The mitigative effect of lotus root (Nelumbo nucifera Gaertn) extract on acute alcoholism through activation of alcohol catabolic enzyme, reduction of oxidative stress, and protection of liver function

Objectives Lotus root (Nelumbo nucifera Gaertn) is a common medicinal-food dual-use vegetable. In this study, the effects of lotus root extract on acute alcoholism were investigated. Methods The Walle-Hoch method was used to determine the ADH activity of lotus root extracts in vitro. Lotus root methanol extract were identified by UPLC-QTOF-MS/MS based metabolomics analysis. Then 109 active ingredients with achievable oral doses and drug-like properties were explored using the TCMSP platform. SwissTargetPrediction Database to predict lotus root treatment targets for acute alcoholismSTRING database (https://www.string-db.org/) was used to construct protein-protein interaction network graphs. Gene ontology (GO) functional, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis of genes common to lotus root and alcoholism by Metascap database. Molecular docking simulations were performed using AutoDock 1.5.6 software. Animal experiments verified the relieving effect of lotus root extract on acute alcoholism after intervention. Results Results indicated the methanol extract of lotus root showed the highest activation rate of ethanol dehydrogenase in vitro (18.87%). The 433 compounds of lotus root methanol extract were identified by UPLC-QTOF-MS/MS based metabolomics analysis. Bioinformatics analysis indicate that there were 224 intersectioning targets between lotus root extract and acute alcoholism. KEGG enrichment analysised shows that lotus root extract may play a role in treating acute alcoholism by intervening with the neuroactive ligand-receptor interaction pathway. The protein-protein interaction network (PPI) analysis found that HSP90AA1, MAPK1 and STAT3 played a key role in lotus root extract-modulated PPI networks. Molecular docking showed that (7R, 8S)-dihydrodihydrodipine cypressol had the best binding ability with MAPK1. Experiments in mice indicate that lotus root extract improved the activity of liver alcohol dehydrogenase (ADH), acetaldehyde dehydrogenase (ALDH), catalase (CAT), superoxide dismutase (SOD) and glutathione peroxidase (GSH-PX), increase glutathione (GSH) and reduce malondialdehyde (MDA) levels, decrease glutamate transaminase (AST), alanine transaminase (ALT) and alkaline phosphatase (AKP) in the serum of mice with acute alcoholism, and accelerate the metabolic rate of alcohol after drinking. This study reveals the mechanism of lotus root to alleviate acute alcoholism, which provides a basis for further research on functional foods using lotus root and offers new possibilities for the treatment of acute alcoholism. Conclusions The results of the current study showed that the methanolic extract of lotus root had the highest activation rate of ethanol dehydrogenase. Network pharmacology results suggest that lotus root extract may play a role in the treatment of alcoholism by regulating signaling pathways, such as neuroactive ligand-receptor interactions, as well as biological processes, such as regulation of secretion, regulation of ion transport, response to lipopolysaccharides, and response to alcohol. Animal experiments confirmed the therapeutic effect of lotus root on acute alcoholism mechanistically through activation of alcohol catabolic enzyme, reduction of oxidative stress and protection of liver function.

[1]  Hailong Yang,et al.  Ameliorating effects of water bamboo shoot (Zizania latifolia) on acute alcoholism in a mice model and its chemical composition , 2022, Food Chemistry.

[2]  M. Whirl‐Carrillo,et al.  An Evidence‐Based Framework for Evaluating Pharmacogenomics Knowledge for Personalized Medicine , 2021, Clinical pharmacology and therapeutics.

[3]  Peter B. McGarvey,et al.  UniProt: the universal protein knowledgebase in 2021 , 2020, Nucleic Acids Res..

[4]  Olivier Michielin,et al.  SwissTargetPrediction: updated data and new features for efficient prediction of protein targets of small molecules , 2019, Nucleic Acids Res..

[5]  Alireza Hadj Khodabakhshi,et al.  Metascape provides a biologist-oriented resource for the analysis of systems-level datasets , 2019, Nature Communications.

