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Overexpressing lnc240 Rescues Learning and Memory Dysfunction in Hepatic Encephalopathy Through miR-1264-5p/MEF2C Axis

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Abstract

Hepatic encephalopathy (HE) is a nervous system disease caused by severe liver diseases and different degrees of learning and memory dysfunction. Long non-coding RNA (lncRNA) is highly expressed in the brain and plays important roles in central nervous system diseases like Alzheimer’s disease. In the present work, we found that the expression of lnc240 in the hippocampus of HE mice was significantly downregulated, but its pathogenesis in HE has not been clarified. This study aimed to explore the effects of lnc240 on the cognitive function of HE. The expression of lnc240, miR-1264-5p, and MEF2C was analyzed with RNA-seq and further determined by qRT-PCR in HE mouse. Double luciferase reporter gene testing confirmed the relationship between lnc240, MEF2C, and miR-1264-5p. The functional role of lnc240 and MEF2C in vitro and in vivo was evaluated by qRT-PCR, western blot analysis, immunofluorescence staining, Golgi staining, electrophysiology, and Morris water maze. The expression of lnc240 was decreased in HE mice. The overexpression of lnc240 could significantly downregulate miR-1264-5p and upregulate MEF2C, also increasing the amplitude and frequency of mEPSC in primary cultured hippocampal neurons. The overexpression of miR-1264-5p reversed the effect of lnc240 on MEF2C. Moreover, in vivo experiments have shown that the overexpression of lnc240 could improve HE mice’s spatial learning and memory functions. Golgi staining suggested that overexpression of lnc240 could increase the density and maturity of dendritic spines in hippocampal neurons of HE mice. Lnc240 can regulate the expression of MEF2C through miR-1264-5p and regulate the synaptic plasticity of hippocampal neurons, thereby saving the learning and memory dysfunction in HE mice, suggesting that lnc240 might be a potential therapeutic target for the treatment of HE.

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References

  1. Bayat M, Khalili A, Bayat G, Akbari S, Yousefi Nejad A, Borhani Haghighi A, Haghani M (2022) Effects of platelet-rich plasma on the memory impairment, apoptosis, and hippocampal synaptic plasticity in a rat model of hepatic encephalopathy. Brain Behav 12(1):e2447. https://doi.org/10.1002/brb3.2447

    Article  CAS  PubMed  Google Scholar 

  2. Hussien YA, Mansour DF, Nada SA, Abd El-Rahman SS, Abdelsalam RM, Attia AS, El-Tanbouly DM (2022) Linagliptin attenuates thioacetamide-induced hepatic encephalopathy in rats: modulation of C/EBP-β and CX3CL1/Fractalkine, neuro-inflammation, oxidative stress and behavioral defects. Life Sci 295:120378. https://doi.org/10.1016/j.lfs.2022.120378

    Article  CAS  PubMed  Google Scholar 

  3. Cabrera-Pastor A, Llansola M, Montoliu C, Malaguarnera M, Balzano T, Taoro-Gonzalez L, García-García R, Mangas-Losada A, Izquierdo-Altarejos P, Arenas YM, Leone P, Felipo V (2019) Peripheral inflammation induces neuroinflammation that alters neurotransmission and cognitive and motor function in hepatic encephalopathy: Underlying mechanisms and therapeutic implications. Acta Physiol (Oxf) 226(2):e13270. https://doi.org/10.1111/apha.13270

    Article  CAS  PubMed  Google Scholar 

  4. Weissenborn K, Giewekemeyer K, Heidenreich S, Bokemeyer M, Berding G, Ahl B (2005) Attention, memory, and cognitive function in hepatic encephalopathy. Metab Brain Dis 20(4):359–367. https://doi.org/10.1007/s11011-005-7919-z

    Article  PubMed  Google Scholar 

  5. Khodir AE, Said E (2020) Nifuroxazide attenuates experimentally-induced hepatic encephalopathy and the associated hyperammonemia and cJNK/caspase-8/TRAIL activation in rats. Life Sci 252:117610. https://doi.org/10.1016/j.lfs.2020.117610

