids were isolated from the whole plant Euphorbia peplus Linn. including seven new ones, named euphjatrophanes A-G (labeled compounds 1, 2, 4-8). Their structures were elucidated with a combination of spectroscopic and single-crystal X-ray crystallography, enabling the identification of compounds 3, 9, and 10 as the previously published euphpepluones G, K, and L, respectively. All compounds were evaluated for their bioactivity with flow cytometry in assays of autophagic flux in HM Cherry-GFP-LC3 (human microglia cells stably expressing the tandem monomeric mCherry-GFP-tagged LC3) cells. Euphpepluone K (9) significantly activated autophagic flux, an effect that was verified with confocal analysis. Moreover, cellular assays showed that euphpepluone K (9) induced autophagy and inhibited Tau pathology.
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Affiliation(s)
- Ying Yan
- State Key Laboratory of Functions and Applications of Medicinal Plants & College of Pharmacy, Guizhou Provincial Engineering Technology Research Center for Chemical Drug R&D, Guizhou Medical University, Guiyang 550014, China
| | - Qi Zhou
- State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming 650201, China
- Kunming College of Life Science, University of Chinese Academy of Sciences, Kunming 650204, China
| | - Xiaoqian Ran
- Kunming College of Life Science, University of Chinese Academy of Sciences, Kunming 650204, China
- Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences & Yunnan Province, and KIZ-CUHK Joint Laboratory of Bioresources and Molecular Research in Common Diseases, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming 650204, China
| | - Qingyun Lu
- State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming 650201, China
- Kunming College of Life Science, University of Chinese Academy of Sciences, Kunming 650204, China
| | - Cuishan Zhang
- State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming 650201, China
- Kunming College of Life Science, University of Chinese Academy of Sciences, Kunming 650204, China
| | - Mingyou Peng
- State Key Laboratory of Functions and Applications of Medicinal Plants & College of Pharmacy, Guizhou Provincial Engineering Technology Research Center for Chemical Drug R&D, Guizhou Medical University, Guiyang 550014, China
| | - Lei Tang
- State Key Laboratory of Functions and Applications of Medicinal Plants & College of Pharmacy, Guizhou Provincial Engineering Technology Research Center for Chemical Drug R&D, Guizhou Medical University, Guiyang 550014, China
| | - Rongcan Luo
- Kunming College of Life Science, University of Chinese Academy of Sciences, Kunming 650204, China
- Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences & Yunnan Province, and KIZ-CUHK Joint Laboratory of Bioresources and Molecular Research in Common Diseases, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming 650204, China
- Correspondence: (R.L.); (Y.D.)
| | - Yingtong Di
- State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming 650201, China
- Kunming College of Life Science, University of Chinese Academy of Sciences, Kunming 650204, China
- Correspondence: (R.L.); (Y.D.)
| | - Xiaojiang Hao
- State Key Laboratory of Functions and Applications of Medicinal Plants & College of Pharmacy, Guizhou Provincial Engineering Technology Research Center for Chemical Drug R&D, Guizhou Medical University, Guiyang 550014, China
- State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming 650201, China
- Kunming College of Life Science, University of Chinese Academy of Sciences, Kunming 650204, China
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42
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Muzio L, Ghirelli A, Agosta F, Martino G. Novel therapeutic approaches for motor neuron disease. HANDBOOK OF CLINICAL NEUROLOGY 2023; 196:523-537. [PMID: 37620088 DOI: 10.1016/b978-0-323-98817-9.00027-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 08/26/2023]
Abstract
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease that leads to the neurodegeneration and death of upper and lower motor neurons (MNs). Although MNs are the main cells involved in the process of neurodegeneration, a growing body of evidence points toward other cell types as concurrent to disease initiation and propagation. Given the current absence of effective therapies, the quest for other therapeutic targets remains open and still challenges the scientific community. Both neuronal and extra-neuronal mechanisms of cellular stress and damage have been studied and have posed the basis for the development of novel therapies that have been investigated on both animal models and humans. In this chapter, a thorough review of the main mechanisms of cellular damage and the respective therapeutic attempts targeting them is reported. The main areas covered include neuroinflammation, protein aggregation, RNA metabolism, and oxidative stress.
