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Wang J, Li S, Ye J, Yan Y, Liu Q, Jia Q, Jia Y, Wang L. Mesencephalic astrocyte-derived neurotrophic factor (MANF): A novel therapeutic target for chemotherapy-induced peripheral neuropathy via regulation of integrated stress response and neuroinflammation. Neuropharmacology 2025; 268:110342. [PMID: 39909174 DOI: 10.1016/j.neuropharm.2025.110342] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2024] [Revised: 01/20/2025] [Accepted: 02/01/2025] [Indexed: 02/07/2025]
Abstract
Chemotherapy-induced peripheral neuropathy (CIPN) represents a severe complication, impacting up to 90% of cancer patients administered with chemotherapeutic agents such as oxaliplatin. The purpose of our study was to examine the potential role and therapeutic efficacy of Mesencephalic Astrocyte-derived Neurotrophic Factor (MANF), given its recognized neuroprotective and immunomodulatory properties in diverse neurological disorders. Utilizing an oxaliplatin-induced CIPN mouse model, we investigated MANF expression in the dorsal root ganglia (DRG) and spinal cord, and evaluated the impacts of AAV-mediated MANF overexpression on CIPN. Our findings revealed substantial downregulation of MANF expression in both the DRG and spinal cord of CIPN inflicted mice, with MANF majorly localized in neurons as opposed to glial cells. Intrathecal administration of AAV-MANF preceding oxaliplatin treatment yielded several beneficial results. MANF overexpression diminished mechanical hypersensitivity and decreased Calcitonin Gene-Related Peptide (CGRP) expression in DRG and the spinal dorsal horn. These enhancements were concomitant with modulation of the integrated stress response (ISR) and neuroinflammation. Intervention with AAV-MANF effectively regulated ISR markers (BiP, CHOP, and p-eIF2α), mitigated activation of microglia and astrocytes in the DRG and spinal dorsal horn, and inhibited NFκB and ERK inflammatory signaling pathways. To conclude, our study underscores the potential of MANF as a viable therapeutic target for CIPN, manifesting its ability to modulate ISR and neuroinflammation. These insights recommend that continued exploration of MANF-centered approaches could facilitate the advancement of more efficacious interventions for this incapacitating chemotherapy complication.
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Affiliation(s)
- Juan Wang
- Department of Pain, Renmin Hospital of Wuhan University, Wuhan, 430060, Hubei Province, China
| | - Shenghong Li
- Department of Pain, Renmin Hospital of Wuhan University, Wuhan, 430060, Hubei Province, China
| | - Jishi Ye
- Department of Pain, Renmin Hospital of Wuhan University, Wuhan, 430060, Hubei Province, China
| | - Yafei Yan
- Department of Pain, Renmin Hospital of Wuhan University, Wuhan, 430060, Hubei Province, China
| | - Qi Liu
- Department of Pain, Renmin Hospital of Wuhan University, Wuhan, 430060, Hubei Province, China
| | - Qiang Jia
- Department of Pain, Renmin Hospital of Wuhan University, Wuhan, 430060, Hubei Province, China
| | - Yifan Jia
- Department of Pain, Renmin Hospital of Wuhan University, Wuhan, 430060, Hubei Province, China.
| | - Long Wang
- Department of Anesthesiology, Renmin Hospital of Wuhan University, Wuhan, 430060, Hubei Province, China.
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Dai P, Wang P, Chen X, Feng S, Wu F, Zheng X, Qin Z. Mesencephalic Astrocyte-Derived Neurotrophic Factor (MANF) Restricts Inflammatory Progression through Limiting Macrophage Infiltration in DRG and Sciatic Nerve during Diabetic Peripheral Neuropathy. ACS Chem Neurosci 2025; 16:945-959. [PMID: 39970444 DOI: 10.1021/acschemneuro.5c00021] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/21/2025] Open
Abstract
Diabetic peripheral neuropathy (DPN) is a prevalent complication affecting over half of individuals with diabetes. This study investigates the role of mesencephalic Astrocyte-derived neurotrophic factor (MANF) in DPN progression and its potential as a therapeutic target. Using a streptozotocin (STZ)-induced diabetic mouse model, we analyzed MANF expression in the dorsal root ganglia (DRG) and sciatic nerve and assessed the effects of recombinant human MANF (rhMANF) administration on DPN symptoms. Our findings show significant upregulation of MANF protein levels in the DRG of diabetic mice, along with an increased presence of MANF-expressing macrophages in both the DRG and sciatic nerve. Intravenous administration of rhMANF from Day 7 to Day 21 post-STZ injection yielded multiple beneficial outcomes. Notably, rhMANF treatment alleviated mechanical hypoalgesia, as measured by the paw mechanical withdrawal threshold (PMWT), and enhanced sciatic nerve conduction, improving motor nerve conduction velocity (MNCV). Additionally, it increased intradermal nerve density, indicated by more PGP9.5-positive nerve fibers in the plantar skin of treated diabetic mice. These improvements were associated with reduced macrophage infiltration in the DRG and sciatic nerve, marked by fewer CD68 and Iba-1 positive cells, and inhibition of inflammatory signaling pathways. Specifically, rhMANF treatment decreased NF-κB p65 phosphorylation and suppressed p38 MAPK phosphorylation, indicating reduced inflammation. In summary, our research underscores MANF's potential as a novel therapeutic target for DPN, particularly due to its anti-inflammatory properties. Further exploration of MANF could lead to the development of more effective treatments for this debilitating aspect of diabetes.
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Affiliation(s)
- Peng Dai
- Department of Anesthesiology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong 510515, P. R. China
- Department of Anesthesiology, The First People's Hospital of Foshan, Foshan, Guangdong 528000, P. R. China
| | - Peng Wang
- Department of Anesthesiology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong 510515, P. R. China
| | - Xin Chen
- Department of Anesthesiology, Shaanxi Provincial People's Hospital, Xi'an, Shaanxi 710068, P. R. China
| | - Shuyun Feng
- Department of Anesthesiology, The First People's Hospital of Foshan, Foshan, Guangdong 528000, P. R. China
| | - Fancan Wu
- Department of Anesthesiology, The First People's Hospital of Foshan, Foshan, Guangdong 528000, P. R. China
| | - Xueqin Zheng
- Department of Anesthesiology, The First People's Hospital of Foshan, Foshan, Guangdong 528000, P. R. China
| | - Zaisheng Qin
- Department of Anesthesiology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong 510515, P. R. China
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Liu S, Wang Y, Zhang Y, Wang X, Wang L. Mesencephalic Astrocyte-Derived Neurotrophic Factor (MANF) Mitigates Neuroinflammation and Cognitive Impairment by Modulating Glial Activation in Sepsis-Associated Encephalopathy. Neurochem Res 2024; 50:39. [PMID: 39612058 DOI: 10.1007/s11064-024-04296-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2024] [Revised: 11/03/2024] [Accepted: 11/20/2024] [Indexed: 11/30/2024]
Abstract
Sepsis-associated encephalopathy (SAE) is a severe neurological complication of sepsis, characterized by cognitive impairment and increased mortality. Owing to the established neuroprotective and immunomodulatory effects of Mesencephalic Astrocyte-derived Neurotrophic Factor (MANF) in a plethora of neurological disorders, our study aimed to investigate the role of MANF in SAE and evaluate its potential as a therapeutic target. Employing a cecal ligation and puncture (CLP) mouse model of sepsis, we analyzed MANF expression in the hippocampus and cortex, and evaluated the influence of intranasally administered recombinant human MANF (rhMANF) on symptoms of SAE. Our results disclosed a substantial increase in MANF protein levels within the hippocampus and cortex of septic mice, primarily found in neurons. Post-CLP surgical administration of rhMANF led to numerous favorable outcomes. Specifically, rhMANF therapy mitigated sepsis-induced behavioral deviations and cognitive impairments, as gauged by SHIRPA scores and Morris water maze tests, and enhanced survival rates in septic mice. These enhancements were concomitant with alterations in neuroinflammation and synaptic integrity. The rhMANF treatment attenuated activation of microglia and astrocytes in the hippocampus and cortex, as evidenced by diminished Iba-1 and GFAP positive cells. It also curtailed the generation of pro-inflammatory cytokines TNF-α and IL-6, and obstructed the p38 MAPK inflammatory pathway. Moreover, rhMANF sustained the expression of synaptic proteins PSD95 and SYN, and conserved neuronal integrity, as demonstrated by Nissl staining. In conclusion, our study underscores the potential of MANF as an innovative therapeutic target for SAE, emphasizing its anti-inflammatory and neuroprotective capabilities.
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Affiliation(s)
- Shuchao Liu
- Eastern District, Department of Critical Care Medicine, Renmin Hospital of Wuhan University, Wuhan, Hubei Province, 430060, China
| | - Ying Wang
- Department of Urology, Renmin Hospital of Wuhan University, Wuhan, Hubei Province, 430060, China
| | - Ye Zhang
- Eastern District, Department of Critical Care Medicine, Renmin Hospital of Wuhan University, Wuhan, Hubei Province, 430060, China
| | - Xiongjie Wang
- Eastern District, Department of Critical Care Medicine, Renmin Hospital of Wuhan University, Wuhan, Hubei Province, 430060, China
| | - Long Wang
- Department of Anesthesiology, Renmin Hospital of Wuhan University, Wuhan, Hubei Province, 430060, China.
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Yuan L, Dai Q, Wang X, Yang J, Yuan B. Unlocking the promise of MANF in diseases: Mechanistic insights and therapeutic potentials. Mol Biol Rep 2024; 51:1160. [PMID: 39549080 DOI: 10.1007/s11033-024-10111-9] [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: 10/09/2024] [Accepted: 11/12/2024] [Indexed: 11/18/2024]
Abstract
Mesencephalic astrocyte-derived neurotrophic factor (MANF) is a ubiquitous neurotrophic factor that exhibits a variety of physiological functions and plays a critical role in the exploitation of therapeutic potential across a range of diseases, including cardiovascular disorders, nervous system diseases, metabolic imbalances, and cancers. In the context of cardiac diseases, MANF significantly promotes cardiomyocyte survival and improves cardiac functionality. Furthermore, MANF not only provides neuroprotection by shielding neurons from damage and promoting nerve regeneration in neurological disorders, but also involves in insulin resistance, lipid metabolism disturbances and fat-containing liver lesions. However, the oncogenic or tumor suppressive function of MANF in cancer remains unclear, requiring further investigation to elucidate its precise role in the process of cancer initiation and progression. This review aims to summarize the latest advancements in understanding the molecular pathways, intricate mechanisms, and therapeutic potential of MANF in the prevention and treatment of various diseases, emphasizing its multifaceted contributions to health and disease management.
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Affiliation(s)
- Lingling Yuan
- Department of Pharmacology, School of Basic Medical Sciences, Anhui Medical University, Hefei, 230032, Anhui, China
| | - Qiqiao Dai
- School of Pharmacy, Anhui Medical University, Hefei, 230032, Anhui, China
| | - Xirui Wang
- School of Pharmacy, Anhui Medical University, Hefei, 230032, Anhui, China
| | - Jing Yang
- Experimental Teaching Center for Preventive Medicine, School of Public Health, Anhui Medical University, Hefei, 230032, Anhui, China
- School of Public Health, Anhui Medical University, 81 Mei Shan Road, Hefei, 230032, Anhui Province, China
| | - Bin Yuan
- Department of Pharmacology, School of Basic Medical Sciences, Anhui Medical University, Hefei, 230032, Anhui, China.
- School of Basic Medical Sciences, Anhui Medical University, 81 Mei Shan Road, Hefei, 230032, Anhui Province, China.
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Taylor SKB, Hartman JH, Gupta BP. The neurotrophic factor MANF regulates autophagy and lysosome function to promote proteostasis in Caenorhabditis elegans. Proc Natl Acad Sci U S A 2024; 121:e2403906121. [PMID: 39418305 PMCID: PMC11513987 DOI: 10.1073/pnas.2403906121] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2024] [Accepted: 08/29/2024] [Indexed: 10/19/2024] Open
Abstract
The conserved mesencephalic astrocyte-derived neurotrophic factor (MANF) is known for protecting dopaminergic neurons and functioning in various other tissues. Previously, we showed that Caenorhabditis elegans manf-1 null mutants exhibit defects such as increased endoplasmic reticulum (ER) stress, dopaminergic neurodegeneration, and abnormal protein aggregation. These findings suggest an essential role for MANF in cellular processes. However, the mechanisms by which intracellular and extracellular MANF regulate broader cellular functions remain unclear. We report a unique mechanism of action for MANF-1 that involves the transcription factor HLH-30/TFEB-mediated signaling to regulate autophagy and lysosomal function. Multiple transgenic strains overexpressing MANF-1 showed extended lifespan of animals, reduced protein aggregation, and improved neuronal survival. Using fluorescently tagged MANF-1, we observed tissue-specific localization of the protein, which was dependent on the ER retention signal. Further subcellular analysis showed that MANF-1 localizes within cells to the lysosomes and utilizes the endosomal pathway. Consistent with the lysosomal localization, our transcriptomic study of MANF-1 and analyses of autophagy regulators demonstrated that MANF-1 promotes proteostasis by regulating autophagic flux and lysosomal activity. Collectively, our findings establish MANF as a critical regulator of stress response, proteostasis, and aging.
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Affiliation(s)
| | - Jessica H. Hartman
- Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, SC29425
- Department of Regenerative Medicine and Cell Biology, Medical University of South Carolina, Charleston, SC29425
| | - Bhagwati P. Gupta
- Department of Biology, McMaster University, Hamilton, ONL8S 4K1, Canada
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Zhang Y, Chen X, Chen L, Shao M, Zhu W, Xing T, Guo T, Jia Q, Yang H, Yin P, Yan XX, Yu J, Li S, Li XJ, Yang S. Increased expression of mesencephalic astrocyte-derived neurotrophic factor (MANF) contributes to synapse loss in Alzheimer's disease. Mol Neurodegener 2024; 19:75. [PMID: 39425207 PMCID: PMC11490049 DOI: 10.1186/s13024-024-00771-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2024] [Accepted: 10/11/2024] [Indexed: 10/21/2024] Open
Abstract
BACKGROUND The activation of endoplasmic reticulum (ER) stress is an early pathological hallmark of Alzheimer's disease (AD) brain, but how ER stress contributes to the onset and development of AD remains poorly characterized. Mesencephalic astrocyte-derived neurotrophic factor (MANF) is a non-canonical neurotrophic factor and an ER stress inducible protein. Previous studies reported that MANF is increased in the brains of both pre-symptomatic and symptomatic AD patients, but the consequence of the early rise in MANF protein is unknown. METHODS We examined the expression of MANF in the brain of AD mouse models at different pathological stages. Through behavioral, electrophysiological, and neuropathological analyses, we assessed the level of synaptic dysfunctions in the MANF transgenic mouse model which overexpresses MANF in the brain and in wild type (WT) mice with MANF overexpression in the hippocampus. Using proteomic and transcriptomic screening, we identified and validated the molecular mechanism underlying the effects of MANF on synaptic function. RESULTS We found that increased expression of MANF correlates with synapse loss in the hippocampus of AD mice. The ectopic expression of MANF in mice via transgenic or viral approaches causes synapse loss and defects in learning and memory. We also identified that MANF interacts with ELAV like RNA-binding protein 2 (ELAVL2) and affects its binding to RNA transcripts that are involved in synaptic functions. Increasing or decreasing MANF expression in the hippocampus of AD mice exacerbates or ameliorates the behavioral deficits and synaptic pathology, respectively. CONCLUSIONS Our study established MANF as a mechanistic link between ER stress and synapse loss in AD and hinted at MANF as a therapeutic target in AD treatment.
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Affiliation(s)
- Yiran Zhang
- Guangdong Key Laboratory of Non-Human Primate Research, Key Laboratory of CNS Regeneration (Ministry of Education), Guangdong-Hong Kong-Macau Institute of CNS Regeneration, Jinan University, Guangzhou, China
| | - Xiusheng Chen
- Guangdong Key Laboratory of Non-Human Primate Research, Key Laboratory of CNS Regeneration (Ministry of Education), Guangdong-Hong Kong-Macau Institute of CNS Regeneration, Jinan University, Guangzhou, China
| | - Laiqiang Chen
- Guangdong Key Laboratory of Non-Human Primate Research, Key Laboratory of CNS Regeneration (Ministry of Education), Guangdong-Hong Kong-Macau Institute of CNS Regeneration, Jinan University, Guangzhou, China
- State Key Laboratory of Bioactive Molecules and Druggability Assessment, Jinan University, Guangzhou, China
| | - Mingting Shao
- Guangdong Key Laboratory of Non-Human Primate Research, Key Laboratory of CNS Regeneration (Ministry of Education), Guangdong-Hong Kong-Macau Institute of CNS Regeneration, Jinan University, Guangzhou, China
| | - Wenzhen Zhu
- Guangdong Key Laboratory of Non-Human Primate Research, Key Laboratory of CNS Regeneration (Ministry of Education), Guangdong-Hong Kong-Macau Institute of CNS Regeneration, Jinan University, Guangzhou, China
| | - Tingting Xing
- Guangdong Key Laboratory of Non-Human Primate Research, Key Laboratory of CNS Regeneration (Ministry of Education), Guangdong-Hong Kong-Macau Institute of CNS Regeneration, Jinan University, Guangzhou, China
| | - Tingting Guo
- Guangdong Key Laboratory of Non-Human Primate Research, Key Laboratory of CNS Regeneration (Ministry of Education), Guangdong-Hong Kong-Macau Institute of CNS Regeneration, Jinan University, Guangzhou, China
| | - Qingqing Jia
- Guangdong Key Laboratory of Non-Human Primate Research, Key Laboratory of CNS Regeneration (Ministry of Education), Guangdong-Hong Kong-Macau Institute of CNS Regeneration, Jinan University, Guangzhou, China
| | - Huiming Yang
- Department of Neurology, The First Affiliated Hospital, Sun Yat-Sen University; Guangdong Provincial Key Laboratory of Diagnosis and Treatment of Major Neurological Diseases, Guangzhou, China
| | - Peng Yin
- Guangdong Key Laboratory of Non-Human Primate Research, Key Laboratory of CNS Regeneration (Ministry of Education), Guangdong-Hong Kong-Macau Institute of CNS Regeneration, Jinan University, Guangzhou, China
- State Key Laboratory of Bioactive Molecules and Druggability Assessment, Jinan University, Guangzhou, China
| | - Xiao-Xin Yan
- Department of Anatomy and Neurobiology, Central South University Xiangya School of Medicine, Changsha, China
| | - Jiandong Yu
- Department of Neurosurgery, The First Affiliated Hospital of Bengbu Medical College, Bengbu, China
| | - Shihua Li
- Guangdong Key Laboratory of Non-Human Primate Research, Key Laboratory of CNS Regeneration (Ministry of Education), Guangdong-Hong Kong-Macau Institute of CNS Regeneration, Jinan University, Guangzhou, China
- State Key Laboratory of Bioactive Molecules and Druggability Assessment, Jinan University, Guangzhou, China
| | - Xiao-Jiang Li
- Guangdong Key Laboratory of Non-Human Primate Research, Key Laboratory of CNS Regeneration (Ministry of Education), Guangdong-Hong Kong-Macau Institute of CNS Regeneration, Jinan University, Guangzhou, China
- State Key Laboratory of Bioactive Molecules and Druggability Assessment, Jinan University, Guangzhou, China
| | - Su Yang
- Guangdong Key Laboratory of Non-Human Primate Research, Key Laboratory of CNS Regeneration (Ministry of Education), Guangdong-Hong Kong-Macau Institute of CNS Regeneration, Jinan University, Guangzhou, China.