    Article  CAS  PubMed  Google Scholar 

  6. Wijdicks EFM (2017) Hepatic encephalopathy. N Engl J Med 376(2):186. https://doi.org/10.1056/NEJMc1614962

    Article  PubMed  Google Scholar 

  7. Bu FT, Wang A, Zhu Y, You HM, Zhang YF, Meng XM, Huang C, Li J (2020) LncRNA NEAT1: shedding light on mechanisms and opportunities in liver diseases. Liver Int 40(11):2612–2626. https://doi.org/10.1111/liv.14629

    Article  CAS  PubMed  Google Scholar 

  8. Wu P, Mo Y, Peng M, Tang T, Zhong Y, Deng X, Xiong F, Guo C, Wu X, Li Y, Li X, Li G, Zeng Z, Xiong W (2020) Emerging role of tumor-related functional peptides encoded by lncRNA and circRNA. Mol Cancer 19(1):22. https://doi.org/10.1186/s12943-020-1147-3

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Wu YY, Kuo HC (2020) Functional roles and networks of non-coding RNAs in the pathogenesis of neurodegenerative diseases. J Biomed Sci 27(1):49. https://doi.org/10.1186/s12929-020-00636-z

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Zhou Z, Qi D, Gan Q, Wang F, Qin B, Li J, Wang H, Wang D (2021) Studies on the regulatory roles and related mechanisms of lncRNAs in the nervous system. Oxid Med Cell Longev 2021:6657944. https://doi.org/10.1155/2021/6657944

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Wang Q, Liu L, Zhang S, Ming Y, Liu S, Cheng K, Zhao Y (2020) Long noncoding RNA NEAT1 suppresses hepatocyte proliferation in fulminant hepatic failure through increased recruitment of EZH2 to the LATS2 promoter region and promotion of H3K27me3 methylation. Exp Mol Med 52(3):461–472. https://doi.org/10.1038/s12276-020-0387-z

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Sultan M, Ben-Ari Z, Masoud R, Pappo O, Harats D, Kamari Y, Safran M (2017) Interleukin-1α and interleukin-1β play a central role in the pathogenesis of fulminant hepatic failure in mice. PLoS One 12(9):e0184084. https://doi.org/10.1371/journal.pone.0184084

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Ding YT, Luan WK, Shen XL, Wang Z, Cao YJ (2022) LncRNA BDNF-AS as ceRNA regulates the miR-9-5p/BACE1 pathway affecting neurotoxicity in Alzheimer's disease. Arch Gerontol Geriat 99. doi: ARTN 104614. https://doi.org/10.1016/j.archger.2021.104614

  14. Wang K, Lu Y, Zhao Z, Zhang C (2021) Bioinformatics-based analysis of lncRNA-mRNA interaction network of mild hepatic encephalopathy in cirrhosis. Comput Math Methods Med 2021:7777699. https://doi.org/10.1155/2021/7777699

    Article  PubMed  PubMed Central  Google Scholar 

  15. Zhang C, Ni W, Zhu Y, Lin J, Li H, Zhao Z, Wang K, Huo H, Luo M (2022) Construction and comprehensive analysis of a lncRNA-mRNA interactive network to reveal a potential lncRNA for hepatic encephalopathy development. Hum Cell 35(4):1060–1070. https://doi.org/10.1007/s13577-022-00714-4

    Article  CAS  PubMed  Google Scholar 

  16. Cheon SY, Jo D, Kim YK, Song J (2022) Long noncoding RNAs regulate hyperammonemia-induced neuronal damage in hepatic encephalopathy. Oxid Med Cell Longev 2022:7628522. https://doi.org/10.1155/2022/7628522

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Zhang H, Zhang W, Yu G, Li F, Hui Y, Cha S, Chen M, Zhu W, Zhang J, Guo G, Gong X (2022) Comprehensive analysis of lncRNAs, miRNAs and mRNAs in mouse hippocampus with hepatic encephalopathy. Front Genet 13:868716. https://doi.org/10.3389/fgene.2022.868716

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Sun X, Han R, Cheng T, Zheng Y, Xiao J, So KF, Zhang L (2019) Corticosterone-mediated microglia activation affects dendritic spine plasticity and motor learning functions in minimal hepatic encephalopathy. Brain Behav Immun 82:178–187. https://doi.org/10.1016/j.bbi.2019.08.184

    Article  CAS  PubMed  Google Scholar 

  19. Vorhees CV, Williams MT (2006) Morris water maze: procedures for assessing spatial and related forms of learning and memory. Nat Protoc 1(2):848–858. https://doi.org/10.1038/nprot.2006.116