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Affiliation(s)
- Luca Muzio
- San Raffaele Scientific Institute, Division of Neuroscience, InsPE, Milan, Italy
| | - Alma Ghirelli
- San Raffaele Scientific Institute, Division of Neuroscience, InsPE, Milan, Italy; Vita-Salute San Raffaele University, Milan, Italy
| | - Federica Agosta
- San Raffaele Scientific Institute, Division of Neuroscience, InsPE, Milan, Italy; Vita-Salute San Raffaele University, Milan, Italy
| | - Gianvito Martino
- San Raffaele Scientific Institute, Division of Neuroscience, InsPE, Milan, Italy; Vita-Salute San Raffaele University, Milan, Italy
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43
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Yang B, Yang Z, Hao L. Dynamics of a model for the degradation mechanism of aggregated α-synuclein in Parkinson's disease. Front Comput Neurosci 2023; 17:1068150. [PMID: 37122994 PMCID: PMC10133481 DOI: 10.3389/fncom.2023.1068150] [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: 10/12/2022] [Accepted: 03/17/2023] [Indexed: 05/02/2023] Open
Abstract
Accumulation of the misfolded synaptic protein α-synuclein (αSyn*) is a hallmark of neurodegenerative disease in Parkinson's disease (PD). Recent studies suggest that the autophagy lysosome pathway (ALP) including both the Beclin1-associated and mTOR-signaling pathways is involved in the αSyn* clearance mechanism. In this study, a mathematical model is proposed for the degradation of αSyn* by ALP with the crosstalk element of mTOR. Using codimension-1 bifurcation analysis, the tri-stability of αSyn* is surveyed under three different stress signals and, in addition, consideration is given to the regulatory mechanisms for the Beclin1- and mTOR-dependent rates on αSyn* degradation using the codimension-1 and-2 bifurcation diagrams. It was found that, especially under internal and external oxidative stresses (S 1), the bistable switch of the aggregation of αSyn* can be transformed from an irreversible to a reversible condition through the ALP degradation pathways. Furthermore, the robustness of the tri-stable state for the stress S 1 to the parameters related to mTOR-mediated ALP was probed. It was confirmed that mTOR-mediated ALP is important for maintaining the essential dynamic features of the tri-stable state. This study may provide a promising avenue for conducting further experiments and simulations of the degradation mechanism of dynamic modeling in PD.
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Affiliation(s)
- Bojie Yang
- School of Mathematical Sciences and LMIB, Beihang University, Beijing, China
| | - Zhuoqin Yang
- School of Mathematical Sciences and LMIB, Beihang University, Beijing, China
- *Correspondence: Zhuoqin Yang
| | - Lijie Hao
- School of Mathematics Science, Tianjin Normal University, Tianjin, China
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44
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Chen J, Li M, Liu Z, Wang Y, Xiong K. Molecular mechanisms of neuronal death in brain injury after subarachnoid hemorrhage. Front Cell Neurosci 2022; 16:1025708. [PMID: 36582214 PMCID: PMC9793715 DOI: 10.3389/fncel.2022.1025708] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2022] [Accepted: 11/08/2022] [Indexed: 12/15/2022] Open
Abstract
Subarachnoid haemorrhage (SAH) is a common cerebrovascular disease with high disability and mortality rates worldwide. The pathophysiological mechanisms involved in an aneurysm rupture in SAH are complex and can be divided into early brain injury and delayed brain injury. The initial mechanical insult results in brain tissue and vascular disruption with hemorrhages and neuronal necrosis. Following this, the secondary injury results in diffused cerebral damage in the peri-core area. However, the molecular mechanisms of neuronal death following an aneurysmal SAH are complex and currently unclear. Furthermore, multiple cell death pathways are stimulated during the pathogenesis of brain damage. Notably, particular attention should be devoted to necrosis, apoptosis, autophagy, necroptosis, pyroptosis and ferroptosis. Thus, this review discussed the mechanism of neuronal death and its influence on brain injury after SAH.