- State Key Laboratory of Bioactive Molecules and Druggability Assessment, Jinan University, Guangzhou, China.
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Cicek C, Telkoparan-Akillilar P, Sertyel S, Bilgi C, Ozgun OD. Investigation of endoplasmic reticulum stress-regulated chaperones as biomarkers in idiopathic nonobstructive azoospermia. Cell Stress Chaperones 2024; 29:654-665. [PMID: 39237030 PMCID: PMC11424951 DOI: 10.1016/j.cstres.2024.08.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2024] [Revised: 08/27/2024] [Accepted: 08/30/2024] [Indexed: 09/07/2024] Open
Abstract
Azoospermia is a condition in which sperm cells are completely absent in a male's ejaculate. Typically, sperm production occurs in the testes and is regulated by a complex series of cellular and molecular interactions. Endoplasmic reticulum (ER) stress arises when there is a deviation from or damage to the normal functions of the ER within cells. In response to this stress, a cascade of response mechanisms is activated to regulate ER stress within cells. This study aims to investigate the role of ER stress-regulated chaperones as potential biomarkers in male infertility. ER stress associated with azoospermia can manifest in cells such as spermatogonia in the testes and can impact sperm production. As a result of ER stress, the expression and activity of a variety of proteins within cells can be altered. Among these proteins are chaperone proteins that regulate the ER stress response. The sample size was calculated to be a minimum of 36 patients in each group. In this preliminary study, we measured and compared serum levels of protein disulfide-isomerase A1, protein disulfide-isomerase A3 (PDIA3), mesencephalic astrocyte-derived neurotrophic factor (MANF), glucose regulatory protein 78 (GRP78), clusterin (CLU), calreticulin (CRT), and calnexin (CNX) between male subjects with idiopathic nonobstructive azoospermia and a control group of noninfertile males. Serum PDIA1 (P = 0.0004), MANF (P = 0.018), PDIA3 (P < 0.0001), GRP78 (P = 0.0027), and CRT (P = 0.0009) levels were higher in the infertile group compared to the control. In summary, this study presents novel findings in a cohort of male infertile patients, emphasizing the significance of incorporating diverse biomarkers. It underscores the promising role of ER stress-regulated proteins as potential serum indicators for male infertility. By elucidating the impact of ER stress on spermatogenic cells, the research illuminates the maintenance or disruption of cellular health. A deeper understanding of these results could open the door to novel treatment approaches for reproductive conditions, including azoospermia.
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Affiliation(s)
- Cigdem Cicek
- Department of Medical Biochemistry, Faculty of Medicine, Yuksek Ihtisas University, Ankara 06530, Turkey.
| | - Pelin Telkoparan-Akillilar
- Department of Medical Biology, Faculty of Medicine, Gazi University, Ankara 06500, Turkey; Department of Medical Biology, Faculty of Medicine, Yuksek Ihtisas University, Ankara 06530, Turkey
| | | | - Cumhur Bilgi
- Alife Hospital Biochemistry Laboratory, Ankara 06794, Turkey
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Dossat AM, Trychta KA, Glotfelty EJ, Hinkle JJ, Fortuno LV, Gore LN, Richie CT, Harvey BK. Excitotoxic glutamate levels cause the secretion of resident endoplasmic reticulum proteins. J Neurochem 2024; 168:2461-2478. [PMID: 38491746 PMCID: PMC11401966 DOI: 10.1111/jnc.16093] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2023] [Revised: 02/09/2024] [Accepted: 02/23/2024] [Indexed: 03/18/2024]
Abstract
Dysregulation of synaptic glutamate levels can lead to excitotoxicity such as that observed in stroke, traumatic brain injury, and epilepsy. The role of increased intracellular calcium (Ca2+) in the development of excitotoxicity is well established. However, less is known regarding the impact of glutamate on endoplasmic reticulum (ER)-Ca2+-mediated processes such as proteostasis. To investigate this, we expressed a secreted ER Ca2+ modulated protein (SERCaMP) in primary cortical neurons to monitor exodosis, a phenomenon whereby ER calcium depletion causes the secretion of ER-resident proteins that perform essential functions to the ER and the cell. Activation of glutamatergic receptors (GluRs) led to an increase in SERCaMP secretion indicating that normally ER-resident proteins are being secreted in a manner consistent with ER Ca2+ depletion. Antagonism of ER Ca2+ channels attenuated the effects of glutamate and GluR agonists on SERCaMP release. We also demonstrate that endogenous proteins containing an ER retention/retrieval sequence (ERS) are secreted in response to GluR activation supporting that neuronal activation by glutamate promotes ER exodosis. Ectopic expression of KDEL receptors attenuated the secretion of ERS-containing proteins caused by GluR agonists. Taken together, our data indicate that excessive GluR activation causes disruption of neuronal proteostasis by triggering the secretion of ER-resident proteins through ER Ca2+ depletion and describes a new facet of excitotoxicity.
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Affiliation(s)
- Amanda M. Dossat
- Intramural Research Program, National Institute on Drug Abuse, Baltimore, Maryland, 21224
| | - Kathleen A. Trychta
- Intramural Research Program, National Institute on Drug Abuse, Baltimore, Maryland, 21224
| | - Elliot J. Glotfelty
- Intramural Research Program, National Institute on Drug Abuse, Baltimore, Maryland, 21224
| | - Joshua J. Hinkle
- Intramural Research Program, National Institute on Drug Abuse, Baltimore, Maryland, 21224
| | - Lowella V. Fortuno
- Intramural Research Program, National Institute on Drug Abuse, Baltimore, Maryland, 21224
| | - Lana N. Gore
- Intramural Research Program, National Institute on Drug Abuse, Baltimore, Maryland, 21224
| | - Christopher T. Richie
- Intramural Research Program, National Institute on Drug Abuse, Baltimore, Maryland, 21224
| | - Brandon K. Harvey
- Intramural Research Program, National Institute on Drug Abuse, Baltimore, Maryland, 21224
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Hrabos D, Poggiolini I, Civitelli L, Galli E, Esapa C, Saarma M, Lindholm P, Parkkinen L. Unfolded protein response markers Grp78 and eIF2alpha are upregulated with increasing alpha-synuclein levels in Lewy body disease. Neuropathol Appl Neurobiol 2024; 50:e12999. [PMID: 39036837 DOI: 10.1111/nan.12999] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2024] [Revised: 06/26/2024] [Accepted: 07/01/2024] [Indexed: 07/23/2024]
Abstract
AIMS Endoplasmic reticulum stress followed by the unfolded protein response is one of the cellular mechanisms contributing to the progression of α-synuclein pathology in Parkinson's disease and other Lewy body diseases. We aimed to investigate the activation of endoplasmic reticulum stress and its correlation with α-synuclein pathology in human post-mortem brain tissue. METHODS We analysed brain tissue from 45 subjects-14 symptomatic patients with Lewy body disease, 19 subjects with incidental Lewy body disease, and 12 healthy controls. The analysed brain regions included the medulla, pons, midbrain, striatum, amygdala and entorhinal, temporal, frontal and occipital cortex. We analysed activation of endoplasmic reticulum stress via levels of the unfolded protein response-related proteins (Grp78, eIF2α) and endoplasmic reticulum stress-regulating neurotrophic factors (MANF, CDNF). RESULTS We showed that regional levels of two endoplasmic reticulum-localised neurotrophic factors, MANF and CDNF, did not change in response to accumulating α-synuclein pathology. The concentration of MANF negatively correlated with age in specific regions. eIF2α was upregulated in the striatum of Lewy body disease patients and correlated with increased α-synuclein levels. We found the upregulation of chaperone Grp78 in the amygdala and nigral dopaminergic neurons of Lewy body disease patients. Grp78 levels in the amygdala strongly correlated with soluble α-synuclein levels. CONCLUSIONS Our data suggest a strong but regionally specific change in Grp78 and eIF2α levels, which positively correlates with soluble α-synuclein levels. Additionally, MANF levels decreased in dopaminergic neurons in the substantia nigra. Our research suggests that endoplasmic reticulum stress activation is not associated with Lewy pathology but rather with soluble α-synuclein concentration and disease progression.
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Affiliation(s)
- Dominik Hrabos
- Nuffield Department of Clinical Neuroscience, University of Oxford, Oxford, UK
- Department of Clinical and Molecular Pathology, Palacky University Olomouc and University Hospital Olomouc, Olomouc, Czech Republic
- Department of Neurology, Palacky University Olomouc and University Hospital Olomouc, Olomouc, Czech Republic
| | - Ilaria Poggiolini
- Nuffield Department of Clinical Neuroscience, University of Oxford, Oxford, UK
| | - Livia Civitelli
- Nuffield Department of Clinical Neuroscience, University of Oxford, Oxford, UK
| | - Emilia Galli
- Institute of Biotechnology, Helsinki Institute of Life Science, University of Helsinki, Helsinki, Finland
| | - Chris Esapa
- Mammalian Genetics Unit, MRC Harwell Institute, Harwell Science and Innovation Campus, Didcot, UK
| | - Mart Saarma
- Institute of Biotechnology, Helsinki Institute of Life Science, University of Helsinki, Helsinki, Finland
| | - Päivi Lindholm
- Institute of Biotechnology, Helsinki Institute of Life Science, University of Helsinki, Helsinki, Finland
| | - Laura Parkkinen
- Nuffield Department of Clinical Neuroscience, University of Oxford, Oxford, UK
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Pravikova PD, Arssan MA, Zalivina EA, Kondaurova EM, Kulikova EA, Belokopytova II, Naumenko VS. Dopamine receptors and key elements of the neurotrophins (BDNF, CDNF) expression patterns during critical periods of ontogenesis in the brain structures of mice with autism-like behavior (BTBR) or its absence (С57BL/6 J). Vavilovskii Zhurnal Genet Selektsii 2024; 28:407-415. [PMID: 39027124 PMCID: PMC11253014 DOI: 10.18699/vjgb-24-46] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2024] [Revised: 03/11/2024] [Accepted: 03/12/2024] [Indexed: 07/20/2024] Open
Abstract
Analysis of the mechanisms underlying autism spectrum disorder (ASD) is an urgent task due to the ever-increasing prevalence of this condition. The study of critical periods of neuroontogenesis is of interest, since the manifestation of ASD is often associated with prenatal disorders of the brain development. One of the currently promising hypotheses postulates a connection between the pathogenesis of ASD and the dysfunction of neurotransmitters and neurotrophins. In this study, we investigated the expression of key dopamine receptors (Drd1, Drd2), brain-derived neurotrophic factor (Bdnf), its receptors (Ntrkb2, Ngfr) and the transcription factor Creb1 that mediates BDNF action, as well as cerebral dopamine neurotrophic factor (Cdnf) during the critical periods of embryogenesis (e14 and e18) and postnatal development (p14, p28, p60) in the hippocampus and frontal cortex of BTBR mice with autism-like behavior compared to the neurotypical C57BL/6 J strain. In BTBR embryos, on the 14th day of prenatal development, an increase in the expression of the Ngfr gene encoding the p75NTR receptor, which may lead to the activation of apoptosis, was found in the hippocampus and frontal cortex. A decrease in the expression of Cdnf, Bdnf and its receptor Ntrkb2, as well as dopamine receptors (Drd1, Drd2) was detected in BTBR mice in the postnatal period of ontogenesis mainly in the frontal cortex, while in the hippocampus of mature mice (p60), only a decrease in the Drd2 mRNA level was revealed. The obtained results suggest that the decrease in the expression levels of CDNF, BDNF-TrkB and dopamine receptors in the frontal cortex in the postnatal period can lead to significant changes in both the morphology of neurons and dopamine neurotransmission in cortical brain structures. At the same time, the increase in p75NTR receptor gene expression observed on the 14th day of embryogenesis, crucial for hippocampus and frontal cortex development, may have direct relevance to the manifestation of early autism.
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Affiliation(s)
- P D Pravikova
- Institute of Cytology and Genetics of the Siberian Branch of the Russian Academy of Sciences, Novosibirsk, Russia
| | - M A Arssan
- Institute of Cytology and Genetics of the Siberian Branch of the Russian Academy of Sciences, Novosibirsk, Russia
| | - E A Zalivina
- Institute of Cytology and Genetics of the Siberian Branch of the Russian Academy of Sciences, Novosibirsk, Russia
| | - E M Kondaurova
- Institute of Cytology and Genetics of the Siberian Branch of the Russian Academy of Sciences, Novosibirsk, Russia
| | - E A Kulikova
- Institute of Cytology and Genetics of the Siberian Branch of the Russian Academy of Sciences, Novosibirsk, Russia
| | - I I Belokopytova
- Institute of Cytology and Genetics of the Siberian Branch of the Russian Academy of Sciences, Novosibirsk, Russia
| | - V S Naumenko
- Institute of Cytology and Genetics of the Siberian Branch of the Russian Academy of Sciences, Novosibirsk, Russia
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11
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Zhao X, Wang Z, Wang J, Xu F, Zhang Y, Han D, Fang W. Mesencephalic astrocyte-derived neurotrophic factor (MANF) alleviates cerebral ischemia/reperfusion injury in mice by regulating microglia polarization via A20/NF-κB pathway. Int Immunopharmacol 2024; 127:111396. [PMID: 38134597 DOI: 10.1016/j.intimp.2023.111396] [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: 03/31/2023] [Revised: 10/31/2023] [Accepted: 12/13/2023] [Indexed: 12/24/2023]
Abstract
Microglia, resident brain immune cells, is critical in inflammation, apoptosis, neurogenesis and neurological recovery during cerebral ischemia/reperfusion (I/R) injury. Mesencephalic astrocyte-derived neurotrophic factor (MANF), a novel identified endoplasmic reticulum stress-inducible neurotrophic factor, can alleviate I/R injury by reducing the inflammatory reaction, but its specific regulatory mechanism on microglia after ischemic stroke has not been fully clarified. To mimic the process of ischemia/reperfusion in vivo and in vitro, middle cerebral artery occlusion/reperfusion (MCAO/R) was induced in C57BL/6J mice and oxygen glucose deprivation/reoxygenation (OGD/R) model was established in BV-2 cells. Moreover, MANF small interfering RNA (siRNA) was used to silence the expression of endogenous MANF, while recombination human MANF protein (rhMANF) acted as an exogenous supplement. Seventy-two hours after MCAO/R, 2,3,5-triphenyltetrazolium staining, neurological scores, brain water content, immunohistochemical staining, immunofluorescent staining, flow cytometry, hematoxylin and eosin staining, quantitative real-time PCR and western blot are applied to evaluate the protective effect and possible mechanism of MANF on cerebral I/R injury. In vitro, cell viability, inflammatory cytokines and the expression of MANF, A20, NF-κB and the markers of microglia were analyzed. The results showed that MANF decreased brain infarct volume, neurological scores, and brain water content. In addition, MANF promoted the polarization of microglia to an anti-inflammatory phenotype both in vivo and in vitro, which are related to A20/NF-κB pathway. In summary, MANF may offer novel therapeutic approaches for ischemic stroke in the process of microglia polarization.
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Affiliation(s)
- Xueyan Zhao
- Department of Pharmacy, Nanjing Drum Tower Hospital, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, Jiangsu, China; Department of Physiology, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, Jiangsu, China.
| | - Ziyu Wang
- Department of Physiology, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, Jiangsu, China.
| | - Jiang Wang
- Department of Physiology, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, Jiangsu, China.
| | - Fenglian Xu
- Department of Physiology, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, Jiangsu, China.
| | - Yi Zhang
- Department of Physiology, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, Jiangsu, China.
| | - Dan Han
- Department of Pharmacy, Nanjing Drum Tower Hospital, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, Jiangsu, China; Department of Pharmacy, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, China.
| | - Weirong Fang
- Department of Physiology, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, Jiangsu, China.
