Identifying Melissa officinalis microRNAs as putative inhibitors in neurodegenerative disorders: a cross-kingdom approach

Abstract

MicroRNAs are endogenous molecules that play a significant regulatory role in numerous physiological processes in plants and animals. The pivotal role of miRNAs is gene silencing by binding to a mature transcript’s 3′ UTR region which could be promising biomarkers for various diseases. Lemon balm (Melissa officinalis) possesses innumerable ethnomedicinal significance. Abundant studies have well-documented the cross-kingdom post-transcriptional regulatory potential of plant-derived small noncoding microRNAs. Under the aegis of a plant genomics approach, substantial advances in the first-ever in-silico microRNA analysis of Melissa officinalis were implemented. The present work aims to identify and uncover the role of Melissa officinalis plant miRNAs in Neurodegenerative disorders. The current study records the transcriptome-wide identification of 29 novel conserved miRNAs using sequence similarity search and mfold web server respectively, with a total of 99 potential human gene targets and top 10 prospective hub nodes as ESR1, CASP8, SPTBN1, RPL27A, IRF8, PRKCB, QKI, IGF2BP1, TTLL12 and NUP153 which were identified using psRNATarget and Cytoscape; targeted by miRNA families such as miR4995, miR397b, miR397-5p, miR397b-5p, miR396g-3p, miR2914, and miR397. Moreover, targeted genes were annotated by Funrich software, and a disease association study was conducted in the KEGG mapper database. The identified class of small RNAs were found to be associated with neurodegenerative disease, and various carcinomas. Consequently, identified top 4 hub genes CASP8, SPTBN1, PRKCB, and TTLL12 show their crucial involvement in the Neurodegenerative disorder pathways such as Alzheimer’s, Parkinson’s, Huntington’s, Spinocerebellar ataxia, and Axonal diseases. The findings can further contribute to understanding miRNA function and their regulatory mechanism in humans, leading to further implementation of other research objectives.

Keywords

Gene enrichment analysis / Melissa officinalis / microRNAs / Neurodegenerative disorder / Protein–protein interaction

References

[1] AbdurakhmonovIY. Genomics era for plants and crop species-advances made and needed task Ahed. Plant Genomics, 2016.

[2] AhmedF, BappyMNI, IslamMS. Identification of conserved miRNAs and their targets in Jatropha curcas: An in silico approach. Journal of Genetic Engineering and Biotechnology, 2023, 21143.

[3] AmbrosV, BartelB, BartelDP, BurgeCB, CarringtonJC, ChenX, DreyfussG, EddySR, Griffiths-JonesSAM, MarshallM. A uniform system for microRNA annotation. RNA, 2003, 9(3): 277-279

[4] AmodioF, CaiazzaM, FimianiF, CalabròP, LimongelliG. MicroRNAs: From junk RNA to life regulators and their role in cardiovascular disease. Cardiogenetics, 2021, 11(4): 230-254.

[5] BanoN, FakhrahS, NayakSP, BagSK, MohantyCS. Identification of miRNA and their target genes in Cestrum nocturnum L. and Cestrum diurnum L. in stress responses. Physiology and Molecular Biology of Plants, 2022, 28(1): 31-49.

[6] BhavsarM, MangukiaN, KumarSP, PatelS, RawalR, MankadA. Identification and characterization of known and new miRNAs from Nicotiana tabacum and nta-miR156’s predictive role in Wnt Signalling Pathway. Advances in Cancer Biology—Metastasis, 2023, 8September 2022100105.

[7] BhavsarM, MangukiaN, PatelS, RawalR, MankadA. Unraveling the miRnome of Nicotiana rustica (Aztec tobacco)—A Genomewide computational assessment. Plant Gene, 2022, 32. 100378

[8] BudakH, AkpinarBA. Plant miRNAs: Biogenesis, organization and origins. Functional and Integrative Genomics, 2015, 15(5): 523-531.

[9] CaiY, YuX, HuS, YuJ. A brief review on the mechanisms of miRNA regulation. Genomics, Proteomics and Bioinformatics, 2009, 7(4): 147-154.

[10] CousinMA, CreightonBA, BreauKA, SpillmannRC, TortiE, DontuS, TripathiS, AjitD, EdwardsRJ, AfriyieS, BayJC, HarperKM, BeltranAA, MunozLJ, Falcon RodriguezL, StankewichMC, PersonRE, SiY, NormandEA, LorenzoDN. Pathogenic SPTBN1 variants cause an autosomal dominant neurodevelopmental syndrome. Nature Genetics, 2021, 53(7): 1006-1021.

[11] DaiX, ZhaoPX. PsRNATarget: A plant small RNA target analysis server. Nucleic Acids Research, 2011, 39(SUPPL. 2): 155-159.