    Article  PubMed  PubMed Central  Google Scholar 

  20. Rahmati M, Keshvari M, Xie W, Yang G, Jin H, Li H, Chehelcheraghi F, Li Y (2022) Resistance training and Urtica dioica increase neurotrophin levels and improve cognitive function by increasing age in the hippocampus of rats. Biomed Pharmacother 153:113306. https://doi.org/10.1016/j.biopha.2022.113306

    Article  CAS  PubMed  Google Scholar 

  21. Gordon J, Amini S (2021) General overview of neuronal cell culture. Methods Mol Biol 2311:1–8. https://doi.org/10.1007/978-1-0716-1437-2_1

    Article  CAS  PubMed  Google Scholar 

  22. Rahmati M, Rashno A (2021) Automated image segmentation method to analyse skeletal muscle cross section in exercise-induced regenerating myofibers. Sci Rep 11(1):21327. https://doi.org/10.1038/s41598-021-00886-3

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Keiser MS, Chen YH, Davidson BL (2018) Techniques for intracranial stereotaxic injections of adeno-associated viral vectors in adult mice. Curr Protoc Mouse Biol 8(4):e57. https://doi.org/10.1002/cpmo.57

    Article  PubMed  Google Scholar 

  24. Rahmati M, Taherabadi SJ (2021) The effects of exercise training on Kinesin and GAP-43 expression in skeletal muscle fibers of STZ-induced diabetic rats. Sci Rep 11(1):9535. https://doi.org/10.1038/s41598-021-89106-6

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Merlini M, Rafalski VA, Rios Coronado PE, Gill TM, Ellisman M, Muthukumar G, Subramanian KS, Ryu JK, Syme CA, Davalos D, Seeley WW, Mucke L, Nelson RB, Akassoglou K (2019) Fibrinogen induces microglia-mediated spine elimination and cognitive impairment in an Alzheimer's disease model. Neuron 101(6):1099–1108e1096. https://doi.org/10.1016/j.neuron.2019.01.014

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Kasai H, Fukuda M, Watanabe S, Hayashi-Takagi A, Noguchi J (2010) Structural dynamics of dendritic spines in memory and cognition. Trends Neurosci 33(3):121–129. https://doi.org/10.1016/j.tins.2010.01.001

    Article  CAS  PubMed  Google Scholar 

  27. Harris KM, Jensen FE, Tsao B (1992) Three-dimensional structure of dendritic spines and synapses in rat hippocampus (CA1) at postnatal day 15 and adult ages: implications for the maturation of synaptic physiology and long-term potentiation. J Neurosci 12(7):2685–2705. https://doi.org/10.1523/JNEUROSCI.12-07-02685.1992

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Vogl AM, Brockmann MM, Giusti SA, Maccarrone G, Vercelli CA, Bauder CA, Richter JS, Roselli F, Hafner AS, Dedic N, Wotjak CT, Vogt-Weisenhorn DM, Choquet D, Turck CW, Stein V, Deussing JM, Refojo D (2015) Neddylation inhibition impairs spine development, destabilizes synapses and deteriorates cognition. Nat Neurosci 18(2):239–251. https://doi.org/10.1038/nn.3912

    Article  CAS  PubMed  Google Scholar 

  29. Wang H, Huo X, Yang XR, He J, Cheng L, Wang N, Deng X, Jin H, Wang N, Wang C, Zhao F, Fang J, Yao M, Fan J, Qin W (2017) STAT3-mediated upregulation of lncRNA HOXD-AS1 as a ceRNA facilitates liver cancer metastasis by regulating SOX4. Mol Cancer 16(1):136. https://doi.org/10.1186/s12943-017-0680-1

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Zhou M, Zhao H, Wang X, Sun J, Su J (2019) Analysis of long noncoding RNAs highlights region-specific altered expression patterns and diagnostic roles in Alzheimer's disease. Brief Bioinform 20(2):598–608. https://doi.org/10.1093/bib/bby021

    Article  CAS  PubMed  Google Scholar 

  31. Cai LJ, Tu L, Huang XM, Huang J, Qiu N, Xie GH, Liao JX, Du W, Zhang YY, Tian JY (2020) LncRNA MALAT1 facilitates inflammasome activation via epigenetic suppression of Nrf2 in Parkinson's disease. Mol Brain 13(1):130. https://doi.org/10.1186/s13041-020-00656-8