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12
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Anttila JE, Mattila OS, Liew HK, Mätlik K, Mervaala E, Lindholm P, Lindahl M, Lindsberg PJ, Tseng KY, Airavaara M. MANF protein expression is upregulated in immune cells in the ischemic human brain and systemic recombinant MANF delivery in rat ischemic stroke model demonstrates anti-inflammatory effects. Acta Neuropathol Commun 2024; 12:10. [PMID: 38229173 DOI: 10.1186/s40478-023-01701-y] [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: 09/26/2023] [Accepted: 12/03/2023] [Indexed: 01/18/2024] Open
Abstract
Mesencephalic astrocyte-derived neurotrophic factor (MANF) has cytoprotective effects on various injuries, including cerebral ischemia, and it can promote recovery even when delivered intracranially several days after ischemic stroke. In the uninjured rodent brain, MANF protein is expressed almost exclusively in neurons, but post-ischemic MANF expression has not been characterized. We aimed to investigate how endogenous cerebral MANF protein expression evolves in infarcted human brains and rodent ischemic stroke models. During infarct progression, the cerebral MANF expression pattern both in human and rat brains shifted drastically from neurons to expression in inflammatory cells. Intense MANF immunoreactivity took place in phagocytic microglia/macrophages in the ischemic territory, peaking at two weeks post-stroke in human and one-week post-stroke in rat ischemic cortex. Using double immunofluorescence and mice lacking MANF gene and protein from neuronal stem cells, neurons, astrocytes, and oligodendrocytes, we verified that MANF expression was induced in microglia/macrophage cells in the ischemic hemisphere. Embarking on the drastic expression transition towards inflammatory cells and the impact of blood-borne inflammation in stroke, we hypothesized that exogenously delivered MANF protein can modulate tissue recovery processes. In an attempt to enhance recovery, we designed a set of proof-of-concept studies using systemic delivery of recombinant MANF in a rat model of cortical ischemic stroke. Intranasal recombinant MANF treatment decreased infarct volume and reduced the severity of neurological deficits. Intravenous recombinant MANF treatment decreased the levels of pro-inflammatory cytokines and increased the levels of anti-inflammatory cytokine IL-10 in the infarcted cortex one-day post-stroke. In conclusion, MANF protein expression is induced in activated microglia/macrophage cells in infarcted human and rodent brains, and this could implicate MANF's involvement in the regulation of post-stroke inflammation in patients and experimental animals. Moreover, systemic delivery of recombinant MANF shows promising immunomodulatory effects and therapeutic potential in experimental ischemic stroke.
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Affiliation(s)
- Jenni E Anttila
- Institute of Biotechnology, University of Helsinki, Helsinki, Finland
| | - Olli S Mattila
- Department of Neurology, Helsinki University Hospital and Clinical Neurosciences, University of Helsinki, 00290, Helsinki, Finland
| | - Hock-Kean Liew
- Department of Medical Research, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Hualien County, Hualien, 970, Taiwan
| | - Kert Mätlik
- Institute of Biotechnology, University of Helsinki, Helsinki, Finland
| | - Eero Mervaala
- Department of Pharmacology, Faculty of Medicine, University of Helsinki, Helsinki, Finland
| | - Päivi Lindholm
- Institute of Biotechnology, University of Helsinki, Helsinki, Finland
| | - Maria Lindahl
- Institute of Biotechnology, University of Helsinki, Helsinki, Finland
| | - Perttu J Lindsberg
- Department of Neurology, Helsinki University Hospital and Clinical Neurosciences, University of Helsinki, 00290, Helsinki, Finland
| | - Kuan-Yin Tseng
- Department of Neurological Surgery, Tri-Service General Hospital and National Defense Medical Center, Taipei, 114, Taiwan.
| | - Mikko Airavaara
- Drug Research Program, Division of Pharmacology and Pharmacotherapy, Faculty of Pharmacy, University of Helsinki, Viikinkaari 5E, P.O. Box 56, 00014, Helsinki, Finland.
- Neuroscience Center, University of Helsinki, 00014, Helsinki, Finland.
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13
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Taylor SKB, Hartman JH, Gupta BP. Neurotrophic factor MANF regulates autophagy and lysosome function to promote proteostasis in C. elegans. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2023.07.31.551399. [PMID: 38260421 PMCID: PMC10802257 DOI: 10.1101/2023.07.31.551399] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/24/2024]
Abstract
The conserved mesencephalic astrocyte-derived neurotrophic factor (MANF) protects dopaminergic neurons but also functions in several other tissues. Previously, we showed that Caenorhabditis elegans manf-1 null mutants have increased ER stress, dopaminergic neurodegeneration, protein aggregation, slower growth, and a reduced lifespan. The multiple requirements of MANF in different systems suggest its essential role in regulating cellular processes. However, how intracellular and extracellular MANF regulates broader cellular function remains unknown. Here, we report a novel mechanism of action for manf-1 that involves the autophagy transcription factor HLH-30/TFEB-mediated signaling to regulate lysosomal function and aging. We generated multiple transgenic strains overexpressing MANF-1 and found that animals had extended lifespan, reduced protein aggregation, and improved neuronal health. Using a fluorescently tagged MANF-1, we observed different tissue localization of MANF-1 depending on the ER retention signal. Further subcellular analysis showed that MANF-1 localizes within cells to the lysosomes. These findings were consistent with our transcriptomic studies and, together with analysis of autophagy regulators, demonstrate that MANF-1 regulates protein homeostasis through increased autophagy and lysosomal activity. Collectively, our findings establish MANF as a critical regulator of the stress response, proteostasis, and aging.
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Affiliation(s)
- Shane K. B. Taylor
- Department of Biology, McMaster University, Hamilton, ON L8S 4K1, Canada
| | - Jessica H. Hartman
- Department of Biochemistry & Molecular Biology and Department of Regenerative Medicine & Cell Biology, Medical University of South Carolina, Charleston, SC 29425, USA
| | - Bhagwati P. Gupta
- Department of Biology, McMaster University, Hamilton, ON L8S 4K1, Canada
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14
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Wang J, Zhou N, Shen P, Li F, Zhao Q, Zang D, Zhang L, Lu W, Tian W, Jing L, Chen Y. Human milk-derived MANF, as an immuno-nutritional factor, maintains the intestinal epithelial barrier and protects against necrotizing enterocolitis. J Nutr Biochem 2023; 121:109431. [PMID: 37652307 DOI: 10.1016/j.jnutbio.2023.109431] [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: 06/05/2023] [Revised: 07/23/2023] [Accepted: 08/23/2023] [Indexed: 09/02/2023]
Abstract
Necrotizing enterocolitis (NEC) is a leading cause of death in preterm infants. Compared to formula milk, breastfeeding protects against NEC. However, the composition of breast milk is quite complicated, and many immunological compositions remain unknown. In this study, we aimed to investigate the concentration of a secreted protein, Mesencephalic astrocyte-derived neurotrophic factor (MANF), in breastmilk and evaluate its immune-regulatory function in protecting the intestinal epithelial barrier. Our data indicated that MANF was secreted in human milk but could not be detected in infant formulas. More importantly, the amount of MANF in colostrum was higher than that in mature milk. We also clarified that MANF was mainly expressed in intestinal macrophages and was capable of inducing apoptosis and decreasing the inflammation of pro-inflammatory macrophages in both NEC intestinal tissues and BMDMs. Mechanismly, MANF protein significantly inhibited the apoptosis of intestinal epithelial cells and protected epithelial tight junctions through downregulation of the NF-κB pathway in pro-inflammatory macrophages. These results reveal the crucial function of human milk-derived MANF in intestinal macrophages, which contributes to downregulating the intestinal inflammatory response and protecting the homeostasis of intestinal epithelial cells. Our study not only demonstrates a potential mechanism underlying breastfeeding protective effects in NEC but also, more importantly, enables clinical translation, facilitating new strategies for the development of nutritional interventions in the prevention of NEC.
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Affiliation(s)
- Jie Wang
- School of Basic Medical Sciences, Anhui Medical University, Hefei, China
| | - Nan Zhou
- School of Basic Medical Sciences, Anhui Medical University, Hefei, China
| | - Peijun Shen
- Anhui Maternal and Child Health Hospital, Hefei, China
| | - Fangmin Li
- School of Basic Medical Sciences, Anhui Medical University, Hefei, China
| | - Qian Zhao
- Department of Pediatrics, The First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Dandan Zang
- Center for Scientific Research, Anhui Medical University, Hefei, China
| | - Liu Zhang
- School of Nursing, Anhui Medical University, Hefei, China
| | - Wen Lu
- School of Basic Medical Sciences, Anhui Medical University, Hefei, China
| | - Wenjing Tian
- School of Basic Medical Sciences, Anhui Medical University, Hefei, China
| | - Ling Jing
- Anhui Maternal and Child Health Hospital, Hefei, China
| | - Ying Chen
- School of Basic Medical Sciences, Anhui Medical University, Hefei, China; School of Nursing, Anhui Medical University, Hefei, China.
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15
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Zhang C, Zhang M, Cao X, Jiao B, Zhang W, Yu S, Zhang X. Navigating the Landscape of MANF Research: A Scientometric Journey with CiteSpace Analysis. Cell Mol Neurobiol 2023; 43:3897-3913. [PMID: 37751132 PMCID: PMC10661837 DOI: 10.1007/s10571-023-01412-x] [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: 07/17/2023] [Accepted: 09/09/2023] [Indexed: 09/27/2023]
Abstract
This study employs bibliometric analysis through CiteSpace to comprehensively evaluate the status and trends of MANF (mesencephalic astrocyte-derived neurotrophic factor) research spanning 25 years (1997-2022). It aims to fill the gap in objective and comprehensive reviews of MANF research. MANF-related studies were extracted from the Web of Science database. MANF publications were quantitatively and qualitatively analyzed for various factors by CiteSpace, including publication volume, journals, countries/regions, institutions, and authors. Keywords and references were visually analyzed to unveil research evolution and hotspot. Analysis of 353 MANF-related articles revealed escalating annual publications, indicating growing recognition of MANF's importance. High-impact journals such as the International Journal of Molecular Sciences and Journal of Biological Chemistry underscored MANF's interdisciplinary significance. Collaborative networks highlighted China and the USA's pivotal roles, while influential figures and partnerships drove understanding of MANF's mechanisms. Co-word analysis of MANF-related keywords exposed key evolutionary hotspots, encompassing neurotrophic effects, cytoprotective roles, MANF-related diseases, and the CDNF/MANF family. This progression from basic understanding to clinical potential showcased MANF's versatility from cellular protection to therapy. Bibliometric analysis reveals MANF's diverse research trends and pathways, from basics to clinical applications, driving medical progress. This comprehensive assessment enriches understanding and empowers researchers for dynamic evolution, advancing innovation, and benefiting patients. Bibliometric analysis of MANF research. The graphical abstract depicts the bibliometric analysis of MANF research, highlighting its aims, methods, and key results.
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Affiliation(s)
- Caixia Zhang
- Department of Anesthesiology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jie Fang Avenue, Wuhan, 430030, Hubei, People's Republic of China
| | - Mi Zhang
- Department of Anesthesiology, Zhongnan Hospital, Wuhan University, Wuhan, Hubei, People's Republic of China
| | - Xueqin Cao
- Department of Anesthesiology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jie Fang Avenue, Wuhan, 430030, Hubei, People's Republic of China
| | - Bo Jiao
- Department of Anesthesiology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jie Fang Avenue, Wuhan, 430030, Hubei, People's Republic of China
| | - Wencui Zhang
- Department of Anesthesiology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jie Fang Avenue, Wuhan, 430030, Hubei, People's Republic of China
| | - Shangchen Yu
- Department of Anesthesiology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jie Fang Avenue, Wuhan, 430030, Hubei, People's Republic of China
| | - Xianwei Zhang
- Department of Anesthesiology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jie Fang Avenue, Wuhan, 430030, Hubei, People's Republic of China.
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16
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Gong L, Dong J, Huang K, Pan K, Wang S, Liu H. Effect of mesencephalic astrocyte-derived neurotrophic factor on the inflammatory response in human gingival fibroblasts cells. Eur J Oral Sci 2023; 131:e12945. [PMID: 37461146 DOI: 10.1111/eos.12945] [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: 01/12/2023] [Accepted: 07/06/2023] [Indexed: 11/04/2023]
Abstract
Mesencephalic astrocyte-derived neurotrophic factor (MANF) is a unique member of the neurotrophic factor family residing in the endoplasmic reticulum, where it functions as a stress response protein maintaining endoplasmic reticulum homeostasis, in addition to being secreted extracellularly as a neurotrophic factor to bind with receptors to initiate intracellular signal transduction pathways. Interestingly, MANF has shown an important protective role in the inflammatory response of many diseases. In neural stem cells, pancreatic β cells, and retinal cells, MANF can inhibit the inflammatory response, modulate the immune response, and promote tissue repair. However, the role of MANF in the periodontal inflammatory response remains unclear. In the present study, we used lipopolysaccharide (LPS) from Porphyromonas gingivalis (Pg) to establish a Pg-LPS-stimulated periodontal inflammatory model in human gingival fibroblasts cells (HGF-1) to investigate the role of MANF in vitro. We found that MANF could inhibit pro-inflammatory cytokine secretion, alleviate the endoplasmic reticulum stress response, promote cell survival, and inhibit cell apoptosis. Therefore, MANF might be a novel promising target for the treatment of periodontitis.
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Affiliation(s)
- Lei Gong
- Department of Laboratory Center, The Affiliated Yantai Yuhuangding Hospital of Qingdao University, Yantai, Shandong, China
| | - Jie Dong
- Department of Laboratory Center, The Affiliated Yantai Yuhuangding Hospital of Qingdao University, Yantai, Shandong, China
| | - Kai Huang
- College of Stomatology, Binzhou Medical University, Yantai, Shandong, China
| | - Keqing Pan
- Department of Stomatology, The Affiliated Hospital of Qingdao University, Qingdao, Shandong, China
| | - Shengzhi Wang
- Department of Stomatology, The Affiliated Yantai Yuhuangding Hospital of Qingdao University, Yantai, Shandong, China
| | - Hao Liu
- Department of Stomatology, The Affiliated Yantai Yuhuangding Hospital of Qingdao University, Yantai, Shandong, China
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17
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Wen W, Wang Y, Li H, Hu D, Zhang Z, Lin H, Luo J. Upregulation of mesencephalic astrocyte-derived neurotrophic factor (MANF) expression offers protection against alcohol neurotoxicity. J Neurochem 2023; 166:943-959. [PMID: 37507360 PMCID: PMC10906989 DOI: 10.1111/jnc.15921] [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: 01/30/2023] [Revised: 07/05/2023] [Accepted: 07/06/2023] [Indexed: 07/30/2023]
Abstract
Alcohol exposure has detrimental effects on both the developing and mature brain. Endoplasmic reticulum (ER) stress is one of the mechanisms that contributes to alcohol-induced neuronal damages. Mesencephalic astrocyte-derived neurotrophic factor (MANF) is an ER stress-responsive protein and is neuroprotective in multiple neuronal injury and neurodegenerative disease models. MANF deficiency has been shown to exacerbate alcohol-induced ER stress and neurodegeneration. However, it is unknown whether MANF supplement is sufficient to protect against alcohol neurotoxicity. Alcohol alters MANF expression in the brain, but the mechanisms underlying alcohol modulation of MANF expression remain unclear. This study was designed to determine how alcohol alters MANF expression in neuronal cells and whether exogeneous MANF can alleviate alcohol neurotoxicity. We showed that alcohol increased MANF transcription and secretion without affecting MANF mRNA stability and protein degradation. ER stress was necessary for alcohol-induced MANF upregulation, as pharmacological inhibition of ER stress by 4-PBA diminished alcohol-induced MANF expression. In addition, the presence of ER stress response element II (ERSE-II) was required for alcohol-stimulated MANF transcription. Mutations or deletion of this sequence abolished alcohol-regulated transcriptional activity. We generated MANF knockout (KO) neuronal cells using CRISPR/Cas9. MANF KO cells exhibited increased unfolded protein response (UPR) and were more susceptible to alcohol-induced cell death. On the other hand, MANF upregulation by the addition of recombinant MANF protein or adenovirus gene transduction protected neuronal cells against alcohol-induced cell death. Further studies using early postnatal mouse pups demonstrated that enhanced MANF expression in the brain by intracerebroventricular (ICV) injection of MANF adeno-associated viruses ameliorated alcohol-induced cell death. Thus, alcohol increased MANF expression through inducing ER stress, which could be a protective response. Exogenous MANF was able to protect against alcohol-induced neurodegeneration.
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Affiliation(s)
- Wen Wen
- Department of Pathology, University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA
| | - Yongchao Wang
- Vanderbilt Memory and Alzheimer’s Center, Department of Neurology, Vanderbilt University Medical Center, Nashville, TN 37372, USA
| | - Hui Li
- Department of Pathology, University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA
| | - Di Hu
- Department of Pathology, University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA
| | - Zuohui Zhang
- Department of Pathology, University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA
| | - Hong Lin
- Department of Pathology, University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA
| | - Jia Luo
- Department of Pathology, University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA
- VA Iowa City Health Care System, Iowa City, IA 52246, USA
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18
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Pakarinen E, Lindholm P. CDNF and MANF in the brain dopamine system and their potential as treatment for Parkinson's disease. Front Psychiatry 2023; 14:1188697. [PMID: 37555005 PMCID: PMC10405524 DOI: 10.3389/fpsyt.2023.1188697] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/17/2023] [Accepted: 05/23/2023] [Indexed: 08/10/2023] Open
Abstract
Parkinson's disease (PD) is a progressive neurodegenerative disease characterized by gradual loss of midbrain dopamine neurons, leading to impaired motor function. Preclinical studies have indicated cerebral dopamine neurotrophic factor (CDNF) and mesencephalic astrocyte-derived neurotrophic factor (MANF) to be potential therapeutic molecules for the treatment of PD. CDNF was proven to be safe and well tolerated when tested in Phase I-II clinical trials in PD patients. Neuroprotective and neurorestorative effects of CDNF and MANF were demonstrated in animal models of PD, where they promoted the survival of dopamine neurons and improved motor function. However, biological roles of endogenous CDNF and MANF proteins in the midbrain dopamine system have been less clear. In addition to extracellular trophic activities, CDNF/MANF proteins function intracellularly in the endoplasmic reticulum (ER), where they modulate protein homeostasis and protect cells against ER stress by regulating the unfolded protein response (UPR). Here, our aim is to give an overview of the biology of endogenous CDNF and MANF in the brain dopamine system. We will discuss recent studies on CDNF and MANF knockout animal models, and effects of CDNF and MANF in preclinical models of PD. To elucidate possible roles of CDNF and MANF in human biology, we will review CDNF and MANF tissue expression patterns and regulation of CDNF/MANF levels in human diseases. Finally, we will discuss novel findings related to the molecular mechanism of CDNF and MANF action in ER stress, UPR, and inflammation, all of which are mechanisms potentially involved in the pathophysiology of PD.