[12] DaiX, ZhuangZ, ZhaoPX. PsRNATarget: A plant small RNA target analysis server (2017 release). Nucleic Acids Research, 2018, 46(W1): W49-W54.

[13] DonchevaNT, MorrisJH, GorodkinJ, JensenLJ. Cytoscape stringapp: Network analysis and visualization of proteomics data. Journal of Proteome Research, 2019, 18(2): 623-632.

[14] DongQ, HuB, ZhangC. microRNAs and their roles in plant development. Frontiers in Plant Science, 2022.

[15] DustinD, GuG, FuquaSAW. ESR1 mutations in breast cancer. Cancer, 2019, 125(21): 3714-3728.

[16] FonsekaP, PathanM, ChittiSV, KangT, MathivananS. FunRich enables enrichment analysis of OMICs datasets. Journal of Molecular Biology, 2021, 43311. 166747

[17] GadhaviH, PatelM, MangukiaN, ShahK, BhadreshaK, PatelSK, RawalRM, PandyaHA. Transcriptome-wide miRNA identification of Bacopa monnieri: a cross-kingdom approach. Plant Signaling and Behavior, 2020.

[18] GregorioKCR, LaurindoCP, MachadoUF. Estrogen and glycemic homeostasis: The fundamental role of nuclear estrogen receptors esr1/esr2 in glucose transporter glut4 regulation. Cells, 2021, 10(1): 1-23.

[19] GulyaevaLF, KushlinskiyNE. Regulatory mechanisms of microRNA expression. Journal of Translational Medicine, 2016, 14(1): 1-10.

[20] HasaneinP, RiahiH. Antinociceptive and antihyperglycemic effects of Melissa officinalis essential oil in an experimental model of diabetes. Medical Principles and Practice, 2015, 24(1): 47-52.

[21] HuangY, JiangL, LiB, FangY, JiY, XuX. Caspase-8 regulates amyloid-beta-induced neuronal apoptosis in Alzheimer's disease. Journal of Neuroscience Research, 2011, 89(4): 554-563.

[22] IkedaM, MizunoT, TakanashiM, AsadaT, FujiiY. βII-Spectrin mutations disrupt neuronal cytoskeleton, leading to neurodegenerative phenotypes. Nature Neuroscience, 2020, 23(5): 611-622.

[23] JhaN, MangukiaN, PatelMP, BhavsarM, GadhaviH, RawalRM, PatelSK. Exploring the MiRnome of Carica papaya: A cross kingdom approach. Gene Reports, 2021, 23March. 101089

[24] JulienO, WellsJA. Caspases and their substrates. Cell Death and Differentiation, 2017, 24(8): 1380-1389.

[25] KruideringM, EvanGI. Caspase-8 in apoptosis: The beginning of “The End”?. IUBMB Life, 2000, 50(2): 85-90.

[26] LeinonenR, SugawaraH, ShumwayM. The sequence read archive. Nucleic Acids Research, 2011, 39(Suppl. 1): 2010-2012.

[27] LiZ, XuR, LiN. Correction: MicroRNAs from plants to animals, do they define a new messenger for communication? (Nutrition and Metabolism (2018) 15 (68) 10.1186/s12986-018-0305-8). Nutrition and Metabolism, 2018.

[28] MirajS, Rafieian-Kopaei, KianiS. Melissa officinalis L.: A review study with an antioxidant prospective. Journal of Evidence-Based Complementary and Alternative Medicine, 2017, 22(3): 385-394.

[29] MitraD, MitraD, Sabri BensaadM, SinhaS, PantK, PantM, PriyadarshiniA, SinghP, DassamiourS, HambabaL, PanneerselvamP, Das MohapatraPK. Evolution of bioinformatics and its impact on modern bio-science in the twenty-first century: Special attention to pharmacology, plant science and drug discovery. Computational Toxicology, 2022, 24100248.

[30] MoradkhaniH, SargsyanE, BibakH, NaseriB, Sadat-HosseiniM, Fayazi-BarjinA, MeftahizadeH. Melissa officinalis L., a valuable medicine plant: A review. Journal of Medicinal Plants Research, 2010, 4(25): 2753-2759

[31] MotwaniH, PatelM, NanavatyV, DixitN, RawalRM, PatelSK, SolankiHA. Small RNA sequencing and identification of Andrographis paniculata miRNAs with potential cross-kingdom human gene targets. Functional and Integrative Genomics, 2023, 23(1): 1-20.

[32] Noorul BasarS, ZamanR. An overview of badranjboya (Melissa officinalis). International Research Journal of Biological Sciences, 2013, 2(12): 107-109

[33] O’MaraTA, GlubbDM, PainterJN, ChengT, DennisJ, AttiaJ, HollidayEG, McEvoyM, ScottRJ, AshtonK, ProiettoT, OttonG, ShahM, AhmedS, HealeyCS, GormanM, MartinL, HodgsonS, FaschingPA, SpurdleAB. Comprehensive genetic assessment of the ESR1 locus identifies a risk region for endometrial cancer. Endocrine-Related Cancer, 2015, 22(5): 851-861.