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Affiliation(s)
- Junhui Chen
- Department of Human Anatomy and Neurobiology, School of Basic Medical Science, Central South University, Changsha, Hunan, China,Department of Neurosurgery, Renmin Hospital of Wuhan University, Wuhan, China,Department of Neurosurgery, 904th Hospital of Joint Logistic Support Force of PLA, Wuxi Clinical College of Anhui Medical University, Wuxi, China
| | - Mingchang Li
- Department of Neurosurgery, Renmin Hospital of Wuhan University, Wuhan, China
| | - Zhuanghua Liu
- Department of Neurosurgery, 904th Hospital of Joint Logistic Support Force of PLA, Wuxi Clinical College of Anhui Medical University, Wuxi, China
| | - Yuhai Wang
- Department of Neurosurgery, 904th Hospital of Joint Logistic Support Force of PLA, Wuxi Clinical College of Anhui Medical University, Wuxi, China,*Correspondence: Yuhai Wang,
| | - Kun Xiong
- Department of Human Anatomy and Neurobiology, School of Basic Medical Science, Central South University, Changsha, Hunan, China,Kun Xiong,
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Lapierre J, Karuppan MKM, Perry M, Rodriguez M, El-Hage N. Different Roles of Beclin1 in the Interaction Between Glia and Neurons after Exposure to Morphine and the HIV- Trans-Activator of Transcription (Tat) Protein. J Neuroimmune Pharmacol 2022; 17:470-486. [PMID: 34741242 PMCID: PMC9068829 DOI: 10.1007/s11481-021-10017-4] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2021] [Accepted: 08/22/2021] [Indexed: 01/18/2023]
Abstract
Previously we showed that Beclin1 has a regulatory role in the secretion of inflammatory molecules in glia after exposure to morphine and Tat (an HIV protein). Here we show increased secretion of neuronal growth factors and increased neuronal survival in Beclin1-deficient glia. However, without glia co-culture, neurons deficient in Beclin1 showed greater death and enhanced dendritic beading when compared to wild-type neurons, suggesting that glial-secreted growth factors compensate for the damage reduced autophagy causes neurons. To assess if our ex vivo results correlated with in vivo studies, we used a wild-type (Becn1+/+) and Beclin1-deficient (Becn1+/+) mouse model and intracranially infused the mice with Tat and subcutaneously administered morphine pellets. After morphine implantation, significantly impaired locomotor activities were detected in both Becn1+/+ and Becn1+/- mice, irrespective of Tat infusion. After induction of pain, morphine-induced antinociception was detected. Interestingly, co-exposure to morphine and Tat increased sensitivity to pain in Becn1+/+ mice, but not in similarly treated Becn1+/- mice. Brain homogenates from Becn1+/+ mice exposed to Tat, alone and in combination with morphine, showed increased secretion of pro-inflammatory cytokines and reduced expression of growth factors when compared to similarly treated Becn1+/- mice. Likewise, increased neuronal loss was detected when both Tat and morphine were administered to Becn1+/+ mice, but not in similarly treated Becn1+/- mice. Overall, our findings show that there is a Beclin1-driven interaction between Tat and morphine in glia and neurons. Moreover, reduced glial-Beclin1 may provide a layer of protection to neurons under stressful conditions, such as when exposed to morphine and Tat.
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Affiliation(s)
- Jessica Lapierre
- Department of Immunology and Nanomedicine, Florida International University, Herbert Wertheim College of Medicine, Miami, FL, 33199, USA
| | - Mohan K M Karuppan
- Department of Immunology and Nanomedicine, Florida International University, Herbert Wertheim College of Medicine, Miami, FL, 33199, USA
| | - Marissa Perry
- Department of Immunology and Nanomedicine, Florida International University, Herbert Wertheim College of Medicine, Miami, FL, 33199, USA
| | - Myosotys Rodriguez
- Department of Immunology and Nanomedicine, Florida International University, Herbert Wertheim College of Medicine, Miami, FL, 33199, USA
| | - Nazira El-Hage
- Department of Immunology and Nanomedicine, Florida International University, Herbert Wertheim College of Medicine, Miami, FL, 33199, USA.