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Affiliation(s)
| | - Päivi Lindholm
- Institute of Biotechnology, Helsinki Institute of Life Science, University of Helsinki, Helsinki, Finland
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19
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Caglayan AB, Beker MC, Sertel Evren E, Caglayan B, Kilic Ü, Ates N, Caglayan A, Dasdelen MF, Doeppner TR, Saarma M, Hermann DM, Kilic E. The Unconventional Growth Factors Cerebral Dopamine Neurotrophic Factor and Mesencephalic Astrocyte-Derived Neurotrophic Factor Promote Post-ischemic Neurological Recovery, Perilesional Brain Remodeling, and Lesion-Remote Axonal Plasticity. Transl Stroke Res 2023; 14:263-277. [PMID: 35583716 DOI: 10.1007/s12975-022-01035-2] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2021] [Revised: 04/20/2022] [Accepted: 05/09/2022] [Indexed: 12/22/2022]
Abstract
Considerable efforts are currently made to develop strategies that boost endogenous recovery once a stroke has occurred. Owing to their restorative properties, neurotrophic factors are attractive candidates that capitalize on endogenous response mechanisms. Non-conventional growth factors cerebral dopamine neurotrophic factor (CDNF) and mesencephalic astrocyte-derived neurotrophic factor (MANF) promote neuronal survival and reduce neurological deficits in the acute phase of ischemic stroke in mice. Their effects on endogenous repair and recovery mechanisms in the stroke recovery phase were so far unknown. By intracerebroventricular delivery of CDNF or MANF starting 3 days post-stroke (1 µg/day for 28 days via miniosmotic pumps), we show that delayed CDNF and MANF administration promoted functional neurological recovery assessed by a battery of behavioral tests, increased long-term neuronal survival, reduced delayed brain atrophy, glial scar formation, and, in case of CDNF but not MANF, increased endogenous neurogenesis in the perilesional brain tissue. Besides, CDNF and MANF administration increased long-distance outgrowth of terminal axons emanating from the contralesional pyramidal tract, which crossed the midline to innervate ipsilesional facial nucleus. This plasticity promoting effect was accompanied by downregulation of the axonal growth inhibitor versican and the guidance molecules ephrin B1 and B2 in the previously ischemic hemisphere at 14 dpi, which represents a sensitive time-point for axonal growth. CDNF and MANF reduced the expression of the proinflammatory cytokines IL1β and TNFα in both hemispheres. The effects of non-conventional growth factors in the ischemic brain should further be examined since they might help to identify targets for restorative stroke therapy.
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Affiliation(s)
- Ahmet Burak Caglayan
- Department of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, NY, USA
- International School of Medicine, Department of Physiology, Istanbul Medipol University, Istanbul, Turkey
- Research Institute for Health Sciences and Technologies (SABITA), Istanbul Medipol University, Istanbul, Turkey
| | - Mustafa Caglar Beker
- Research Institute for Health Sciences and Technologies (SABITA), Istanbul Medipol University, Istanbul, Turkey
- School of Medicine, Dept. of Physiology, Regenerative and Restorative Medical Research Center, Istanbul Medipol University, Ekinciler Cad. 19, TR-34810, Istanbul, Turkey
| | - Elif Sertel Evren
- Research Institute for Health Sciences and Technologies (SABITA), Istanbul Medipol University, Istanbul, Turkey
- School of Medicine, Dept. of Physiology, Regenerative and Restorative Medical Research Center, Istanbul Medipol University, Ekinciler Cad. 19, TR-34810, Istanbul, Turkey
| | - Berrak Caglayan
- Research Institute for Health Sciences and Technologies (SABITA), Istanbul Medipol University, Istanbul, Turkey
- International School of Medicine, Dept. of Medical Biology, Istanbul Medipol University, Istanbul, Turkey
| | - Ülkan Kilic
- Hamidiye School of Medicine, Department of Medical Biology, University of Health Sciences Turkey, Istanbul, Turkey
| | - Nilay Ates
- Research Institute for Health Sciences and Technologies (SABITA), Istanbul Medipol University, Istanbul, Turkey
- Faculty of Medicine, Department of Pharmacology, Istanbul Medipol University, Istanbul, Turkey
| | - Aysun Caglayan
- Research Institute for Health Sciences and Technologies (SABITA), Istanbul Medipol University, Istanbul, Turkey
- School of Medicine, Dept. of Physiology, Regenerative and Restorative Medical Research Center, Istanbul Medipol University, Ekinciler Cad. 19, TR-34810, Istanbul, Turkey
| | - Muhammed Furkan Dasdelen
- Research Institute for Health Sciences and Technologies (SABITA), Istanbul Medipol University, Istanbul, Turkey
- School of Medicine, Dept. of Physiology, Regenerative and Restorative Medical Research Center, Istanbul Medipol University, Ekinciler Cad. 19, TR-34810, Istanbul, Turkey
| | - Thorsten Roland Doeppner
- Research Institute for Health Sciences and Technologies (SABITA), Istanbul Medipol University, Istanbul, Turkey
- Department of Neurology, University Medical Center Göttingen, Göttingen, Germany
- Department of Neurology, University Hospital Giessen, Giessen, Germany
| | - Mart Saarma
- Institute of Biotechnology, Helsinki Institute of Life Science, University of Helsinki, Helsinki, Finland
| | - Dirk Matthias Hermann
- Department of Neurology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
| | - Ertugrul Kilic
- Research Institute for Health Sciences and Technologies (SABITA), Istanbul Medipol University, Istanbul, Turkey.
- School of Medicine, Dept. of Physiology, Regenerative and Restorative Medical Research Center, Istanbul Medipol University, Ekinciler Cad. 19, TR-34810, Istanbul, Turkey.
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20
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Sivakumar B, Krishnan A. Mesencephalic Astrocyte-Derived Neurotrophic Factor (MANF): An Emerging Therapeutic Target for Neurodegenerative Disorders. Cells 2023; 12:cells12071032. [PMID: 37048105 PMCID: PMC10093115 DOI: 10.3390/cells12071032] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2023] [Revised: 03/12/2023] [Accepted: 03/26/2023] [Indexed: 03/30/2023] Open
Abstract
Mesencephalic astrocyte-derived neurotrophic factor (MANF) is a member of the new family of neurotrophic factors (NTFs) with a unique structure and functions compared to other conventionally known NTFs. MANF is broadly expressed in developing and mature tissues, including the central nervous system and peripheral nervous system tissues. Growing research demonstrated that MANF protects neurons from endoplasmic reticulum (ER) stress-associated complications by restoring ER homeostasis and regulating unfolded protein response. This review discusses MANF signaling in neurodegenerative conditions with specific emphasis given to its overall effect and mechanisms of action in experimental models of Parkinson’s disease, Alzheimer’s disease, and stroke. Additional perspectives on its potential unexplored roles in other neurodegenerative conditions are also given.
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Affiliation(s)
- Bhadrapriya Sivakumar
- Department of Anatomy, Physiology, and Pharmacology, College of Medicine, University of Saskatchewan, Saskatoon, SK S7N 5E5, Canada
- Cameco MS Neuroscience Research Centre (CMSNRC), Saskatoon, SK S7K 0M7, Canada
| | - Anand Krishnan
- Department of Anatomy, Physiology, and Pharmacology, College of Medicine, University of Saskatchewan, Saskatoon, SK S7N 5E5, Canada
- Cameco MS Neuroscience Research Centre (CMSNRC), Saskatoon, SK S7K 0M7, Canada
- Correspondence: ; Tel.: +1-306-655-8711
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21
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Fingelkurts AA, Fingelkurts AA. Turning Back the Clock: A Retrospective Single-Blind Study on Brain Age Change in Response to Nutraceuticals Supplementation vs. Lifestyle Modifications. Brain Sci 2023; 13:520. [PMID: 36979330 PMCID: PMC10046544 DOI: 10.3390/brainsci13030520] [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: 02/20/2023] [Revised: 03/17/2023] [Accepted: 03/19/2023] [Indexed: 03/30/2023] Open
Abstract
BACKGROUND There is a growing consensus that chronological age (CA) is not an accurate indicator of the aging process and that biological age (BA) instead is a better measure of an individual's risk of age-related outcomes and a more accurate predictor of mortality than actual CA. In this context, BA measures the "true" age, which is an integrated result of an individual's level of damage accumulation across all levels of biological organization, along with preserved resources. The BA is plastic and depends upon epigenetics. Brain state is an important factor contributing to health- and lifespan. METHODS AND OBJECTIVE Quantitative electroencephalography (qEEG)-derived brain BA (BBA) is a suitable and promising measure of brain aging. In the present study, we aimed to show that BBA can be decelerated or even reversed in humans (N = 89) by using customized programs of nutraceutical compounds or lifestyle changes (mean duration = 13 months). RESULTS We observed that BBA was younger than CA in both groups at the end of the intervention. Furthermore, the BBA of the participants in the nutraceuticals group was 2.83 years younger at the endpoint of the intervention compared with their BBA score at the beginning of the intervention, while the BBA of the participants in the lifestyle group was only 0.02 years younger at the end of the intervention. These results were accompanied by improvements in mental-physical health comorbidities in both groups. The pre-intervention BBA score and the sex of the participants were considered confounding factors and analyzed separately. CONCLUSIONS Overall, the obtained results support the feasibility of the goal of this study and also provide the first robust evidence that halting and reversal of brain aging are possible in humans within a reasonable (practical) timeframe of approximately one year.
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22
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Zhang Q, Shi S, Tang Y, Qu C, Wen S, Pan Y. Manf Enhances the Pyroptosis Inhibition of Bone Marrow-derived Mesenchymal Stem Cells to Relieve Cerebral Infarction Injury. Neuroscience 2023; 510:109-128. [PMID: 36529294 DOI: 10.1016/j.neuroscience.2022.11.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2022] [Revised: 10/30/2022] [Accepted: 11/04/2022] [Indexed: 12/17/2022]
Abstract
Cerebral infarction is a common disease characterized by high mortality, a narrow therapeutic window, and limited therapeutic options. Recently, cell therapy based on gene modification has brought a glimmer of hope to the treatment of cerebral infarction although the explicit underlying mechanism is beyond being well dissected. In the present study, we constructed an animal model of middle cerebral artery occlusion (MCAO), compared differentially expressed genes (DEGs) between the sham and MCAO groups by single-cell RNA sequencing (scRNA-seq) to explore the potential cell death-related pathways involved in cerebral infarction, and transfected Manf into BMSCs by lentivirus. Subsequently, we injected BMSCs (bone marrow-derived mesenchymal stem cells), Manf-modified BMSCs, or lentivirus encoding Manf into the brain. Their effects on MANF content, apoptosis, pyroptosis, infarct volume in the brain, and neurological function were evaluated after MCAO. We found that the DEGs upregulated in four major cell clusters after MCAO and were enriched with not only apoptosis, ferroptosis, and necroptosis but also with pyroptosis-related pathways. In addition, transfection of Manf into BMSCs significantly increased the expression and secretion of MANF in BMSCs; BMSCs, Manf-modified BMSCs, and Manf treatment all resulted in an increase in Manf content in the brain, a decrease in the expression of apoptosis- and pyroptosis-related molecules, a reduction in infarct volume, and an improvement in neurological function after MCAO. Moreover, Manf-modified BMSCs have the strongest therapeutic effect. Collectively, Manf-modified BMSCs ameliorate ischemic injury after cerebral infarction by repressing apoptosis- and pyroptosis-related molecules, which represents a new cell therapy strategy for cerebral infarction.
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Affiliation(s)
- Qi Zhang
- Department of Neurology, the First Clinical College of Harbin Medical University, No. 23, Youzheng Street, Nangang District, Harbin 150001, Heilongjiang Province, China
| | - Shanshan Shi
- Department of Neurology, the First Clinical College of Harbin Medical University, No. 23, Youzheng Street, Nangang District, Harbin 150001, Heilongjiang Province, China
| | - Yushi Tang
- Department of Neurology, the First Clinical College of Harbin Medical University, No. 23, Youzheng Street, Nangang District, Harbin 150001, Heilongjiang Province, China
| | - Changda Qu
- Department of Neurology, the First Clinical College of Harbin Medical University, No. 23, Youzheng Street, Nangang District, Harbin 150001, Heilongjiang Province, China
| | - Shirong Wen
- Department of Neurology, the First Clinical College of Harbin Medical University, No. 23, Youzheng Street, Nangang District, Harbin 150001, Heilongjiang Province, China
| | - Yujun Pan
- Department of Neurology, the First Clinical College of Harbin Medical University, No. 23, Youzheng Street, Nangang District, Harbin 150001, Heilongjiang Province, China.
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23
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Yang L, Shen WW, Shao W, Zhao Q, Pang GZ, Yang Y, Tao XF, Zhang WP, Mei Q, Shen YX. MANF ameliorates DSS-induced mouse colitis via restricting Ly6C hiCX3CR1 int macrophage transformation and suppressing CHOP-BATF2 signaling pathway. Acta Pharmacol Sin 2023; 44:1175-1190. [PMID: 36635421 DOI: 10.1038/s41401-022-01045-8] [Citation(s) in RCA: 23] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/28/2022] [Accepted: 12/19/2022] [Indexed: 01/14/2023]
Abstract
Mesencephalic astrocyte-derived neurotrophic factor (MANF), an endoplasmic reticulum stress-inducible secreting protein, has evolutionarily conserved immune-regulatory function that contributes to the negative regulation of inflammation in macrophages. In this study, we investigated the profiles of MANF in the macrophages of the patients with active inflammatory bowel disease (IBD) and the mice with experimental colitis, which was induced in both myeloid cell-specific MANF knockout mice and wild-type mice by 3% dextran sodium sulfate (DSS) for 7 days. We found that MANF expression was significantly increased in intestinal macrophages from both the mice with experimental colitis and patients with active IBD. DSS-induced colitis was exacerbated in myeloid cell-specific MANF knockout mice. Injection of recombinant human MANF (rhMANF, 10 mg·kg-1·d-1, i.v.) from D4 to D6 significantly ameliorated experimental colitis in DSS-treated mice. More importantly, MANF deficiency in myeloid cells resulted in a dramatic increase in the number of Ly6ChiCX3CRint proinflammatory macrophages in colon lamina propria of DSS-treated mice, and the proinflammatory cytokines and chemokines were upregulated as well. Meanwhile, we demonstrated that MANF attenuated Th17-mediated immunopathology by inhibiting BATF2-mediated innate immune response and downregulating CXCL9, CXCL10, CXCL11 and IL-12p40; MANF functioned as a negative regulator in inflammatory macrophages via inhibiting CHOP-BATF2 signaling pathway, thereby protecting against DSS-induced mouse colitis. These results suggest that MANF ameliorates colon injury by negatively regulating inflammatory macrophage transformation, which shed light on a potential therapeutic target for IBD.
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Affiliation(s)
- Lin Yang
- School of Basic Medical Sciences, Anhui Medical University, Hefei, 230032, China.,Biopharmaceutical Institute, Anhui Medical University, Hefei, 230032, China
| | - Wen-Wen Shen
- School of Basic Medical Sciences, Anhui Medical University, Hefei, 230032, China.,Biopharmaceutical Institute, Anhui Medical University, Hefei, 230032, China
| | - Wei Shao
- School of Basic Medical Sciences, Anhui Medical University, Hefei, 230032, China.,Biopharmaceutical Institute, Anhui Medical University, Hefei, 230032, China
| | - Qing Zhao
- School of Basic Medical Sciences, Anhui Medical University, Hefei, 230032, China.,Biopharmaceutical Institute, Anhui Medical University, Hefei, 230032, China
| | - Gao-Zong Pang
- School of Basic Medical Sciences, Anhui Medical University, Hefei, 230032, China.,Biopharmaceutical Institute, Anhui Medical University, Hefei, 230032, China
| | - Yi Yang
- School of Basic Medical Sciences, Anhui Medical University, Hefei, 230032, China.,Biopharmaceutical Institute, Anhui Medical University, Hefei, 230032, China.,First Affiliated Hospital of Anhui Medical University, Hefei, 230032, China
| | - Xiao-Fang Tao
- School of Basic Medical Sciences, Anhui Medical University, Hefei, 230032, China.,Biopharmaceutical Institute, Anhui Medical University, Hefei, 230032, China
| | - Wei-Ping Zhang
- First Affiliated Hospital of Anhui Medical University, Hefei, 230032, China
| | - Qiong Mei
- School of Basic Medical Sciences, Anhui Medical University, Hefei, 230032, China.,Biopharmaceutical Institute, Anhui Medical University, Hefei, 230032, China
| | - Yu-Xian Shen
- School of Basic Medical Sciences, Anhui Medical University, Hefei, 230032, China. .,Biopharmaceutical Institute, Anhui Medical University, Hefei, 230032, China.
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24
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Deng H, Zhang P, Gao X, Chen W, Li J, Wang F, Gu Y, Hou X. Emerging trophic activities of mesencephalic astrocyte-derived neurotrophic factor in tissue repair and regeneration. Int Immunopharmacol 2023; 114:109598. [PMID: 36538855 DOI: 10.1016/j.intimp.2022.109598] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2022] [Revised: 12/05/2022] [Accepted: 12/12/2022] [Indexed: 12/23/2022]
Abstract
Mesencephalic astrocyte-derived neurotrophic factor (MANF) is a soluble endoplasmic reticulum (ER) luminal protein and its expression and secretion can be induced by ER stress. Despite initially being classified as a neurotrophic factor, MANF has been demonstrated to have restorative and protective effects in many different cell types such as neurons, liver cells, retinal cells, cardiac myocytes, and pancreatic β cells. However, underlying molecular mechanisms are complex and remain incompletely understood. The aims of this review are to highlight the latest advances in the understanding of the trophic activities of MANF in tissue repair and regeneration as well as underlying molecular mechanisms. The structural motifs and immune modulation of MANF are also described. We therefore propose that MANF might be a promising therapeutic target for tissue repair.
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Affiliation(s)
- Haiyan Deng
- School of Medicine, Ningbo University, Ningbo, Zhejiang 315211, PR China
| | - Pingping Zhang
- Institute of Clinical Pharmacology, Anhui Medical University, Key Laboratory of Anti-inflammatory and Immune Medicine, Ministry of Education, Anhui Collaborative Innovation Center of Anti-inflammatory and Immune Medicine, Hefei, PR China
| | - Xianxian Gao
- School of Medicine, Ningbo University, Ningbo, Zhejiang 315211, PR China
| | - Weiyi Chen
- School of Medicine, Ningbo University, Ningbo, Zhejiang 315211, PR China
| | - Jianing Li
- School of Medicine, Ningbo University, Ningbo, Zhejiang 315211, PR China
| | - Fuyan Wang
- School of Medicine, Ningbo University, Ningbo, Zhejiang 315211, PR China; Qingdao Hospital of Traditional Chinese Medicine (Qingdao Hiser Hospital), Qingdao, 266000, PR China
| | - Yiyue Gu
- Department of Cardiology, Xuzhou No.1 Peoples Hospital, Xuzhou, PR China
| | - Xin Hou
- School of Medicine, Ningbo University, Ningbo, Zhejiang 315211, PR China; The Affiliated Hospital of Medical School, Ningbo University, Ningbo, PR China.