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Xue W, Chen J, Liu X, Gong W, Zheng J, Guo X, Liu Y, Liu L, Ma J, Wang P, Li Z, Xue Y (2018) PVT1 regulates the malignant behaviors of human glioma cells by targeting miR-190a-5p and miR-488-3p. Biochim Biophys Acta Mol Basis Dis 1864(5 Pt A):1783–1794. https://doi.org/10.1016/j.bbadis.2018.02.022

    Article  CAS  PubMed  Google Scholar 

  33. Zhang G, Ni X (2021) Knockdown of TUG1 rescues cardiomyocyte hypertrophy through targeting the miR-497/MEF2C axis. Open Life Sci 16(1):242–251. https://doi.org/10.1515/biol-2021-0025

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Song G, Shen Y, Ruan Z, Li X, Chen Y, Yuan W, Ding X, Zhu L, Qian L (2016) LncRNA-uc.167 influences cell proliferation, apoptosis and differentiation of P19 cells by regulating Mef2c. Gene 590(1):97–108. https://doi.org/10.1016/j.gene.2016.06.006

    Article  CAS  PubMed  Google Scholar 

  35. Bai M, Ye D, Guo X, Xi J, Liu N, Wu Y, Jia W, Wang G, Chen W, Li G, Jiapaer Z, Kang J (2020) Critical regulation of a NDIME/MEF2C axis in embryonic stem cell neural differentiation and autism. EMBO Rep 21(11):e50283. https://doi.org/10.15252/embr.202050283

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Yang Y, Zhao F, Yuan Z, Wang C, Chen K, Xiao W (2021) Inhibition of miR-218-5p reduces myocardial ischemia-reperfusion injury in a Sprague-Dawley rat model by reducing oxidative stress and inflammation through MEF2C/NF-κB pathway. Int Immunopharmacol 101(Pt B):108299. https://doi.org/10.1016/j.intimp.2021.108299

    Article  CAS  PubMed  Google Scholar 

  37. Rahmati M, Keshvari M, Mirnasouri R, Chehelcheraghi F (2021) Exercise and Urtica dioica extract ameliorate hippocampal insulin signaling, oxidative stress, neuroinflammation, and cognitive function in STZ-induced diabetic rats. Biomed Pharmacother 139:111577. https://doi.org/10.1016/j.biopha.2021.111577

    Article  CAS  PubMed  Google Scholar 

  38. Keshvari M, Rahmati M, Mirnasouri R, Chehelcheraghi F (2020) Effects of endurance exercise and Urtica dioica on the functional, histological and molecular aspects of the hippocampus in STZ-Induced diabetic rats. J Ethnopharmacol 256:112801. https://doi.org/10.1016/j.jep.2020.112801

    Article  CAS  PubMed  Google Scholar 

  39. Zhang Z, Zhao Y (2022) Progress on the roles of MEF2C in neuropsychiatric diseases. Mol Brain 15(1):8. https://doi.org/10.1186/s13041-021-00892-6

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Flavell SW, Kim TK, Gray JM, Harmin DA, Hemberg M, Hong EJ, Markenscoff-Papadimitriou E, Bear DM, Greenberg ME (2008) Genome-wide analysis of MEF2 transcriptional program reveals synaptic target genes and neuronal activity-dependent polyadenylation site selection. Neuron 60(6):1022–1038. https://doi.org/10.1016/j.neuron.2008.11.029

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Madugula K, Mulherkar R, Khan ZK, Chigbu DI, Patel D, Harhaj EW, Jain P (2019) MEF-2 isoforms' (A-D) roles in development and tumorigenesis. Oncotarget 10(28):2755–2787. https://doi.org/10.18632/oncotarget.26763

    Article  PubMed  PubMed Central  Google Scholar 

  42. Assali A, Harrington AJ, Cowan CW (2019) Emerging roles for MEF2 in brain development and mental disorders. Curr Opin Neurobiol 59:49–58. https://doi.org/10.1016/j.conb.2019.04.008

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Gu X, Fu C, Lin L, Liu S, Su X, Li A, Wu Q, Jia C, Zhang P, Chen L, Zhu X, Wang X (2018) miR-124 and miR-9 mediated downregulation of HDAC5 promotes neurite development through activating MEF2C-GPM6A pathway. J Cell Physiol 233(1):673–687. https://doi.org/10.1002/jcp.25927