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Xu F, Wu Y, Yang Q, Cheng Y, Xu J, Zhang Y, Dai H, Wang B, Ma Q, Chen Y, Lin F, Wang C. Engineered Extracellular Vesicles with SHP2 High Expression Promote Mitophagy for Alzheimer's Disease Treatment. ADVANCED MATERIALS (DEERFIELD BEACH, FLA.) 2022; 34:e2207107. [PMID: 36193769 DOI: 10.1002/adma.202207107] [Citation(s) in RCA: 48] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/04/2022] [Revised: 09/18/2022] [Indexed: 06/16/2023]
Abstract
Mitochondrial dysfunction is a fundamental pathological feature of Alzheimer's disease (AD). However, toxicity and poor brain enrichment of existing mitophagy inducers limit their further applications. In this study, a platform for AD therapy is developed using nanosized mesenchymal-stem-cells-derived extracellular vesicles with tyrosine phosphatase-2 (SHP2) high-expression (MSC-EVs-SHP2). The high blood-brain barrier penetration ability of MSC-EVs-SHP2 is demonstrated in AD-mice, facilitating SHP2 delivery to the brain. In addition, MSC-EVs-SHP2 significantly induces mitophagy of neuronal cells, which alleviates mitochondrial damage-mediated apoptosis and NLRP3 inflammasome activation. Mitophagy further diminishes neuronal cells apoptosis and neuroinflammation, culminating with rescued synaptic loss and cognitive decline in an AD mouse model. The EV-engineering technology provides a potential platform for effective AD therapy by inducing mitophagy.
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Affiliation(s)
- Fang Xu
- Institute of Functional Nano & Soft Materials (FUNSOM), Jiangsu Key Laboratory for Carbon-Based Functional Materials & Devices, Soochow University, 199 Ren'ai Road, Suzhou, Jiangsu, 215123, P. R. China
| | - Yi Wu
- Institute of Functional Nano & Soft Materials (FUNSOM), Jiangsu Key Laboratory for Carbon-Based Functional Materials & Devices, Soochow University, 199 Ren'ai Road, Suzhou, Jiangsu, 215123, P. R. China
| | - Qianyu Yang
- Institute of Functional Nano & Soft Materials (FUNSOM), Jiangsu Key Laboratory for Carbon-Based Functional Materials & Devices, Soochow University, 199 Ren'ai Road, Suzhou, Jiangsu, 215123, P. R. China
| | - Ying Cheng
- Institute of Pharmacology, Laboratory of Aging and Nervous Diseases, Jiangsu Key Laboratory of Neuropsychiatric Disease, College of Pharmaceutical Sciences, Soochow University, 199 Ren'ai Road, Suzhou, 215123, P. R. China
| | - Jialu Xu
- Institute of Functional Nano & Soft Materials (FUNSOM), Jiangsu Key Laboratory for Carbon-Based Functional Materials & Devices, Soochow University, 199 Ren'ai Road, Suzhou, Jiangsu, 215123, P. R. China
| | - Yue Zhang
- Institute of Functional Nano & Soft Materials (FUNSOM), Jiangsu Key Laboratory for Carbon-Based Functional Materials & Devices, Soochow University, 199 Ren'ai Road, Suzhou, Jiangsu, 215123, P. R. China
| | - Huaxing Dai
- Institute of Functional Nano & Soft Materials (FUNSOM), Jiangsu Key Laboratory for Carbon-Based Functional Materials & Devices, Soochow University, 199 Ren'ai Road, Suzhou, Jiangsu, 215123, P. R. China
| | - Beilei Wang
- Institute of Functional Nano & Soft Materials (FUNSOM), Jiangsu Key Laboratory for Carbon-Based Functional Materials & Devices, Soochow University, 199 Ren'ai Road, Suzhou, Jiangsu, 215123, P. R. China
| | - Qingle Ma
- Institute of Functional Nano & Soft Materials (FUNSOM), Jiangsu Key Laboratory for Carbon-Based Functional Materials & Devices, Soochow University, 199 Ren'ai Road, Suzhou, Jiangsu, 215123, P. R. China
| | - Yitong Chen