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25
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MANF/EWSR1/ANXA6 pathway might as the bridge between hypolipidemia and major depressive disorder. Transl Psychiatry 2022; 12:527. [PMID: 36585419 PMCID: PMC9803680 DOI: 10.1038/s41398-022-02287-0] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/17/2022] [Revised: 12/08/2022] [Accepted: 12/13/2022] [Indexed: 12/31/2022] Open
Abstract
Major depressive disorder (MDD) involves changes in lipid metabolism, but previous findings are contradictory. Mesencephalic astrocyte-derived neurotrophic factor (MANF) is considered to be a regulator of lipid metabolism. To date, the function of MANF has been studied in many brain disorders, but not in MDD. Therefore, to better understand the role of lipids in MDD, this study was conducted to examine lipid levels in the serum of MDD patients and to investigate the potential function of MANF in MDD. First, the data on total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and triglyceride (TG) in serum from 354 MDD patients and 360 healthy controls (HCs) were collected and analyzed. The results showed that there were significantly lower concentrations of TC and LDL-C in MDD patients compared with HCs, and TC levels were positively correlated with LDL-C levels. Bioinformatics analysis indicated that MANF/EWSR1/ANXA6 pathway might serve as the connecting bridge through which hypolipidemia played a functional role in MDD. Second, to verify this hypothesis, serum samples were collected from 143 MDD patients, and 67 HCs to measure the levels of MANF, EWSR1, and ANXA6 using ELISA kits. The results showed that compared to HCs, MDD patients had a significantly lower level of MANF and higher levels of ANXA6 and EWSR1, and these molecules were significantly correlated with both TC level and Hamilton Depression Rating Scales (HDRS) score. In addition, a discriminative model consisting of MANF, EWSR1, and ANXA6 was identified. This model was capable of distinguishing MDD subjects from HCs, yielded an area under curve of 0.9994 in the training set and 0.9569 in the testing set. Taken together, our results suggested that MANF/EWSR1/ANXA6 pathway might act as the bridge between hypolipidemia and MDD, and these molecules held promise as potential biomarkers for MDD.
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26
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Liu YY, Huo D, Zeng LT, Fan GQ, Shen T, Zhang TM, Cai JP, Cui J. Mesencephalic astrocyte-derived neurotrophic factor (MANF): Structure, functions and therapeutic potential. Ageing Res Rev 2022; 82:101763. [PMID: 36272696 DOI: 10.1016/j.arr.2022.101763] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2022] [Revised: 09/18/2022] [Accepted: 10/15/2022] [Indexed: 01/31/2023]
Abstract
Mesencephalic astrocyte-derived neurotrophic factor (MANF) is a novel evolutionarily conserved protein present in both vertebrate and invertebrate species. MANF shows distinct structural and functional properties than the traditional neurotrophic factors (NTF). MANF is composed of an N-terminal saposin-like lipid-binding domain and a C-terminal SAF-A/B, Acinus and PIAS (SAP) domain connected by a short linker. The two well-described activities of MANF include (1) role as a neurotrophic factor that plays direct neuroprotective effects in the nervous system and (2) cell protective effects in the animal models of non-neuronal diseases, including retinal damage, diabetes mellitus, liver injury, myocardial infarction, nephrotic syndrome, etc. The main objective of the current review is to provide up-to-date insights regarding the structure of MANF, mechanisms regulating its expression and secretion, physiological functions in various tissues and organs, protective effects during aging, and potential clinical applications. Together, this review highlights the importance of MANF in reversing age-related dysfunction and geroprotection.
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Affiliation(s)
- Yuan-Yuan Liu
- The Key Laboratory of Geriatrics, Beijing Institute of Geriatrics, Institute of Geriatric Medicine, Chinese Academy of Medical Science, Beijing Hospital/National Center of Gerontology of National Health Commission, Beijing, PR China
| | - Da Huo
- The Key Laboratory of Geriatrics, Beijing Institute of Geriatrics, Institute of Geriatric Medicine, Chinese Academy of Medical Science, Beijing Hospital/National Center of Gerontology of National Health Commission, Beijing, PR China
| | - Lv-Tao Zeng
- The Key Laboratory of Geriatrics, Beijing Institute of Geriatrics, Institute of Geriatric Medicine, Chinese Academy of Medical Science, Beijing Hospital/National Center of Gerontology of National Health Commission, Beijing, PR China
| | - Guo-Qing Fan
- The Key Laboratory of Geriatrics, Beijing Institute of Geriatrics, Institute of Geriatric Medicine, Chinese Academy of Medical Science, Beijing Hospital/National Center of Gerontology of National Health Commission, Beijing, PR China
| | - Tao Shen
- The Key Laboratory of Geriatrics, Beijing Institute of Geriatrics, Institute of Geriatric Medicine, Chinese Academy of Medical Science, Beijing Hospital/National Center of Gerontology of National Health Commission, Beijing, PR China
| | - Tie-Mei Zhang
- The Key Laboratory of Geriatrics, Beijing Institute of Geriatrics, Institute of Geriatric Medicine, Chinese Academy of Medical Science, Beijing Hospital/National Center of Gerontology of National Health Commission, Beijing, PR China
| | - Jian-Ping Cai
- The Key Laboratory of Geriatrics, Beijing Institute of Geriatrics, Institute of Geriatric Medicine, Chinese Academy of Medical Science, Beijing Hospital/National Center of Gerontology of National Health Commission, Beijing, PR China.
| | - Ju Cui
- The Key Laboratory of Geriatrics, Beijing Institute of Geriatrics, Institute of Geriatric Medicine, Chinese Academy of Medical Science, Beijing Hospital/National Center of Gerontology of National Health Commission, Beijing, PR China.
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27
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Tang Q, Liu Q, Li J, Yan J, Jing X, Zhang J, Xia Y, Xu Y, Li Y, He J. MANF in POMC Neurons Promotes Brown Adipose Tissue Thermogenesis and Protects Against Diet-Induced Obesity. Diabetes 2022; 71:2344-2359. [PMID: 35972224 PMCID: PMC9630086 DOI: 10.2337/db21-1128] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/13/2021] [Accepted: 08/07/2022] [Indexed: 01/25/2023]
Abstract
Mesencephalic astrocyte-derived neurotrophic factor (MANF) is an emerging regulator in metabolic control. Hypothalamic proopiomelanocortin (POMC) neurons play critical roles in maintaining whole-body energy homeostasis. Whether MANF in POMC neurons is required for the proper regulation of energy balance remains unknown. Here, we showed that mice lacking MANF in POMC neurons were more prone to develop diet-induced obesity. In addition, the ablation of MANF induced endoplasmic reticulum (ER) stress and leptin resistance in the hypothalamus, reduced POMC expression and posttranslational processing, and ultimately decreased sympathetic nerve activity and thermogenesis in brown adipose tissue (BAT). Conversely, MANF overexpression in hypothalamic POMC neurons attenuated ER stress, increased POMC expression and processing, and then stimulated sympathetic innervation and activity in BAT, resulting in increased BAT thermogenesis, thus protecting mice against dietary obesity. Overall, our findings provide evidence that MANF is required for POMC neurons to combat obesity.
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Affiliation(s)
- Qin Tang
- Laboratory of Clinical Pharmacy and Adverse Drug Reaction, West China Hospital, Sichuan University, Chengdu, China
| | - Qinhui Liu
- Laboratory of Clinical Pharmacy and Adverse Drug Reaction, West China Hospital, Sichuan University, Chengdu, China
| | - Jiahui Li
- Laboratory of Clinical Pharmacy and Adverse Drug Reaction, West China Hospital, Sichuan University, Chengdu, China
- Department of Pharmacy, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China
| | - Jiamin Yan
- Laboratory of Clinical Pharmacy and Adverse Drug Reaction, West China Hospital, Sichuan University, Chengdu, China
- Department of Pharmacy, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China
| | - Xiandan Jing
- Laboratory of Clinical Pharmacy and Adverse Drug Reaction, West China Hospital, Sichuan University, Chengdu, China
| | - Jinhang Zhang
- Laboratory of Clinical Pharmacy and Adverse Drug Reaction, West China Hospital, Sichuan University, Chengdu, China
- Department of Pharmacy, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China
| | - Yan Xia
- Laboratory of Clinical Pharmacy and Adverse Drug Reaction, West China Hospital, Sichuan University, Chengdu, China
- Department of Pharmacy, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China
| | - Ying Xu
- Laboratory of Clinical Pharmacy and Adverse Drug Reaction, West China Hospital, Sichuan University, Chengdu, China
- Department of Pharmacy, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China
| | - Yanping Li
- Laboratory of Clinical Pharmacy and Adverse Drug Reaction, West China Hospital, Sichuan University, Chengdu, China
| | - Jinhan He
- Laboratory of Clinical Pharmacy and Adverse Drug Reaction, West China Hospital, Sichuan University, Chengdu, China
- Department of Pharmacy, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China
- Corresponding author: Jinhan He,
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28
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Increased serum concentrations of Mesencephalic astrocyte-derived neurotrophic factor in patients and rats with ischemic stroke. J Stroke Cerebrovasc Dis 2022; 31:106752. [PMID: 36087374 DOI: 10.1016/j.jstrokecerebrovasdis.2022.106752] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2022] [Revised: 08/24/2022] [Accepted: 08/29/2022] [Indexed: 11/24/2022] Open
Abstract
OBJECTIVES Although Mesencephalic astrocyte-derived neurotrophic factor (MANF) shows protection in multiple cells, the role of circulating MANF in patients with acute ischemic stroke (AIS) and transient ischemic attack (TIA) remains unclear. Here, we aimed to explore the value of circulating MANF levels in cerebral ischemic events. MATERIALS AND METHODS Using a rat cerebral ischemic model, MANF expression in ischemic brains and serum was detected. 50 AIS patients, 56 TIA patients and 48 controls were enrolled, and MANF mRNA, inflammatory cytokines and MANF concentrations in serum and different blood cell types were detected. The National Institutes of Health Stroke Scale (NIHSS) score and Alberta Stroke Program Early CT Score (ASPECTS) were used to evaluate stroke severity. Cerebrovascular recurrence within 90 d was documented during TIA follow-up. RESULTS MANF expression increased at 2h, peaking at 24h and decreased to baseline at 7d in rat ischemic brains and serum. Serum MANF concentrations increased at 24h and 7d in AIS patients compared to controls and were correlated with NIHSS score, ASPECTS and inflammatory cytokines. MANF protein was present in blood cells, while MANF mRNA levels did not differ between AIS patients and controls. MANF levels revealed a good value to diagnose TIA with area under the curve (AUC) of 0.949 (95% CI: 0.9093-0.9892). MANF levels were lower in TIA patients with recurrence compared to non-recurrence patients. The AUC for MANF to predict a re-event was 0.80 (95% CI: 0.6746-0.9282). CONCLUSIONS Serum MANF levels correlate with neuroprotection, stroke severity, inflammation, and TIA recurrence.
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29
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Lõhelaid H, Anttila JE, Liew HK, Tseng KY, Teppo J, Stratoulias V, Airavaara M. UPR Responsive Genes Manf and Xbp1 in Stroke. Front Cell Neurosci 2022; 16:900725. [PMID: 35783104 PMCID: PMC9240287 DOI: 10.3389/fncel.2022.900725] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2022] [Accepted: 05/02/2022] [Indexed: 11/13/2022] Open
Abstract
Stroke is a devastating medical condition with no treatment to hasten recovery. Its abrupt nature results in cataclysmic changes in the affected tissues. Resident cells fail to cope with the cellular stress resulting in massive cell death, which cannot be endogenously repaired. A potential strategy to improve stroke outcomes is to boost endogenous pro-survival pathways. The unfolded protein response (UPR), an evolutionarily conserved stress response, provides a promising opportunity to ameliorate the survival of stressed cells. Recent studies from us and others have pointed toward mesencephalic astrocyte-derived neurotrophic factor (MANF) being a UPR responsive gene with an active role in maintaining proteostasis. Its pro-survival effects have been demonstrated in several disease models such as diabetes, neurodegeneration, and stroke. MANF has an ER-signal peptide and an ER-retention signal; it is secreted by ER calcium depletion and exits cells upon cell death. Although its functions remain elusive, conducted experiments suggest that the endogenous MANF in the ER lumen and exogenously administered MANF protein have different mechanisms of action. Here, we will revisit recent and older bodies of literature aiming to delineate the expression profile of MANF. We will focus on its neuroprotective roles in regulating neurogenesis and inflammation upon post-stroke administration. At the same time, we will investigate commonalities and differences with another UPR responsive gene, X-box binding protein 1 (XBP1), which has recently been associated with MANF’s function. This will be the first systematic comparison of these two UPR responsive genes aiming at revealing previously uncovered associations between them. Overall, understanding the mode of action of these UPR responsive genes could provide novel approaches to promote cell survival.
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Affiliation(s)
- Helike Lõhelaid
- HiLIFE – Neuroscience Center, University of Helsinki, Helsinki, Finland
- *Correspondence: Helike Lõhelaid,
| | - Jenni E. Anttila
- Drug Research Program, Division of Pharmacology and Pharmacotherapy, Faculty of Pharmacy, University of Helsinki, Helsinki, Finland
- Individualized Drug Therapy Research Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland
| | - Hock-Kean Liew
- Department of Medical Research, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Hualien City, Taiwan
| | - Kuan-Yin Tseng
- Department of Neurological Surgery, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan
| | - Jaakko Teppo
- Drug Research Program, Division of Pharmaceutical Chemistry and Technology, Faculty of Pharmacy, University of Helsinki, Helsinki, Finland
| | | | - Mikko Airavaara
- HiLIFE – Neuroscience Center, University of Helsinki, Helsinki, Finland
- Drug Research Program, Division of Pharmacology and Pharmacotherapy, Faculty of Pharmacy, University of Helsinki, Helsinki, Finland
- Mikko Airavaara,
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Wang Y, Wen W, Li H, Xu H, Xu M, Ma M, Luo J. Deficiency of mesencephalic astrocyte-derived neurotrophic factor affects neurogenesis in mouse brain. Brain Res Bull 2022; 183:49-56. [PMID: 35227768 PMCID: PMC10014018 DOI: 10.1016/j.brainresbull.2022.02.019] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2021] [Revised: 02/18/2022] [Accepted: 02/24/2022] [Indexed: 12/31/2022]
Abstract
The mechanisms underlying the regulation of neurogenesis in the adult brain remain unclear. Mesencephalic astrocyte-derived neurotrophic factor (MANF) is a neurotrophic factor that has been implicated in various neuropathological processes and endoplasmic reticulum stress. However, the role of MANF in neurogenesis has not been investigated. Using a central nervous system (CNS)-specific Manf knock-out mouse model, we examined the role of MANF in mouse neurogenesis. We demonstrated that MANF deficiency increased BrdU labeling and Ki-67 positive cells in the subgranular zone and subventricular zone. MANF knock-out-induced upregulation of proliferative activity was accompanied by a decrease of cell cycle inhibitors (p15 and p27), an increase of G2/M marker (phospho-histone H3), as well as an increase of neural progenitor markers (Sox2 and NeuroD1) in the brain. In vitro studies using N2A neuroblastoma cells showed that the gain-of-function of MANF inhibited cell cycle progression, whereas the loss-of-function of MANF promoted cell cycle progression. Collectively, our findings indicate MANF deficiency affects cell proliferation and suggest a role of MANF in the neurogenesis of the adult brain.
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Affiliation(s)
- Yongchao Wang
- Department of Medicine, Vanderbilt University Medical Center, Nashville, TN 37372, USA
| | - Wen Wen
- Department of Pathology, University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA
| | - Hui Li
- Department of Pathology, University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA
| | - Hong Xu
- Department of Pharmacology and Nutritional Sciences, University of Kentucky College of Medicine, Lexington, KY 40536, USA
| | - Mei Xu
- Department of Pharmacology and Nutritional Sciences, University of Kentucky College of Medicine, Lexington, KY 40536, USA
| | - Murong Ma
- Department of Pharmacology and Nutritional Sciences, University of Kentucky College of Medicine, Lexington, KY 40536, USA
| | - Jia Luo
- Department of Pathology, University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA; Iowa City VA Health Care System, Iowa City, IA 52246, USA.
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31
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Wen W, Li H, Luo J. Potential Role of MANF, an ER Stress Responsive Neurotrophic Factor, in Protecting Against Alcohol Neurotoxicity. Mol Neurobiol 2022; 59:2992-3015. [PMID: 35254650 PMCID: PMC10928853 DOI: 10.1007/s12035-022-02786-7] [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: 11/12/2021] [Accepted: 02/26/2022] [Indexed: 10/18/2022]
Abstract
Alcohol exposure during pregnancy is harmful to the fetus and causes a wide range of long-lasting physiological and neurocognitive impairments, collectively referred to as fetal alcohol spectrum disorders (FASD). The neurobehavioral deficits observed in FASD result from structural and functional damages in the brain, with neurodegeneration being the most destructive consequence. Currently, there are no therapies for FASD. It is exigent to delineate the underlying mechanisms of alcohol neurotoxicity and develop an effective strategy of treatment. ER stress, caused by the accumulation of unfolded/misfolded proteins in the ER, is the hallmark of many neurodegenerative diseases, including alcohol-induced neurodegeneration. Mesencephalic astrocyte-derived neurotrophic factor (MANF) is a newly discovered endoplasmic reticulum (ER) stress responsive neurotrophic factor that regulates diverse neuronal functions. This review summarizes the recent findings revealing the effects of MANF on the CNS and its protective role against neurodegeneration. Particularly, we focus the role of MANF on alcohol-induced ER stress and neurodegeneration and discuss the therapeutic potential of MANF in treating alcohol neurotoxicity such as FASD.
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Affiliation(s)
- Wen Wen
- Department of Pathology, University of Iowa Carver College of Medicine, Iowa City, IA, 52242, USA
| | - Hui Li
- Department of Pathology, University of Iowa Carver College of Medicine, Iowa City, IA, 52242, USA
| | - Jia Luo
- Department of Pathology, University of Iowa Carver College of Medicine, Iowa City, IA, 52242, USA.