[6]  Damian Szklarczyk,et al.  STRING v11: protein–protein association networks with increased coverage, supporting functional discovery in genome-wide experimental datasets , 2018, Nucleic Acids Res..

[7]  David S. Wishart,et al.  DrugBank 5.0: a major update to the DrugBank database for 2018 , 2017, Nucleic Acids Res..

[8]  G. Nardone,et al.  Alcoholic disease: liver and beyond. , 2014, World journal of gastroenterology.

[9]  K. Chang,et al.  Comparative analysis of antioxidant activity and functional components of the ethanol extract of lotus (Nelumbo nucifera) from various growing regions. , 2014, Journal of agricultural and food chemistry.

[10]  Wei Zhou,et al.  TCMSP: a database of systems pharmacology for drug discovery from herbal medicines , 2014, Journal of Cheminformatics.

[11]  Hua Yu,et al.  A Novel Chemometric Method for the Prediction of Human Oral Bioavailability , 2012, International journal of molecular sciences.

[12]  Hayato Nakagawa,et al.  Molecular Mechanisms of Liver Injury and Hepatocarcinogenesis: Focusing on the Role of Stress-Activated MAPK , 2012, Pathology research international.

[13]  Laura Inés Furlong,et al.  DisGeNET: a Cytoscape plugin to visualize, integrate, search and analyze gene-disease networks , 2010, Bioinform..

[14]  David S. Goodsell,et al.  AutoDock4 and AutoDockTools4: Automated docking with selective receptor flexibility , 2009, J. Comput. Chem..

[15]  Yanli Wang,et al.  PubChem: a public information system for analyzing bioactivities of small molecules , 2009, Nucleic Acids Res..

[16]  Lorenzo Leggio,et al.  Acute alcohol intoxication. , 2008, European journal of internal medicine.

[17]  A. Dolganiuc,et al.  Acute alcohol intake induces SOCS1 and SOCS3 and inhibits cytokine-induced STAT1 and STAT3 signaling in human monocytes. , 2008, Alcoholism, clinical and experimental research.

[18]  C. Fielding,et al.  IL-6 Regulates Neutrophil Trafficking during Acute Inflammation via STAT31 , 2008, The Journal of Immunology.

[19]  E. Solary,et al.  Heat shock proteins: essential proteins for apoptosis regulation , 2008, Journal of cellular and molecular medicine.

[20]  J. Grandis,et al.  STAT3 as a therapeutic target in head and neck cancer , 2006, Expert opinion on biological therapy.

[21]  Qing Zhang,et al.  The RCSB Protein Data Bank: a redesigned query system and relational database based on the mmCIF schema , 2004, Nucleic Acids Res..

[22]  Chieh-fu Chen,et al.  The extracts from Nelumbo Nucifera suppress cell cycle progression, cytokine genes expression, and cell proliferation in human peripheral blood mononuclear cells. , 2004, Life sciences.

[23]  P. Shannon,et al.  Cytoscape: A Software Environment for Integrated Models of Biomolecular Interaction Networks , 2003 .

[24]  D. Valle,et al.  Online Mendelian Inheritance In Man (OMIM) , 2000, Human mutation.

[25]  M. Ingelman-Sundberg,et al.  Role of cytochrome P4502E1‐dependent formation of hydroxyethyl free radical in the development of liver damage in rats intragastrically fed with ethanol , 1996, Hepatology.

[26]  Jiayang Sun,et al.  Effects of different processing methods on the lipid composition of hazelnut oil: A lipidomics analysis , 2022, Food Science and Human Wellness.

[27]  Tsippi Iny Stein,et al.  The GeneCards Suite , 2021, Practical Guide to Life Science Databases.

[28]  Liu Juan-jua.  Therapeutic effect of GSH on the treatment of alcoholic liver diseases. , 2004 .

[29]  Defeng Wu,et al.  Alcohol, Oxidative Stress, and Free Radical Damage , 2003, Alcohol research & health : the journal of the National Institute on Alcohol Abuse and Alcoholism.

[30]  W. Delano.  The PyMOL Molecular Graphics System , 2002 .