- Institute of Functional Nano & Soft Materials (FUNSOM), Jiangsu Key Laboratory for Carbon-Based Functional Materials & Devices, Soochow University, 199 Ren'ai Road, Suzhou, Jiangsu, 215123, P. R. China
| | - Fang Lin
- Institute of Pharmacology, Laboratory of Aging and Nervous Diseases, Jiangsu Key Laboratory of Neuropsychiatric Disease, College of Pharmaceutical Sciences, Soochow University, 199 Ren'ai Road, Suzhou, 215123, P. R. China
| | - Chao Wang
- Institute of Functional Nano & Soft Materials (FUNSOM), Jiangsu Key Laboratory for Carbon-Based Functional Materials & Devices, Soochow University, 199 Ren'ai Road, Suzhou, Jiangsu, 215123, P. R. China
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Chen H, Zhu Y, Zhang YL, Zeng MN, Cao YG, Sun PT, Cao B, Du K, Zhao X, Wang XW, Zheng XK, Feng WS. Neolignans and amide alkaloids from the stems of Piper kadsura and their neuroprotective activity. PHYTOCHEMISTRY 2022; 203:113336. [PMID: 35933005 DOI: 10.1016/j.phytochem.2022.113336] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/25/2022] [Revised: 07/05/2022] [Accepted: 07/20/2022] [Indexed: 06/15/2023]
Abstract
Four undescribed neolignans and three undescribed amide alkaloids, along with twelve known compounds, were isolated from the stems of Piper kadsura (Choisy) Ohwi. The structures of the new compounds were determined by spectroscopic analysis, quantum-chemical calculations, and Mo2(OAc)4-induced ECD analysis. The neuroprotective effects of these compounds against Aβ25-35-induced cell damage in PC12 cells were investigated, and eight compounds exhibited significant neuroprotective effects against Aβ25-35-induced PC12 cell damage, with the EC50 values of 3.06-29.3 μM. Three of these compounds were selected for further experiments, and they appear to reduce apoptosis and enhance autophagy against Aβ25-35-induced PC12 cell damage.
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Affiliation(s)
- Hui Chen
- School of Pharmacy, Henan University of Chinese Medicine, Zhengzhou, 450046, PR China; Co-Construction Collaborative Innovation Center for Chinese Medicine and Respiratory Diseases by Henan & Education Ministry of PR China, Zhengzhou, 450046, PR China; NMPA Key Laboratory for Quality Control of Traditional Chinese Medicine (Chinese Materia Medica and prepared slices), Zhengzhou, 450018, PR China.
| | - Ying Zhu
- School of Pharmacy, Henan University of Chinese Medicine, Zhengzhou, 450046, PR China
| | - Ya-Lun Zhang
- School of Pharmacy, Henan University of Chinese Medicine, Zhengzhou, 450046, PR China
| | - Meng-Nan Zeng
- School of Pharmacy, Henan University of Chinese Medicine, Zhengzhou, 450046, PR China; Co-Construction Collaborative Innovation Center for Chinese Medicine and Respiratory Diseases by Henan & Education Ministry of PR China, Zhengzhou, 450046, PR China
| | - Yan-Gang Cao
- School of Pharmacy, Henan University of Chinese Medicine, Zhengzhou, 450046, PR China
| | - Pan-Ting Sun
- School of Pharmacy, Henan University of Chinese Medicine, Zhengzhou, 450046, PR China
| | - Bing Cao
- School of Pharmacy, Henan University of Chinese Medicine, Zhengzhou, 450046, PR China
| | - Kun Du
- School of Pharmacy, Henan University of Chinese Medicine, Zhengzhou, 450046, PR China
| | - Xuan Zhao
- School of Pharmacy, Henan University of Chinese Medicine, Zhengzhou, 450046, PR China
| | - Xiao-Wei Wang
- NMPA Key Laboratory for Quality Control of Traditional Chinese Medicine (Chinese Materia Medica and prepared slices), Zhengzhou, 450018, PR China.