- Iowa City VA Health Care System, Iowa City, IA, 52246, USA.
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Stefani A, Pierantozzi M, Cardarelli S, Stefani L, Cerroni R, Conti M, Garasto E, Mercuri NB, Marini C, Sucapane P. Neurotrophins as Therapeutic Agents for Parkinson’s Disease; New Chances From Focused Ultrasound? Front Neurosci 2022; 16:846681. [PMID: 35401084 PMCID: PMC8990810 DOI: 10.3389/fnins.2022.846681] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2021] [Accepted: 01/31/2022] [Indexed: 01/02/2023] Open
Abstract
Magnetic Resonance–guided Focused Ultrasound (MRgFUS) represents an effective micro-lesioning approach to target pharmaco-resistant tremor, mostly in patients afflicted by essential tremor (ET) and/or Parkinson’s disease (PD). So far, experimental protocols are verifying the clinical extension to other facets of the movement disorder galaxy (i.e., internal pallidus for disabling dyskinesias). Aside from those neurosurgical options, one of the most intriguing opportunities of this technique relies on its capability to remedy the impermeability of blood–brain barrier (BBB). Temporary BBB opening through low-intensity focused ultrasound turned out to be safe and feasible in patients with PD, Alzheimer’s disease, and amyotrophic lateral sclerosis. As a mere consequence of the procedures, some groups described even reversible but significant mild cognitive amelioration, up to hippocampal neurogenesis partially associated to the increased of endogenous brain-derived neurotrophic factor (BDNF). A further development elevates MRgFUS to the status of therapeutic tool for drug delivery of putative neurorestorative therapies. Since 2012, FUS-assisted intravenous administration of BDNF or neurturin allowed hippocampal or striatal delivery. Experimental studies emphasized synergistic modalities. In a rodent model for Huntington’s disease, engineered liposomes can carry glial cell line–derived neurotrophic factor (GDNF) plasmid DNA (GDNFp) to form a GDNFp-liposome (GDNFp-LPs) complex through pulsed FUS exposures with microbubbles; in a subacute MPTP-PD model, the combination of intravenous administration of neurotrophic factors (either through protein or gene delivery) plus FUS did curb nigrostriatal degeneration. Here, we explore these arguments, focusing on the current, translational application of neurotrophins in neurodegenerative diseases.
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Affiliation(s)
- Alessandro Stefani
- Department of System Medicine, Parkinson Center, University Tor Vergata, Rome, Italy
- *Correspondence: Alessandro Stefani,
| | | | - Silvia Cardarelli
- Department of System Medicine, Parkinson Center, University Tor Vergata, Rome, Italy
| | - Lucrezia Stefani
- Department of System Medicine, Parkinson Center, University Tor Vergata, Rome, Italy
| | - Rocco Cerroni
- Department of System Medicine, Parkinson Center, University Tor Vergata, Rome, Italy
| | - Matteo Conti
- Department of System Medicine, UOC Neurology, University Tor Vergata, Rome, Italy
| | - Elena Garasto
- Department of System Medicine, UOC Neurology, University Tor Vergata, Rome, Italy
| | - Nicola B. Mercuri
- Department of System Medicine, UOC Neurology, University Tor Vergata, Rome, Italy
| | - Carmine Marini
- UOC Neurology and Stroke Unit, University of L’Aquila, L’Aquila, Italy
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Pakarinen E, Lindholm P, Saarma M, Lindahl M. CDNF and MANF regulate ER stress in a tissue-specific manner. Cell Mol Life Sci 2022; 79:124. [PMID: 35129674 PMCID: PMC8821067 DOI: 10.1007/s00018-022-04157-w] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2021] [Revised: 01/11/2022] [Accepted: 01/19/2022] [Indexed: 12/19/2022]
Abstract
Cerebral dopamine neurotrophic factor (CDNF) and mesencephalic astrocyte-derived neurotrophic factor (MANF) display cytoprotective effects in animal models of neurodegenerative diseases. These endoplasmic reticulum (ER)-resident proteins belong to the same protein family and function as ER stress regulators. The relationship between CDNF and MANF function, as well as their capability for functional compensation, is unknown. We aimed to investigate these questions by generating mice lacking both CDNF and MANF. Results showed that CDNF-deficient Manf−/− mice presented the same phenotypes of growth defect and diabetes as Manf−/− mice. In the muscle, CDNF deficiency resulted in increased activation of unfolded protein response (UPR), which was aggravated when MANF was ablated. In the brain, the combined loss of CDNF and MANF did not exacerbate UPR activation caused by the loss of MANF alone. Consequently, CDNF and MANF deficiency in the brain did not cause degeneration of dopamine neurons. In conclusion, CDNF and MANF present functional redundancy in the muscle, but not in the other tissues examined here. Thus, they regulate the UPR in a tissue-specific manner.
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Affiliation(s)
- Emmi Pakarinen
- Institute of Biotechnology, HiLIFE Unit, University of Helsinki, 00014, Helsinki, Finland
| | - Päivi Lindholm
- Institute of Biotechnology, HiLIFE Unit, University of Helsinki, 00014, Helsinki, Finland
| | - Mart Saarma
- Institute of Biotechnology, HiLIFE Unit, University of Helsinki, 00014, Helsinki, Finland
| | - Maria Lindahl
- Institute of Biotechnology, HiLIFE Unit, University of Helsinki, 00014, Helsinki, Finland.
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Li H, Wen W, Luo J. Targeting Endoplasmic Reticulum Stress as an Effective Treatment for Alcoholic Pancreatitis. Biomedicines 2022; 10:biomedicines10010108. [PMID: 35052788 PMCID: PMC8773075 DOI: 10.3390/biomedicines10010108] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2021] [Revised: 12/28/2021] [Accepted: 12/30/2021] [Indexed: 02/04/2023] Open
Abstract
Pancreatitis and alcoholic pancreatitis are serious health concerns with an urgent need for effective treatment strategies. Alcohol is a known etiological factor for pancreatitis, including acute pancreatitis (AP) and chronic pancreatitis (CP). Excessive alcohol consumption induces many pathological stress responses; of particular note is endoplasmic reticulum (ER) stress and adaptive unfolded protein response (UPR). ER stress results from the accumulation of unfolded/misfolded protein in the ER and is implicated in the pathogenesis of alcoholic pancreatitis. Here, we summarize the possible mechanisms by which ER stress contributes to alcoholic pancreatitis. We also discuss potential approaches targeting ER stress and UPR in developing novel therapeutic strategies for the disease.
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Affiliation(s)
- Hui Li
- Department of Pathology, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA; (H.L.); (W.W.)
| | - Wen Wen
- Department of Pathology, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA; (H.L.); (W.W.)
| | - Jia Luo
- Department of Pathology, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA; (H.L.); (W.W.)
- Iowa City VA Health Care System, Iowa City, IA 52246, USA
- Correspondence: ; Tel.: +1-319-335-2256
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Zhou Q, Yang L, Wang Q, Li Y, Wei C, Xie L. Mechanistic investigations of diabetic ocular surface diseases. Front Endocrinol (Lausanne) 2022; 13:1079541. [PMID: 36589805 PMCID: PMC9800783 DOI: 10.3389/fendo.2022.1079541] [Citation(s) in RCA: 33] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/25/2022] [Accepted: 12/02/2022] [Indexed: 12/23/2022] Open
Abstract
With the global prevalence of diabetes mellitus over recent decades, more patients suffered from various diabetic complications, including diabetic ocular surface diseases that may seriously affect the quality of life and even vision sight. The major diabetic ocular surface diseases include diabetic keratopathy and dry eye. Diabetic keratopathy is characterized with the delayed corneal epithelial wound healing, reduced corneal nerve density, decreased corneal sensation and feeling of burning or dryness. Diabetic dry eye is manifested as the reduction of tear secretion accompanied with the ocular discomfort. The early clinical symptoms include dry eye and corneal nerve degeneration, suggesting the early diagnosis should be focused on the examination of confocal microscopy and dry eye symptoms. The pathogenesis of diabetic keratopathy involves the accumulation of advanced glycation end-products, impaired neurotrophic innervations and limbal stem cell function, and dysregulated growth factor signaling, and inflammation alterations. Diabetic dry eye may be associated with the abnormal mitochondrial metabolism of lacrimal gland caused by the overactivation of sympathetic nervous system. Considering the important roles of the dense innervations in the homeostatic maintenance of cornea and lacrimal gland, further studies on the neuroepithelial and neuroimmune interactions will reveal the predominant pathogenic mechanisms and develop the targeting intervention strategies of diabetic ocular surface complications.
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Affiliation(s)
- Qingjun Zhou
- State Key Laboratory Cultivation Base, Eye Institute of Shandong First Medical University, Qingdao, China
- Shandong Provincial Key Laboratory of Ophthalmology, Eye Institute of Shandong First Medical University, Qingdao, China
| | - Lingling Yang
- State Key Laboratory Cultivation Base, Eye Institute of Shandong First Medical University, Qingdao, China
- Shandong Provincial Key Laboratory of Ophthalmology, Eye Institute of Shandong First Medical University, Qingdao, China
| | - Qun Wang
- State Key Laboratory Cultivation Base, Eye Institute of Shandong First Medical University, Qingdao, China
- Shandong Provincial Key Laboratory of Ophthalmology, Eye Institute of Shandong First Medical University, Qingdao, China
| | - Ya Li
- State Key Laboratory Cultivation Base, Eye Institute of Shandong First Medical University, Qingdao, China
- Shandong Provincial Key Laboratory of Ophthalmology, Eye Institute of Shandong First Medical University, Qingdao, China
| | - Chao Wei
- State Key Laboratory Cultivation Base, Eye Institute of Shandong First Medical University, Qingdao, China
- Shandong Provincial Key Laboratory of Ophthalmology, Eye Institute of Shandong First Medical University, Qingdao, China
| | - Lixin Xie
- State Key Laboratory Cultivation Base, Eye Institute of Shandong First Medical University, Qingdao, China
- Shandong Provincial Key Laboratory of Ophthalmology, Eye Institute of Shandong First Medical University, Qingdao, China
- *Correspondence: Lixin Xie,
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Lindholm P, Saarma M. Cerebral dopamine neurotrophic factor protects and repairs dopamine neurons by novel mechanism. Mol Psychiatry 2022; 27:1310-1321. [PMID: 34907395 PMCID: PMC9095478 DOI: 10.1038/s41380-021-01394-6] [Citation(s) in RCA: 44] [Impact Index Per Article: 14.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/14/2021] [Revised: 11/09/2021] [Accepted: 11/15/2021] [Indexed: 12/20/2022]
Abstract
Midbrain dopamine neurons deteriorate in Parkinson's disease (PD) that is a progressive neurodegenerative movement disorder. No cure is available that would stop the dopaminergic decline or restore function of injured neurons in PD. Neurotrophic factors (NTFs), e.g., glial cell line-derived neurotrophic factor (GDNF) are small, secreted proteins that promote neuron survival during mammalian development and regulate adult neuronal plasticity, and they are studied as potential therapeutic agents for the treatment of neurodegenerative diseases. However, results from clinical trials of GDNF and related NTF neurturin (NRTN) in PD have been modest so far. In this review, we focus on cerebral dopamine neurotrophic factor (CDNF), an unconventional neurotrophic protein. CDNF delivered to the brain parenchyma protects and restores dopamine neurons in animal models of PD. In a recent Phase I-II clinical trial CDNF was found safe and well tolerated. CDNF deletion in mice led to age-dependent functional changes in the brain dopaminergic system and loss of enteric neurons resulting in slower gastrointestinal motility. These defects in Cdnf-/- mice intriguingly resemble deficiencies observed in early stage PD. Different from classical NTFs, CDNF can function both as an extracellular trophic factor and as an intracellular, endoplasmic reticulum (ER) luminal protein that protects neurons and other cell types against ER stress. Similarly to the homologous mesencephalic astrocyte-derived neurotrophic factor (MANF), CDNF is able to regulate ER stress-induced unfolded protein response (UPR) signaling and promote protein homeostasis in the ER. Since ER stress is thought to be one of the pathophysiological mechanisms contributing to the dopaminergic degeneration in PD, CDNF, and its small-molecule derivatives that are under development may provide useful tools for experimental medicine and future therapies for the treatment of PD and other neurodegenerative protein-misfolding diseases.
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Affiliation(s)
- Päivi Lindholm
- grid.7737.40000 0004 0410 2071Institute of Biotechnology, Helsinki Institute of Life Science, University of Helsinki, FI-00014 Helsinki, Finland
| | - Mart Saarma
- Institute of Biotechnology, Helsinki Institute of Life Science, University of Helsinki, FI-00014, Helsinki, Finland.
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Han D, Li F, Zhang H, Ji C, Shu Q, Wang C, Ni H, Zhu Y, Wang S. Mesencephalic astrocyte-derived neurotrophic factor restores blood-brain barrier integrity of aged mice after ischaemic stroke/reperfusion through anti-inflammation via TLR4/MyD88/NF-κB pathway. J Drug Target 2021; 30:430-441. [PMID: 34747270 DOI: 10.1080/1061186x.2021.2003803] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Ischaemic stroke remains a leading cause of disability and mortality worldwide and ageing-associated inflammation for the aged patients specifically leads to worse post-stroke blood-brain barrier (BBB) disruption than young subjects. Accordingly, suppression of excessive inflammation can alleviate BBB injury, which provides potential therapeutic treatment for ischaemic stroke of the aged. Prior studies revealed that mesencephalic astrocyte-derived neurotrophic factor (MANF) regulated inflammatory response and alleviated liver injury in ageing. However, it is unclear whether MANF confer similar benefit to BBB of aged mice suffered from ischaemic stroke. Transient cerebral ischaemia induced by middle cerebral artery occlusion (MCAO) was conducted in aged mice (18-20 months old). MANF was injected into the right lateral ventricle 2 h after MCAO. BBB integrity, tight junctional proteins, ultrastructure of microvessels, infarct volume, neurological scores, brain water content, pro-inflammatory cytokines and neutrophil infiltration rate were determined 72 h after MCAO. H2O2-induced senescent bEnd.3 cells were applied in the in vitro study to investigate the possible mechanism. First, we confirmed that ischaemic stroke/reperfusion in senescent condition promoted the over-expression of MANF on brain endothelial cells. Then, MANF supplement could suppress the pro-inflammatory factor production, restore BBB integrity and then alleviate infarct volume, neurological scores, brain water content and neutrophil infiltration rate. In addition, MANF maintained BBB integrity after ischaemic stroke of aged condition dependent on TLR4/MyD88/NF-κB pathway via intervention of pro-inflammatory factors production. In summary, the recognition of MANF in the process of BBB breakdown at aged condition may offer novel therapeutic approaches for ischaemic stroke.
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Affiliation(s)
- Dan Han
- Department of Pharmacy, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, China.,Nanjing Medical Center for Clinical Pharmacy, Nanjing, China.,School of Pharmacy, China Pharmaceutical University, Nanjing, China
| | - Fengyang Li
- Department of Pharmacology, Key Laboratory of Chemical Biology, School of Pharmaceutical Sciences, Shandong University, Jinan, China
| | - Haixia Zhang
- Department of Pharmacy, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, China
| | - Cheng Ji
- Department of Pharmacy, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, China
| | - Qing Shu
- Department of Pharmacy, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, China
| | - Cheng Wang
- School of Pharmacy, Changzhou University, Changzhou, China
| | - Huanyu Ni
- Department of Pharmacy, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, China
| | - Yun Zhu
- Department of Pharmacy, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, China
| | - Siliang Wang
- Department of Pharmacy, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, China
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MANF: A Novel Endoplasmic Reticulum Stress Response Protein-The Role in Neurological and Metabolic Disorders. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2021; 2021:6467679. [PMID: 34745419 PMCID: PMC8568515 DOI: 10.1155/2021/6467679] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/11/2021] [Accepted: 10/04/2021] [Indexed: 02/05/2023]
Abstract
The mesencephalic astrocyte-derived neurotrophic factor (MANF), also named as arginine-rich protein (ARP) or arginine-rich mutated in early-stage tumors (ARMET), is a novel evolutionary conserved protein related to unfolded protein response. Growing evidence suggests that MANF critically involves in many ER stress-related diseases with a protective effect. Here, we review the function of MANF based on its structure in neurological and metabolic disorders and summarize its potential applications in disease diagnosis and therapies.
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Shen Y, Li R, Yu S, Zhao Q, Wang Z, Sheng H, Yang W. Activation of the ATF6 (Activating Transcription Factor 6) Signaling Pathway in Neurons Improves Outcome After Cardiac Arrest in Mice. J Am Heart Assoc 2021; 10:e020216. [PMID: 34111943 PMCID: PMC8477867 DOI: 10.1161/jaha.120.020216] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/18/2020] [Accepted: 04/21/2021] [Indexed: 11/16/2022]
Abstract
Background Ischemia/reperfusion injury impairs proteostasis, and triggers adaptive cellular responses, such as the unfolded protein response (UPR), which functions to restore endoplasmic reticulum homeostasis. After cardiac arrest (CA) and resuscitation, the UPR is activated in various organs including the brain. However, the role of the UPR in CA has remained largely unknown. Here we aimed to investigate effects of activation of the ATF6 (activating transcription factor 6) UPR branch in CA. Methods and Results Conditional and inducible sATF6-KI (short-form ATF6 knock-in) mice and a selective ATF6 pathway activator 147 were used. CA was induced in mice by KCl injection, followed by cardiopulmonary resuscitation. We first found that neurologic function was significantly improved, and neuronal damage was mitigated after the ATF6 pathway was activated in neurons of sATF6-KI mice subjected to CA/cardiopulmonary resuscitation. Further RNA sequencing analysis indicated that such beneficial effects were likely attributable to increased expression of pro-proteostatic genes regulated by ATF6. Especially, key components of the endoplasmic reticulum-associated degradation process, which clears potentially toxic unfolded/misfolded proteins in the endoplasmic reticulum, were upregulated in the sATF6-KI brain. Accordingly, the CA-induced increase in K48-linked polyubiquitin in the brain was higher in sATF6-KI mice relative to control mice. Finally, CA outcome, including the survival rate, was significantly improved in mice treated with compound 147. Conclusions This is the first experimental study to determine the role of the ATF6 UPR branch in CA outcome. Our data indicate that the ATF6 UPR branch is a prosurvival pathway and may be considered as a therapeutic target for CA.