    Article  CAS  PubMed  Google Scholar 

  44. Kim B, Choi Y, Kim HS, Im HI (2019) Methyl-CpG binding protein 2 in Alzheimer dementia. Int Neurourol J 23(Suppl 2):S72–S81. https://doi.org/10.5213/inj.1938196.098

    Article  PubMed  PubMed Central  Google Scholar 

  45. Zhang ZG, Li Y, Ng CT, Song YQ (2015) Inflammation in Alzheimer's disease and molecular genetics: recent update. Arch Immunol Ther Exp (Warsz) 63(5):333–344. https://doi.org/10.1007/s00005-015-0351-0

    Article  CAS  PubMed  Google Scholar 

  46. Karch CM, Goate AM (2015) Alzheimer's disease risk genes and mechanisms of disease pathogenesis. Biol Psychiatry 77(1):43–51. https://doi.org/10.1016/j.biopsych.2014.05.006

    Article  CAS  PubMed  Google Scholar 

  47. Ren J, Zhang S, Wang X, Deng Y, Zhao Y, Xiao Y, Liu J, Chu L, Qi X (2022) MEF2C ameliorates learning, memory, and molecular pathological changes in Alzheimer’s disease in vivo and in vitro. Acta Biochim Biophys Sin (Shanghai) 54(1):1–14. https://doi.org/10.3724/abbs.2021012

    Article  CAS  PubMed  Google Scholar 

  48. Akhtar MW, Kim MS, Adachi M, Morris MJ, Qi X, Richardson JA, Bassel-Duby R, Olson EN, Kavalali ET, Monteggia LM (2012) In vivo analysis of MEF2 transcription factors in synapse regulation and neuronal survival. PLoS One 7(4):e34863. https://doi.org/10.1371/journal.pone.0034863

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

We would like to express our sincere gratitude to the editor and anonymous reviewers for their valuable comments, which have greatly improved this paper.

Funding

This work was supported by grants from the National Natural Science Foundation of China (81771144, 82101438, 81671946); the Natural Science Foundation of Guangdong Province, China (2021A1515011134); and the Medical Science and Technology Research Fund of Guangdong province, China (A2021276).

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  1. Huijie Zhang, Guangyin Yu, and Jiong Li have contributed equally to this work and share first authorship.

Authors and Affiliations

  1. Neuroscience Laboratory for Cognitive and Developmental Disorders, Department of Anatomy, Medical College of Jinan University, Guangzhou, 510630, Guangdong, China

    Huijie Zhang, Guangyin Yu, Jiong Li, Chunyi Tu, Yuqing Hui, Danlei Liu, Meiying Chen, Jifeng Zhang & Guoqing Guo

  2. Department of Gastroenterology, The First Affiliated Hospital of Jinan University, Guangzhou, 510630, Guangdong, China

    Huijie Zhang, Chunyi Tu, Yuqing Hui, Danlei Liu & Xiaobing Gong

  3. Department of Gastroenterology, Guangzhou Women and Children’s Medical Center, Guangzhou, 510623, Guangdong, China

    Huijie Zhang

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Contributions

Guoqing Guo, Xiaobing Gong, Jifeng Zhang, and Guangyin Yu conceived and designed the experiments and revised the manuscript; Huijie Zhang, Jiong Li, and Chunyi Tu performed the experiments; Yuqing Hui, Danlei Liu, and Meiying Chen assisted in some of the experimental work; Guangyin Yu and Jiongli analyzed data; and Guangyin Yu and Huijie Zhang wrote the paper. All authors have read and approved the final manuscript.

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Correspondence to Jifeng Zhang, Xiaobing Gong or Guoqing Guo.

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The animal experiments were approved by the ethics committee of Jinan University. The mice were housed under a 12-h light/dark cycle with unlimited access to standard rat chow and water. Animal care procedures were carried out following the provisions outlined in the National Health and Medical Research Council animal ethics and ARRIVE guidelines.

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Zhang, H., Yu, G., Li, J. et al. Overexpressing lnc240 Rescues Learning and Memory Dysfunction in Hepatic Encephalopathy Through miR-1264-5p/MEF2C Axis. Mol Neurobiol 60, 2277–2294 (2023). https://doi.org/10.1007/s12035-023-03205-1

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