| | - Xiao-Ke Zheng
- School of Pharmacy, Henan University of Chinese Medicine, Zhengzhou, 450046, PR China; Co-Construction Collaborative Innovation Center for Chinese Medicine and Respiratory Diseases by Henan & Education Ministry of PR China, Zhengzhou, 450046, PR China
| | - Wei-Sheng Feng
- School of Pharmacy, Henan University of Chinese Medicine, Zhengzhou, 450046, PR China; Co-Construction Collaborative Innovation Center for Chinese Medicine and Respiratory Diseases by Henan & Education Ministry of PR China, Zhengzhou, 450046, PR China.
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48
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Liu Q, Yang Y, Cheng M, Cheng F, Chen S, Zheng Q, Sun Y, Chen L. The marine natural product, dicitrinone B, induces apoptosis through autophagy blockade in breast cancer. Int J Mol Med 2022; 50:130. [PMID: 36052845 PMCID: PMC9448296 DOI: 10.3892/ijmm.2022.5186] [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: 05/12/2022] [Accepted: 08/11/2022] [Indexed: 12/24/2022] Open
Abstract
Being a highly conserved catabolic process, autophagy is induced by various forms of cellular stress, and its modulation has considerable potential as a cancer therapeutic approach. In the present study, it was demonstrated that dicitrinone B (DB), a rare carbon-bridged citrinin dimer, may exert anticancer effects by blocking autophagy at a late stage, without disrupting lysosomal function in MCF7 breast cancer and MDA-MB-231 triple-negative breast cancer cells. Furthermore, it was discovered that DB significantly enhanced intracellular reactive oxygen species (ROS) production and that the removal of ROS was followed by the attenuation of autophagy inhibition. In addition, DB exerted notable inhibitory effects on the proliferation and promoting effects on the apoptosis of MCF7 and MDA-MB-231 cells. In combination with conventional chemotherapeutic drugs, DB exhibited a further enhanced synergistic effect than when used as a single agent. Overall, the data of the present study demonstrate that DB may prove to be a promising autophagy inhibitor with anticancer activity against breast cancer.
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Affiliation(s)
- Qinying Liu
- Fujian Provincial Key Laboratory of Tumor Biotherapy, Fujian Medical University Cancer Hospital and Fujian Cancer Hospital, Fuzhou, Fujian 350014, P.R. China
| | - Yi Yang
- Fujian Provincial Key Laboratory of Medical Instrument and Pharmaceutical Technology, College of Biological Science and Technology, Fuzhou University, Fuzhou, Fujian 350108, P.R. China
| | - Miaomiao Cheng
- Fujian Provincial Key Laboratory of Medical Instrument and Pharmaceutical Technology, College of Biological Science and Technology, Fuzhou University, Fuzhou, Fujian 350108, P.R. China
| | - Fangting Cheng
- Fujian Provincial Key Laboratory of Medical Instrument and Pharmaceutical Technology, College of Biological Science and Technology, Fuzhou University, Fuzhou, Fujian 350108, P.R. China
| | - Shanshan Chen
- Fujian Provincial Key Laboratory of Tumor Biotherapy, Fujian Medical University Cancer Hospital and Fujian Cancer Hospital, Fuzhou, Fujian 350014, P.R. China
| | - Qiuhong Zheng
- Fujian Provincial Key Laboratory of Tumor Biotherapy, Fujian Medical University Cancer Hospital and Fujian Cancer Hospital, Fuzhou, Fujian 350014, P.R. China
| | - Yang Sun
- Fujian Provincial Key Laboratory of Tumor Biotherapy, Fujian Medical University Cancer Hospital and Fujian Cancer Hospital, Fuzhou, Fujian 350014, P.R. China
| | - Li Chen
- Fujian Provincial Key Laboratory of Medical Instrument and Pharmaceutical Technology, College of Biological Science and Technology, Fuzhou University, Fuzhou, Fujian 350108, P.R. China
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Jeong YH, Kim TI, Oh YC, Ma JY. Selaginella tamariscina Inhibits Glutamate-Induced Autophagic Cell Death by Activating the PI3K/AKT/mTOR Signaling Pathways. Int J Mol Sci 2022; 23:ijms231911445. [PMID: 36232743 PMCID: PMC9569781 DOI: 10.3390/ijms231911445] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2022] [Revised: 09/20/2022] [Accepted: 09/23/2022] [Indexed: 11/21/2022] Open