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Affiliation(s)
- Yuntian Shen
- Department of AnesthesiologyCenter for Perioperative Organ ProtectionDuke University Medical CenterDurhamNC
| | - Ran Li
- Department of AnesthesiologyCenter for Perioperative Organ ProtectionDuke University Medical CenterDurhamNC
| | - Shu Yu
- Department of AnesthesiologyCenter for Perioperative Organ ProtectionDuke University Medical CenterDurhamNC
| | - Qiang Zhao
- Department of AnesthesiologyCenter for Perioperative Organ ProtectionDuke University Medical CenterDurhamNC
| | - Zhuoran Wang
- Department of AnesthesiologyCenter for Perioperative Organ ProtectionDuke University Medical CenterDurhamNC
| | - Huaxin Sheng
- Department of AnesthesiologyCenter for Perioperative Organ ProtectionDuke University Medical CenterDurhamNC
| | - Wei Yang
- Department of AnesthesiologyCenter for Perioperative Organ ProtectionDuke University Medical CenterDurhamNC
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Liu XC, Qi XH, Fang H, Zhou KQ, Wang QS, Chen GH. Increased MANF Expression in the Inferior Temporal Gyrus in Patients With Alzheimer Disease. Front Aging Neurosci 2021; 13:639318. [PMID: 33994992 PMCID: PMC8117094 DOI: 10.3389/fnagi.2021.639318] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2020] [Accepted: 04/08/2021] [Indexed: 11/21/2022] Open
Abstract
Alzheimer disease (AD) is an aging-related disorder linked to endoplasmic reticulum (ER) stress. The main pathologic feature of AD is the presence of extracellular senile plaques and intraneuronal neurofibrillary tangles (NFTs) in the brain. In neurodegenerative diseases, the unfolded protein response (UPR) induced by ER stress ensures cell survival. Mesencephalic astrocyte-derived neurotrophic factor (MANF) protects against ER stress and has been implicated in the pathogenesis of AD. MANF is expressed in neurons of the brain and spinal cord. However, there have been no investigations on MANF expression in the brain of AD patients. This was addressed in the present study by immunohistochemistry, western blotting, and quantitative analyses of postmortem brain specimens. We examined the localization and expression levels of MANF in the inferior temporal gyrus of the cortex (ITGC) in AD patients (n = 5), preclinical (pre-)AD patients (n = 5), and age-matched non-dementia controls (n = 5) by double immunofluorescence labeling with antibodies against the neuron-specific nuclear protein neuronal nuclei (NeuN), ER chaperone protein 78-kDa glucose-regulated protein (GRP78), and MANF. The results showed that MANF was mainly expressed in neurons of the ITGC in all 3 groups; However, the number of MANF-positive neurons was significantly higher in pre-AD (Braak stage III/IV) and AD (Braak stage V/VI) patients than that in the control group. Thus, MANF is overexpressed in AD and pre-AD, suggesting that it can serve as a diagnostic marker for early stage disease.
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Affiliation(s)
- Xue-Chun Liu
- Department of Neurology (Sleep Disorders), The Affiliated Chaohu Hospital of Anhui Medical University, Hefei, China.,Department of Neurology, Chinese PLA Clinical College, Anhui Medical University, Hefei, China
| | - Xiu-Hong Qi
- Hefei National Laboratory for Physical Sciences at the Microscale, School of Life Sciences, Chinese Academy of Sciences Key Laboratory of Brain Function and Diseases, University of Science and Technology of China, Hefei, China
| | - Hui Fang
- Hefei National Laboratory for Physical Sciences at the Microscale, School of Life Sciences, Chinese Academy of Sciences Key Laboratory of Brain Function and Diseases, University of Science and Technology of China, Hefei, China
| | - Ke-Qing Zhou
- Hefei National Laboratory for Physical Sciences at the Microscale, School of Life Sciences, Chinese Academy of Sciences Key Laboratory of Brain Function and Diseases, University of Science and Technology of China, Hefei, China
| | - Qing-Song Wang
- Department of Neurology, Chinese PLA Clinical College, Anhui Medical University, Hefei, China
| | - Gui-Hai Chen
- Department of Neurology (Sleep Disorders), The Affiliated Chaohu Hospital of Anhui Medical University, Hefei, China
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Peled M, Bar-Lev TH, Talalai E, Aspitz HZ, Daniel-Meshulam I, Bar J, Kamer I, Ofek E, Mor A, Onn A. Mesencephalic astrocyte-derived neurotrophic factor is secreted from interferon-γ-activated tumor cells through ER calcium depletion. PLoS One 2021; 16:e0250178. [PMID: 33891607 PMCID: PMC8064521 DOI: 10.1371/journal.pone.0250178] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2020] [Accepted: 03/31/2021] [Indexed: 01/05/2023] Open
Abstract
The most successful immunotherapeutic agents are blocking antibodies to either programmed cell death-1 (PD-1), an inhibitory receptor expressed on T lymphocytes, or to its ligand, programmed cell death-ligand 1 (PD-L1). Nevertheless, many patients do not respond, and additional approaches, specifically blocking other inhibitory receptors on T cells, are being explored. Importantly, the source of the ligands for these receptors are often the tumor cells. Indeed, cancer cells express high levels of PD-L1 upon stimulation with interferon-γ (IFN-γ), a major cytokine in the tumor microenvironment. The increase in PD-L1 expression serves as a negative feedback towards the immune system, and allows the tumor to evade the attack of immune cells. A potential novel immunoregulator is mesencephalic astrocyte-derived neurotrophic factor (MANF), an endoplasmic reticulum (ER)-resident protein that is secreted from pancreatic beta cells upon cytokines activation, and can induce an alternatively activated macrophage phenotype (M2), and thus may support tumor growth. While MANF was shown to be secreted from pancreatic beta cells, its IFN-γ-induced secretion from tumor cells has never been assessed. Here we found that IFN-γ induced MANF secretion from diverse tumor cell-lines-melanoma cells, colon carcinoma cells and hepatoma cells. Mechanistically, there was no increase in MANF RNA or intracellular protein levels upon IFN-γ stimulation. However, IFN-γ induced ER calcium depletion, which was necessary for MANF secretion, as Dantrolene, an inhibitor of ER calcium release, prevented its secretion. Thus, MANF is secreted from IFN-γ-stimulated tumor cells, and further studies are required to assess its potential as a drug target for cancer immunotherapy.
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Affiliation(s)
- Michael Peled
- Institute of Pulmonary Medicine, Sheba Medical Center, Tel Hashomer, Israel
- Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel
- * E-mail:
| | - Tali H. Bar-Lev
- Institute of Pulmonary Medicine, Sheba Medical Center, Tel Hashomer, Israel
| | - Efrosiniia Talalai
- Institute of Pulmonary Medicine, Sheba Medical Center, Tel Hashomer, Israel
- Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel
| | - Haggar Zoë Aspitz
- Institute of Pulmonary Medicine, Sheba Medical Center, Tel Hashomer, Israel
- Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel
| | | | - Jair Bar
- Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel
- Thoracic Oncology Unit, Institute of Oncology, Sheba Medical Center, Tel Hashomer, Israel
| | - Iris Kamer
- Thoracic Oncology Unit, Institute of Oncology, Sheba Medical Center, Tel Hashomer, Israel
| | - Efrat Ofek
- Pathology Department, Tel HaShomer Hospital, Tel Hashomer, Israel
| | - Adam Mor
- Columbia Center for Translational Immunology, Columbia University Medical Center, New York, NY, United States of America
| | - Amir Onn
- Institute of Pulmonary Medicine, Sheba Medical Center, Tel Hashomer, Israel
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Wu T, Liu Q, Li Y, Li H, Chen L, Yang X, Tang Q, Pu S, Kuang J, Li R, Huang Y, Zhang J, Zhang Z, Zhou J, Huang C, Zhang G, Zhao Y, Zou M, Jiang W, Mo L, He J. Feeding-induced hepatokine, Manf, ameliorates diet-induced obesity by promoting adipose browning via p38 MAPK pathway. J Exp Med 2021; 218:211993. [PMID: 33856409 PMCID: PMC8054200 DOI: 10.1084/jem.20201203] [Citation(s) in RCA: 45] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2020] [Revised: 12/19/2020] [Accepted: 02/12/2021] [Indexed: 02/05/2023] Open
Abstract
Activating beige adipocytes in white adipose tissue (WAT) to increase energy expenditure is a promising strategy to combat obesity. We identified that mesencephalic astrocyte–derived neurotrophic factor (Manf) is a feeding-induced hepatokine. Liver-specific Manf overexpression protected mice against high-fat diet–induced obesity and promoted browning of inguinal subcutaneous WAT (iWAT). Manf overexpression in liver was also associated with decreased adipose inflammation and improved insulin sensitivity and hepatic steatosis. Mechanistically, Manf could directly promote browning of white adipocytes via the p38 MAPK pathway. Blockade of p38 MAPK abolished Manf-induced browning. Consistently, liver-specific Manf knockout mice showed impaired iWAT browning and exacerbated diet-induced obesity, insulin resistance, and hepatic steatosis. Recombinant Manf reduced obesity and improved insulin resistance in both diet-induced and genetic obese mouse models. Finally, we showed that circulating Manf level was positively correlated with BMI in humans. This study reveals the crucial role of Manf in regulating thermogenesis in adipose tissue, representing a potential therapeutic target for obesity and related metabolic disorders.
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Affiliation(s)
- Tong Wu
- Department of Pharmacy, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, China.,Laboratory of Clinical Pharmacy and Adverse Drug Reaction, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, China
| | - Qinhui Liu
- Laboratory of Clinical Pharmacy and Adverse Drug Reaction, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, China
| | - Yanping Li
- Laboratory of Clinical Pharmacy and Adverse Drug Reaction, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, China
| | - Hong Li
- Department of Pharmacy, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, China.,Laboratory of Clinical Pharmacy and Adverse Drug Reaction, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, China
| | - Lei Chen
- Department of Pharmacy, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, China.,Laboratory of Clinical Pharmacy and Adverse Drug Reaction, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, China
| | - Xuping Yang
- Department of Pharmacy, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, China.,Laboratory of Clinical Pharmacy and Adverse Drug Reaction, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, China
| | - Qin Tang
- Department of Pharmacy, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, China.,Laboratory of Clinical Pharmacy and Adverse Drug Reaction, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, China
| | - Shiyun Pu
- Department of Pharmacy, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, China.,Laboratory of Clinical Pharmacy and Adverse Drug Reaction, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, China
| | - Jiangying Kuang
- Department of Pharmacy, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, China.,Laboratory of Clinical Pharmacy and Adverse Drug Reaction, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, China
| | - Rui Li
- Department of Pharmacy, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, China.,Laboratory of Clinical Pharmacy and Adverse Drug Reaction, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, China
| | - Ya Huang
- Department of Pharmacy, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, China.,Laboratory of Clinical Pharmacy and Adverse Drug Reaction, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, China
| | - Jinhang Zhang
- Department of Pharmacy, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, China.,Laboratory of Clinical Pharmacy and Adverse Drug Reaction, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, China
| | - Zijing Zhang
- Department of Pharmacy, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, China.,Laboratory of Clinical Pharmacy and Adverse Drug Reaction, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, China
| | - Jian Zhou
- Department of Pharmacy, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, China.,Laboratory of Clinical Pharmacy and Adverse Drug Reaction, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, China
| | - Cuiyuan Huang
- Department of Pharmacy, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, China.,Laboratory of Clinical Pharmacy and Adverse Drug Reaction, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, China
| | - Guorong Zhang
- Department of Pharmacy, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, China.,Laboratory of Clinical Pharmacy and Adverse Drug Reaction, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, China
| | - Yingnan Zhao
- Department of Pharmacy, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, China.,Laboratory of Clinical Pharmacy and Adverse Drug Reaction, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, China
| | - Min Zou
- Department of Pharmacy, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, China
| | - Wei Jiang
- Molecular Medicine Research Center, West China Hospital of Sichuan University, Chengdu, China
| | - Li Mo
- Center of Gerontology and Geriatrics, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, China
| | - Jinhan He
- Department of Pharmacy, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, China.,Laboratory of Clinical Pharmacy and Adverse Drug Reaction, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, China
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Mesencephalic astrocyte-derived neurotrophic factor alleviates alcohol induced hepatic steatosis via activating Stat3-mediated autophagy. Biochem Biophys Res Commun 2021; 550:197-203. [PMID: 33713857 DOI: 10.1016/j.bbrc.2021.02.123] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2021] [Accepted: 02/24/2021] [Indexed: 02/08/2023]
Abstract
Alcoholic fatty liver disease (AFLD) is induced by alcohol consumption and may progress to more severe liver diseases such as alcoholic steatohepatitis, fibrosis and cirrhosis, and even hepatocellular carcinoma. Mesencephalic astrocyte-derived neurotrophic factor (MANF) participates in maintaining lipid homeostasis. However, the role of MANF in the pathogenesis of AFLD remains unclear. We established an AFLD mouse model following the US National Institute on Alcohol Abuse and Alcoholism procedure. Both mRNA and protein levels of MANF were significantly increased in the chronic binge alcohol feeding model. Liver-specific knockout of MANF aggravated hepatic lipid accumulation. Similarly, liver-specific overexpression of MANF alleviated AFLD in mouse livers. MANF affected hepatic lipid metabolism by modulating autophagy. The levels of LC3-II and Atg5-Atg12 were decreased in mouse livers with MANF liver-specific knockout and increased with MANF liver-specific overexpression. Furthermore, MANF changed the phosphorylation of Stat3 and its nuclear localization. MANF may have a protective role in the development of AFLD.
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Tejedor G, Luz-Crawford P, Barthelaix A, Toupet K, Roudières S, Autelitano F, Jorgensen C, Djouad F. MANF Produced by MRL Mouse-Derived Mesenchymal Stem Cells Is Pro-regenerative and Protects From Osteoarthritis. Front Cell Dev Biol 2021; 9:579951. [PMID: 33738280 PMCID: PMC7960785 DOI: 10.3389/fcell.2021.579951] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2020] [Accepted: 02/02/2021] [Indexed: 12/16/2022] Open
Abstract
The super healer Murphy Roths Large (MRL) mouse represents the “holy grail” of mammalian regenerative model to decipher the key mechanisms that underlies regeneration in mammals. At a time when mesenchymal stem cell (MSC)-based therapy represents the most promising approach to treat degenerative diseases such as osteoarthritis (OA), identification of key factors responsible for the regenerative potential of MSC derived from MRL mouse would be a major step forward for regenerative medicine. In the present study, we assessed and compared MSC derived from MRL (MRL MSC) and C57BL/6 (BL6 MSC) mice. First, we compare the phenotype and the differentiation potential of MRL and BL6 MSC and did not observe any difference. Then, we evaluated the proliferation and migration potential of the cells and found that while MRL MSC proliferate at a slower rate than BL6 MSC, they migrate at a significantly higher rate. This higher migration potential is mediated, in part, by MRL MSC-secreted products since MRL MSC conditioned medium that contains a complex of released factors significantly increased the migration potential of BL6 MSC. A comparative analysis of the secretome by quantitative shotgun proteomics and Western blotting revealed that MRL MSC produce and release higher levels of mesencephalic astrocyte-derived neurotrophic factor (MANF) as compared to MSC derived from BL6, BALB/c, and DBA1 mice. MANF knockdown in MRL MSC using a specific small interfering RNA (siRNA) reduced both MRL MSC migration potential in scratch wound assay and their regenerative potential in the ear punch model in BL6 mice. Finally, injection of MRL MSC silenced for MANF did not protect mice from OA development. In conclusion, our results evidence that the enhanced regenerative potential and protection from OA of MRL mice might be, in part, attributed to their MSC, an effective reservoir of MANF.
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Affiliation(s)
- Gautier Tejedor
- IRMB, INSERM, University of Montpellier, Montpellier, France
| | - Patricia Luz-Crawford
- Laboratorio de Inmunología Celular y Molecular, Facultad de Medicina, Universidad de los Andes, Santiago, Chile
| | | | - Karine Toupet
- IRMB, INSERM, University of Montpellier, Montpellier, France
| | | | | | - Christian Jorgensen
- IRMB, INSERM, University of Montpellier, Montpellier, France.,Centre Hospitalier Universitaire de Montpellier, Montpellier, France
| | - Farida Djouad
- IRMB, INSERM, University of Montpellier, Montpellier, France
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45
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Eesmaa A, Yu LY, Göös H, Nõges K, Kovaleva V, Hellman M, Zimmermann R, Jung M, Permi P, Varjosalo M, Lindholm P, Saarma M. The cytoprotective protein MANF promotes neuronal survival independently from its role as a GRP78 cofactor. J Biol Chem 2021; 296:100295. [PMID: 33460650 PMCID: PMC7949057 DOI: 10.1016/j.jbc.2021.100295] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2020] [Revised: 01/07/2021] [Accepted: 01/12/2021] [Indexed: 12/14/2022] Open
Abstract
Mesencephalic astrocyte-derived neurotrophic factor (MANF) is an endoplasmic reticulum (ER)-stress-regulated protein exhibiting cytoprotective properties through a poorly understood mechanism in various in vitro and in vivo models of neuronal and non-neuronal damage. Although initially characterized as a secreted neurotrophic factor for midbrain dopamine neurons, MANF has recently gained more interest for its intracellular role in regulating the ER homeostasis, including serving as a cofactor of the chaperone glucose-regulated protein 78 (GRP78). We aimed for a better understanding of the neuroprotective mechanisms of MANF. Here we show for the first time that MANF promotes the survival of ER-stressed neurons in vitro as a general unfolded protein response (UPR) regulator, affecting several UPR pathways simultaneously. Interestingly, MANF does not affect naïve neurons. We hypothesize that MANF regulates UPR signaling toward a mode more compatible with neuronal survival. Screening of MANF interacting proteins from two mammalian cell lines revealed a conserved interactome of 15 proteins including several ER chaperones such as GRP78, GRP170, protein disulfide isomerase family A member 1, and protein disulfide isomerase family A member 6. Further characterization confirmed previously published finding that MANF is a cofactor of GRP78 interacting with its nucleotide binding domain. Using microscale thermophoresis and nuclear magnetic resonance spectroscopy, we discovered that MANF is an ATP binding protein and that ATP blocks the MANF-GRP78 interaction. Interestingly, functional analysis of the antiapoptotic properties of MANF mutants in cultured neurons revealed divergent roles of MANF as a GRP78 cofactor and as an antiapoptotic regulator of UPR. We conclude that the co-factor type interaction with GRP78 is dispensable for the survival-promoting activity of MANF in neurons.