[34] PaulS, de la Fuente-JiménezJL, ManriquezCG, SharmaA. Identification, characterization and expression analysis of passion fruit (Passiflora edulis) microRNAs. 3 Biotech, 2020, 10(1): 1-9.

[35] PetrisorG, MotelicaL, CraciunLN, OpreaOC, FicaiD, FicaiA. Melissa officinalis: Composition, pharmacological effects and derived release systems—A review. International Journal of Molecular Sciences, 2022.

[36] RanganathanK, SivasankarV. MicroRNAs—Biology and clinical applications. Journal of Oral and Maxillofacial Pathology, 2014, 18(2): 229-234.

[37] Reza-ZaldívarEE, Jacobo-VelázquezDA. Targeting metabolic syndrome pathways: Carrot microRNAs as potential modulators. ACS Omega, 2023.

[38] RioloG, CantaraS, MarzocchiC, RicciC. miRNA targets: From prediction tools to experimental validation. Methods and Protocols, 2021, 4(1): 1-20.

[39] SaiyedAN, VasavadaAR, JoharSRK. Employing in silico investigations to determine the cross-kingdom approach for Curcuma longa miRNAs and their human targets. Beni-Suef University Journal of Basic and Applied Sciences, 2023.

[40] SamadAFA, KamaroddinMF, SajadM. Cross-kingdom regulation by plant microRNAs provides novel insight into gene regulation. Advances in Nutrition, 2021, 12(1): 197-211.

[41] SrivastavaH, MaheshwariKK. Melissa officinalis—an overview and its properties as an anxiolytic. International Journal of Pharmaceutical Sciences and Medicine, 2023, 8(3): 33-41.

[42] SzklarczykD, GableAL, NastouKC, LyonD, KirschR, PyysaloS, DonchevaNT, LegeayM, FangT, BorkP, JensenLJ, von MeringC. Erratum: The STRING database in 2021: customizable protein–protein networks, and functional characterization of user-uploaded gene/measurement sets (Nucleic Acids Research (2021) 49 (D605–D612) 10.1093/nar/gkaa1074). Nucleic Acids Research, 2021, 491810800.

[43] TamuraK, StecherG, KumarS. MEGA11: Molecular evolutionary genetics analysis version 11. Molecular Biology and Evolution, 2021, 38(7): 3022-3027.

[44] TrivediTS, ShaikhAM, MankadAU, RawalRM, PatelSK. Genome-wide characterization of fennel (Anethum foeniculum) MiRNome and identification of its potential targets in homo sapiens and Arabidopsis thaliana: An inter and intra-species computational scrutiny. Biochemical Genetics, 2023.

[45] Turhan, H. (n.d.). N23—Lemon balmo title. https://doi.org/10.1533/9781845691717.3.390

[46] VigneshD, ParameswariP, Bin ImS, Jin KimH, Pyo LimY. MiRPI: Portable software to identify conserved miRNAs, targets and to calculate precursor statistics. Genomics and Informatics, 2011, 911

[47] WangX, GaoG, ChenZ, ChenZ, HanM, XieX, JinQ, DuH, CaoZ, ZhangH. Identification of the miRNA signature and key genes in colorectal cancer lymph node metastasis. Cancer Cell International, 2021, 21(1): 1-12.

[48] Wellington and Hayden. (n.d.).

[49] YouFM. Plant genomics—Advancing our understanding of plants. International Journal of Molecular Sciences, 2023, 24(14): 5-7.

[50] ZhangL, HouD, ChenX, LiD, ZhuL, ZhangY, LiJ, BianZ, LiangX, CaiX, YinY, WangC, ZhangT, ZhuD, ZhangD, XuJ, ChenQ, BaY, LiuJ, ZhangCY. Exogenous plant MIR168a specifically targets mammalian LDLRAP1: Evidence of cross-kingdom regulation by microRNA. Cell Research, 2012, 22(1): 107-126.

[51] ZhouG, SoufanO, EwaldJ, HancockREW, BasuN, XiaJ. NetworkAnalyst 3.0: A visual analytics platform for comprehensive gene expression profiling and meta-analysis. Nucleic Acids Research, 2019, 47(W1): W234-W241.

[52] ZukerM. Mfold web server for nucleic acid folding and hybridization prediction. Nucleic Acids Research, 2003, 31(13): 3406-3415.

RIGHTS & PERMISSIONS

Shenzhen University School of Medicine; Fondazione Istituto FIRC di Oncologia Molecolare