Abstract
Glutamate-induced neural toxicity in autophagic neuron death is partially mediated by increased oxidative stress. Therefore, reducing oxidative stress in the brain is critical for treating or preventing neurodegenerative diseases. Selaginella tamariscina is a traditional medicinal plant for treating gastrointestinal bleeding, hematuria, leucorrhea, inflammation, chronic hepatitis, gout, and hyperuricemia. We investigate the inhibitory effects of Selaginella tamariscina ethanol extract (STE) on neurotoxicity and autophagic cell death in glutamate-exposed HT22 mouse hippocampal cells. STE significantly increased cell viability and mitochondrial membrane potential and decreased the expression of reactive oxygen species, lactate dehydrogenase release, and cell apoptosis in glutamate-exposed HT22 cells. In addition, while glutamate induced the excessive activation of mitophagy, STE attenuated glutamate-induced light chain (LC) 3 II and Beclin-1 expression and increased p62 expression. Furthermore, STE strongly enhanced the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt)/mammalian target of rapamycin (mTOR) phosphorylation activation. STE strongly inhibited glutamate-induced autophagy by activating the PI3K/Akt/mTOR signaling pathway. In contrast, the addition of LY294002, a PI3K/Akt inhibitor, remarkably suppressed cell viability and p-Akt and p62 expression, while markedly increasing the expression of LC3 II and Beclin-1. Our findings indicate that autophagy inhibition by activating PI3K/Akt/mTOR phosphorylation levels could be responsible for the neuroprotective effects of STE on glutamate neuronal damage.
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Affiliation(s)
| | | | - You-Chang Oh
- Correspondence: (Y.-C.O.); (J.Y.M.); Tel.: +82-53-940-3882 (Y.-C.O.); +82-53-940-3812 (J.Y.M.)
| | - Jin Yeul Ma
- Correspondence: (Y.-C.O.); (J.Y.M.); Tel.: +82-53-940-3882 (Y.-C.O.); +82-53-940-3812 (J.Y.M.)
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50
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Zhao X, Zhang Q, Zheng R. The interplay between oxidative stress and autophagy in chronic obstructive pulmonary disease. Front Physiol 2022; 13:1004275. [PMID: 36225291 PMCID: PMC9548529 DOI: 10.3389/fphys.2022.1004275] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2022] [Accepted: 09/07/2022] [Indexed: 11/13/2022] Open
Abstract
Autophagy is a highly conserved process that is indispensable for cell survival, embryonic development, and tissue homeostasis. Activation of autophagy protects cells against oxidative stress and is a major adaptive response to injury. When autophagy is dysregulated by factors such as smoking, environmental insults and aging, it can lead to enhanced formation of aggressors and production of reactive oxygen species (ROS), resulting in oxidative stress and oxidative damage to cells. ROS activates autophagy, which in turn promotes cell adaptation and reduces oxidative damage by degrading and circulating damaged macromolecules and dysfunctional cell organelles. The cellular response triggered by oxidative stress includes changes in signaling pathways that ultimately regulate autophagy. Chronic obstructive pulmonary disease (COPD) is the most common lung disease among the elderly worldwide, with a high mortality rate. As an induced response to oxidative stress, autophagy plays an important role in the pathogenesis of COPD. This review discusses the regulation of oxidative stress and autophagy in COPD, and aims to provide new avenues for future research on target-specific treatments for COPD.
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Affiliation(s)
| | | | - Rui Zheng
- *Correspondence: Qiang Zhang, ; Rui Zheng,
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