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Affiliation(s)
- Ave Eesmaa
- Institute of Biotechnology, HiLIFE, University of Helsinki, Helsinki, Finland
| | - Li-Ying Yu
- Institute of Biotechnology, HiLIFE, University of Helsinki, Helsinki, Finland
| | - Helka Göös
- Institute of Biotechnology, HiLIFE, University of Helsinki, Helsinki, Finland
| | - Kristofer Nõges
- Institute of Biotechnology, HiLIFE, University of Helsinki, Helsinki, Finland
| | - Vera Kovaleva
- Institute of Biotechnology, HiLIFE, University of Helsinki, Helsinki, Finland
| | - Maarit Hellman
- Department of Chemistry, Nanoscience Center, University of Jyväskylä, Jyväskylä, Finland
| | - Richard Zimmermann
- Medical Biochemistry and Molecular Biology, Saarland University, Homburg, Germany
| | - Martin Jung
- Medical Biochemistry and Molecular Biology, Saarland University, Homburg, Germany
| | - Perttu Permi
- Department of Chemistry, Nanoscience Center, University of Jyväskylä, Jyväskylä, Finland; Department of Biological and Environmental Science, Nanoscience Center, University of Jyväskylä, Jyväskylä, Finland
| | - Markku Varjosalo
- Institute of Biotechnology, HiLIFE, University of Helsinki, Helsinki, Finland
| | - Päivi Lindholm
- Institute of Biotechnology, HiLIFE, University of Helsinki, Helsinki, Finland.
| | - Mart Saarma
- Institute of Biotechnology, HiLIFE, University of Helsinki, Helsinki, Finland.
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Wang P, Yang Y, Pang G, Zhang C, Wei C, Tao X, Liu J, Xu J, Zhang W, Shen Y. Hepatocyte-derived MANF is protective for rifampicin-induced cholestatic hepatic injury via inhibiting ATF4-CHOP signal activation. Free Radic Biol Med 2021; 162:283-297. [PMID: 33127565 DOI: 10.1016/j.freeradbiomed.2020.10.028] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/22/2020] [Accepted: 10/18/2020] [Indexed: 02/03/2023]
Abstract
Rifampicin (RFP) has been known to be potentially hepatotoxic and often used as an inducer of cholestatic hepatic injury. Here we found that mesencephalic astrocyte-derived neurotrophic factor (MANF), an endoplasmic reticulum (ER) stress inducible protein, is a protector in RFP-induced liver injury. In cholestatic hepatic injury mice induced by RFP, the liver/body ratio and the levels of serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), total bile acid (TBA), total bilirubin (TBIL), and direct bilirubin (DBIL) were significantly increased. Meanwhile, the protein and mRNA levels of MANF were remarkably elevated in the liver injury mice. In hepatocyte-specific MANF knockout (HKO) mice, an extra increase in the liver/body ratio and serum ALT, AST, ALP, TBA, TBIL, and DBIL levels was detected after treatment with RFP. In addition, recombinant human MANF (rhMANF) treatment efficiently reduced the liver/body ratio and serum ALT, AST, ALP, TBA, TBIL, and DBIL levels in RFP-induced liver injury mice. Furthermore, we found there is an increase in the number of the apoptotic cells, detected by TUNEL staining in the liver tissues of HKO mice. Meanwhile, the protein levels of C/EBP-homologous protein (CHOP), Ki67, and the proliferating cell nuclear antigen (PCNA), as well as the mRNA level of Ki67 were elevated after treated with RFP, and these parameters were increased more significantly in HKO mice than that in wild type (WT) controls in RFP-induced liver injury. The rhMANF treatment can rescue the cell apoptosis and reduce the protein and mRNA levels of CHOP, Ki67, and PCNA elevated by MANF deletion and RFP. In HKO mice, immunoglobulin heavy chain binding protein (BIP) and activating transcription factor 4 (ATF4) were predominantly increased after treatment with RFP, which were reduced by rhMANF treatment. Therefore, we conclude that hepatocyte-derived MANF is protective for RFP-induced cholestatic hepatic injury via inhibiting ATF4-CHOP signal activation and subsequent cell apoptosis.
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Affiliation(s)
- Peng Wang
- School of Basic Medical Sciences, Anhui Medical University, Hefei, 230032, Anhui, China; Biopharmaceutical Research Institute, Anhui Medical University, Hefei, 230032, Anhui, China.
| | - Yi Yang
- School of Basic Medical Sciences, Anhui Medical University, Hefei, 230032, Anhui, China; Biopharmaceutical Research Institute, Anhui Medical University, Hefei, 230032, Anhui, China.
| | - Gaozong Pang
- School of Basic Medical Sciences, Anhui Medical University, Hefei, 230032, Anhui, China; Biopharmaceutical Research Institute, Anhui Medical University, Hefei, 230032, Anhui, China.
| | - Chaoyi Zhang
- School of Basic Medical Sciences, Anhui Medical University, Hefei, 230032, Anhui, China; Biopharmaceutical Research Institute, Anhui Medical University, Hefei, 230032, Anhui, China.
| | - Chuansheng Wei
- School of Basic Medical Sciences, Anhui Medical University, Hefei, 230032, Anhui, China; Biopharmaceutical Research Institute, Anhui Medical University, Hefei, 230032, Anhui, China.
| | - Xiaofang Tao
- School of Basic Medical Sciences, Anhui Medical University, Hefei, 230032, Anhui, China; Biopharmaceutical Research Institute, Anhui Medical University, Hefei, 230032, Anhui, China.
| | - Jun Liu
- School of Basic Medical Sciences, Anhui Medical University, Hefei, 230032, Anhui, China; Biopharmaceutical Research Institute, Anhui Medical University, Hefei, 230032, Anhui, China.
| | - Jianming Xu
- Department of Gastroenterology, The First Affiliated Hospital of Anhui Medical University, Hefei, 230022, Anhui, China.
| | - Weiping Zhang
- Department of Gastroenterology, The First Affiliated Hospital of Anhui Medical University, Hefei, 230022, Anhui, China.
| | - Yuxian Shen
- School of Basic Medical Sciences, Anhui Medical University, Hefei, 230032, Anhui, China; Biopharmaceutical Research Institute, Anhui Medical University, Hefei, 230032, Anhui, China.
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Wang Y, Wen W, Li H, Clementino M, Xu H, Xu M, Ma M, Frank J, Luo J. MANF is neuroprotective against ethanol-induced neurodegeneration through ameliorating ER stress. Neurobiol Dis 2021; 148:105216. [PMID: 33296727 PMCID: PMC7856049 DOI: 10.1016/j.nbd.2020.105216] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2020] [Revised: 11/18/2020] [Accepted: 12/03/2020] [Indexed: 12/23/2022] Open
Abstract
Fetal alcohol spectrum disorders (FASD) are a spectrum of developmental disorders caused by prenatal alcohol exposure. Neuronal loss or neurodegeneration in the central nervous system (CNS) is one of the most devastating features in FASD. It is imperative to delineate the underlying mechanisms to facilitate the treatment of FASD. Endoplasmic reticulum (ER) stress is a hallmark and an underlying mechanism of many neurodegenerative diseases, including ethanol-induced neurodegeneration. Mesencephalic astrocyte-derived neurotrophic factor (MANF) responds to ER stress and has been identified as a protein upregulated in response to ethanol exposure during the brain development. To investigate the role of MANF in ethanol-induced neurodegeneration and its association with ER stress regulation, we established a CNS-specific Manf knockout mouse model and examined the effects of MANF deficiency on ethanol-induced neuronal apoptosis and ER stress using a third-trimester equivalent mouse model. We found MANF deficiency exacerbated ethanol-induced neuronal apoptosis and ER stress and that blocking ER stress abrogated the harmful effects of MANF deficiency on ethanol-induced neuronal apoptosis. Moreover, using an animal model of ER-stress-induced neurodegeneration, we demonstrated that MANF deficiency potentiated tunicamycin (TM)-induced ER stress and neurodegeneration. A whole transcriptome RNA sequencing also supported the functionality of MANF in ER stress modulation and revealed targets that may mediate the ER stress-buffering capacity of MANF. Collectively, these results suggest that MANF is a neurotrophic factor that can protect neurons against ethanol-induced neurodegeneration by ameliorating ER stress.
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Affiliation(s)
- Yongchao Wang
- Department of Cell and Development Biology, Vanderbilt University School of Medicine, Nashville, TN 37232, United States of America
| | - Wen Wen
- Department of Pathology, University of Iowa Carver College of Medicine, Iowa City, IA 52242, United States of America
| | - Hui Li
- Department of Pathology, University of Iowa Carver College of Medicine, Iowa City, IA 52242, United States of America
| | - Marco Clementino
- Department of Toxicology and Cancer Biology, University of Kentucky College of Medicine, Lexington, KY 40536, United States of America
| | - Hong Xu
- Department of Pharmacology and Nutritional Sciences, University of Kentucky College of Medicine, Lexington, KY 40536, United States of America
| | - Mei Xu
- Department of Pharmacology and Nutritional Sciences, University of Kentucky College of Medicine, Lexington, KY 40536, United States of America
| | - Murong Ma
- Department of Pharmacology and Nutritional Sciences, University of Kentucky College of Medicine, Lexington, KY 40536, United States of America
| | - Jacqueline Frank
- Department of Neurology, University of Kentucky College of Medicine, Lexington, KY 40536, United States of America
| | - Jia Luo
- Department of Pathology, University of Iowa Carver College of Medicine, Iowa City, IA 52242, United States of America; Iowa City VA Health Care System, Iowa City, IA 52246, United States of America.
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Ren Z, Wang Y, Chen Q, Long J, Zhang R, Wu X, Qian W, Chen Y, Liu D, Ren W. Correlation of Significantly Decreased Serum Circulating Mesencephalic Astrocyte-Derived Neurotrophic Factor Level With an Increased Risk of Future Cardiovascular Disease in Adult Patients With Growth Hormone Deficiency. Front Endocrinol (Lausanne) 2021; 12:671126. [PMID: 34220710 PMCID: PMC8242342 DOI: 10.3389/fendo.2021.671126] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/23/2021] [Accepted: 06/01/2021] [Indexed: 11/24/2022] Open
Abstract
OBJECTIVE Adult growth hormone deficiency (AGHD) is a rare chronic inflammatory disease caused by damage to the pituitary gland and is accompanied by disorders of multiple metabolic pathways. By examining the correlation between the serum mesencephalic astrocyte-derived neurotrophic factor (MANF) levels of AGHD patients and those of normal controls, we hope to elucidate the close relationship among MANF, lipid metabolism and insulin resistance in AGHD and discuss the potential therapeutic value of MANF. METHODS This study included 101 AGHD patients and 100 healthy subjects matched for sex, age, height, and weight. Anthropometric parameters and biochemical indicators such as body mass index, waist circumference, hip circumference, serum MANF level, blood lipids and insulin level were measured. The above patients were also divided into several subgroups for correlation analysis based on indicators such as insulin resistance and BMI. RESULTS The serum circulating MANF content of AGHD patients was significantly lower than that of the normal control group (5.235 (0.507-17.62) ng/ml (n=101) vs. 10.30 (1.84-16.65) ng/ml (n=100); p<0.0001), and circulating MANF levels were linearly correlated with HOMA-IR in the AGHD population (R=0.481, P=0.0041). When MANF was at pathological concentrations (lower than the mean circulating MANF of normal controls), the lowest concentration tertile (OR=21.429 p<0.0001) had a significantly higher disease odds ratio, Framingham risk score and 10-year risk of atherosclerotic cardiovascular disease than the highest concentration tertile. CONCLUSIONS MANF has a significant correlation with insulin resistance in the AGHD state. There is a strong correlation with abnormal glucose and lipid metabolism in the obese AGHD population. MANF is also a good assessment factor for the risk of cardiovascular disease in AGHD patients and has excellent therapeutic potential.
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Affiliation(s)
- Ziyu Ren
- Department of Endocrinology and Metabolism, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Yunting Wang
- Department of Endocrinology and Metabolism, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Qing Chen
- Department of Endocrinology and Metabolism, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Jiangchuan Long
- Department of Endocrinology and Metabolism, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Rui Zhang
- Department of Endocrinology and Metabolism, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Xun Wu
- Department of Endocrinology and Metabolism, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Wenjie Qian
- Department of Endocrinology and Metabolism, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Yue Chen
- General Practice, The 958 Hospital of the People’s Liberation Army, Chongqing, China
| | - Dongfang Liu
- Department of Endocrinology and Metabolism, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
- *Correspondence: Dongfang Liu, ; ; Wei Ren,
| | - Wei Ren
- Department of Endocrinology and Metabolism, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
- *Correspondence: Dongfang Liu, ; ; Wei Ren,
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Hou C, Mei Q, Song X, Bao Q, Li X, Wang D, Shen Y. Mono-macrophage-Derived MANF Protects Against Lipopolysaccharide-Induced Acute Kidney Injury via Inhibiting Inflammation and Renal M1 Macrophages. Inflammation 2020; 44:693-703. [PMID: 33145627 DOI: 10.1007/s10753-020-01368-w] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2020] [Revised: 10/08/2020] [Accepted: 10/15/2020] [Indexed: 01/07/2023]
Abstract
The outburst of renal inflammatory response has been found to be a crucial cause of acute kidney injury (AKI). Attenuating the renal inflammation is an effective way for AKI treatment. Mesencephalic astrocyte-derived neurotrophic factor (MANF) has been proven to be an anti-inflammatory factor. However, the effect of MANF on renal inflammation induced by AKI is unknown. In this study, we have investigated the effect of mono-macrophage-derived MANF on AKI. We constructed the mono-macrophage-specific MANF knockout (Mø MANF-/-) mouse and used lipopolysaccharide (LPS) to induce AKI in wild-type (WT) and Mø MANF-/- mice. With mono-macrophage-specific MANF deficiency, Mø MANF-/- mice had a lower survival rate, more severe renal injury, and higher serum level of pro-inflammatory TNF-α after AKI was induced by LPS. Also, compared with WT mice, there were more M1 macrophages in renal tissues of Mø MANF-/- mice with LPS treatment, which might be attributed to the enhanced NF-κB activation in the renal microenvironment. Our study indicates the immunoregulatory role of mono-macrophage-derived MANF in the pathophysiological process of AKI, as well as the potential clinical application of MANF for AKI treatment.
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Affiliation(s)
- Chao Hou
- School of Basic Medical Sciences, Anhui Medical University, 81 Meishan Road, Hefei, 230032, Anhui, China
- Biopharmaceutical Research Institute, Anhui Medical University, Hefei, 230032, Anhui, China
| | - Qiong Mei
- School of Basic Medical Sciences, Anhui Medical University, 81 Meishan Road, Hefei, 230032, Anhui, China
- Biopharmaceutical Research Institute, Anhui Medical University, Hefei, 230032, Anhui, China
| | - Xuegang Song
- School of Basic Medical Sciences, Anhui Medical University, 81 Meishan Road, Hefei, 230032, Anhui, China
| | - Qin Bao
- School of Basic Medical Sciences, Anhui Medical University, 81 Meishan Road, Hefei, 230032, Anhui, China
| | - Xiang Li
- School of Basic Medical Sciences, Anhui Medical University, 81 Meishan Road, Hefei, 230032, Anhui, China
- Biopharmaceutical Research Institute, Anhui Medical University, Hefei, 230032, Anhui, China
| | - Dong Wang
- School of Basic Medical Sciences, Anhui Medical University, 81 Meishan Road, Hefei, 230032, Anhui, China.
- Biopharmaceutical Research Institute, Anhui Medical University, Hefei, 230032, Anhui, China.
| | - Yuxian Shen
- School of Basic Medical Sciences, Anhui Medical University, 81 Meishan Road, Hefei, 230032, Anhui, China.
- Biopharmaceutical Research Institute, Anhui Medical University, Hefei, 230032, Anhui, China.
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Popova NK, Kulikov AV, Naumenko VS. Spaceflight and brain plasticity: Spaceflight effects on regional expression of neurotransmitter systems and neurotrophic factors encoding genes. Neurosci Biobehav Rev 2020; 119:396-405. [PMID: 33086127 DOI: 10.1016/j.neubiorev.2020.10.010] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2020] [Revised: 07/14/2020] [Accepted: 10/13/2020] [Indexed: 12/13/2022]
Abstract
The critical problem of space exploration is the effect of long-term space travel on brain functioning. Current information concerning the effects of actual spaceflight on the brain was obtained on rats and mice flown on five missions of Soviet/Russian biosatellites, NASA Neurolab Mission STS90, and International Space Station (ISS). The review provides converging lines of evidence that: 1) long-term spaceflight affects both principle regulators of brain neuroplasticity - neurotransmitters (5-HT and DA) and neurotrophic factors (CDNF, GDNF but not BDNF); 2) 5-HT- (5-HT2A receptor and MAO A) and especially DA-related genes (TH, MAO A, COMT, D1 receptor, CDNF and GDNF) belong to the risk neurogenes; 3) brain response to spaceflight is region-specific. Substantia nigra, striatum and hypothalamus are highly sensitive to the long-term spaceflight: in these brain areas spaceflight decreased the expression of both DA-related and neurotrophic factors genes. Since DA system is involved in the regulation of movement and cognition the data discussed in the review could explain dysfunction of locomotion and behavior of astronauts and direct further investigations to the DA system.
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Affiliation(s)
- Nina K Popova
- Institute of Cytology and Genetics, Siberian Division of Russian Academy of Sciences, Novosibirsk, 630090, Russia.
| | - Alexander V Kulikov
- Institute of Cytology and Genetics, Siberian Division of Russian Academy of Sciences, Novosibirsk, 630090, Russia
| | - Vladimir S Naumenko
- Institute of Cytology and Genetics, Siberian Division of Russian Academy of Sciences, Novosibirsk, 630090, Russia.
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