Induction of stress resistance and extension of lifespan in Chaenorhabditis elegans serotonin-receptor knockout strains by withanolide A

Publication type:
Journal article
Metadata:
Autoren
Autoren-URL
https://www.webofscience.com/api/gateway?GWVersion=2&SrcApp=fis-test-1&SrcAuth=WosAPI&KeyUT=WOS:000627864600004&DestLinkType=FullRecord&DestApp=WOS_CPL
DOI
10.1016/j.phymed.2021.153482
eISSN
1618-095X
Externe Identifier
  • Clarivate Analytics Document Solution ID: QV3GV
  • PubMed Identifier: 33611213
ISSN
0944-7113
Zeitschrift
PHYTOMEDICINE
Schlüsselwörter
  • Ageing
  • C. elegans
  • Depression
  • Phytotherapy
  • Solanaceae
  • Stress
  • Withania somnifera
Artikelnummer
ARTN 153482
Datum der Veröffentlichung
2021
Status
Published
Titel
Induction of stress resistance and extension of lifespan in <i>Chaenorhabditis elegans</i> serotonin-receptor knockout strains by withanolide A
Sub types
  • Article
Ausgabe der Zeitschrift
84

Data source: Web of Science (Lite)

Other metadata sources:
Autoren
DOI
10.1016/j.phymed.2021.153482
ISSN
0944-7113
Zeitschrift
Phytomedicine
Sprache
en
Artikelnummer
153482
Paginierung
153482 - 153482
Datum der Veröffentlichung
2021
Status
Published
Herausgeber
Elsevier BV
Herausgeber URL
http://dx.doi.org/10.1016/j.phymed.2021.153482
Datum der Datenerfassung
2023
Titel
Induction of stress resistance and extension of lifespan in Chaenorhabditis elegans serotonin-receptor knockout strains by withanolide A
Ausgabe der Zeitschrift
84

Data source: Crossref

Abstract
<h4>Introduction</h4>Approximately 300 million people worldwide suffer from depression. The COVID-19 crisis may dramatically increase these numbers. Severe side effects and resistance development limit the use of standard antidepressants. The steroidal lactone withanolide A (WA) from Withania somnifera may be a promising alternative. Caenorhabditis elegans was used as model to explore WA's anti-depressive and anti-stress potential.<h4>Methods</h4>C. elegans wildtype (N2) and deficient strains (AQ866, DA1814, DA2100, DA2109 and MT9772) were used to assess oxidative, osmotic or heat stress as measured by generation of reactive oxygen species (ROS), determination of lifespan, and mRNA expression of serotonin receptor (ser-1, ser-4, ser-7) and serotonin transporter genes (mod-5). The protective effect of WA was compared to fluoxetine as clinically established antidepressant. Additionally, WA's effect on lifespan was determined. Furthermore, the binding affinities and pKi values of WA, fluoxetine and serotonin as natural ligand to Ser-1, Ser-4, Ser-7, Mod-5 and their human orthologues proteins were calculated by molecular docking.<h4>Results</h4>Baseline oxidative stress was higher in deficient than wildtype worms. WA and fluoxetine reduced ROS levels in all strains except MT9772. WA and fluoxetine prolonged survival times in wildtype and mutants under osmotic stress. WA but not fluoxetine increased lifespan of all heat-stressed C. elegans strains except DA2100. Furthermore, WA but not fluoxetine extended lifespan in all non-stressed C. elegans strains. WA also induced mRNA expression of serotonin receptors and transporters in wildtype and mutants. WA bound with higher affinity and lower pKi values to all C. elegans and human serotonin receptors and transporters than serotonin, indicating that WA may competitively displaced serotonin from the binding pockets of these proteins.<h4>Conclusion</h4>WA reduced stress and increased lifespan by ROS scavenging and interference with the serotonin system. Hence, WA may serve as promising candidate to treat depression.
Addresses
  • Department of Pharmaceutical Biology, Institute of Biochemistry and Pharmacy, Johannes Gutenberg University, Staudinger Weg 5, 55128 Mainz, Germany.
Autoren
DOI
10.1016/j.phymed.2021.153482
eISSN
1618-095X
Externe Identifier
  • PubMed Identifier: 33611213
Funding acknowledgements
  • Deutsche Forschungsgemeinschaft:
Open access
false
ISSN
0944-7113
Zeitschrift
Phytomedicine : international journal of phytotherapy and phytopharmacology
Schlüsselwörter
  • Animals
  • Caenorhabditis elegans
  • Withania
  • Reactive Oxygen Species
  • Fluoxetine
  • Caenorhabditis elegans Proteins
  • Receptors, Serotonin
  • Plant Extracts
  • Oxidative Stress
  • Longevity
  • Withanolides
  • Gene Knockout Techniques
  • Molecular Docking Simulation
Sprache
eng
Medium
Print-Electronic
Online publication date
2021
Paginierung
153482
Datum der Veröffentlichung
2021
Status
Published
Datum der Datenerfassung
2021
Titel
Induction of stress resistance and extension of lifespan in Chaenorhabditis elegans serotonin-receptor knockout strains by withanolide A.
Sub types
  • Journal Article
Ausgabe der Zeitschrift
84

Data source: Europe PubMed Central

Abstract
INTRODUCTION: Approximately 300 million people worldwide suffer from depression. The COVID-19 crisis may dramatically increase these numbers. Severe side effects and resistance development limit the use of standard antidepressants. The steroidal lactone withanolide A (WA) from Withania somnifera may be a promising alternative. Caenorhabditis elegans was used as model to explore WA's anti-depressive and anti-stress potential. METHODS: C. elegans wildtype (N2) and deficient strains (AQ866, DA1814, DA2100, DA2109 and MT9772) were used to assess oxidative, osmotic or heat stress as measured by generation of reactive oxygen species (ROS), determination of lifespan, and mRNA expression of serotonin receptor (ser-1, ser-4, ser-7) and serotonin transporter genes (mod-5). The protective effect of WA was compared to fluoxetine as clinically established antidepressant. Additionally, WA's effect on lifespan was determined. Furthermore, the binding affinities and pKi values of WA, fluoxetine and serotonin as natural ligand to Ser-1, Ser-4, Ser-7, Mod-5 and their human orthologues proteins were calculated by molecular docking. RESULTS: Baseline oxidative stress was higher in deficient than wildtype worms. WA and fluoxetine reduced ROS levels in all strains except MT9772. WA and fluoxetine prolonged survival times in wildtype and mutants under osmotic stress. WA but not fluoxetine increased lifespan of all heat-stressed C. elegans strains except DA2100. Furthermore, WA but not fluoxetine extended lifespan in all non-stressed C. elegans strains. WA also induced mRNA expression of serotonin receptors and transporters in wildtype and mutants. WA bound with higher affinity and lower pKi values to all C. elegans and human serotonin receptors and transporters than serotonin, indicating that WA may competitively displaced serotonin from the binding pockets of these proteins. CONCLUSION: WA reduced stress and increased lifespan by ROS scavenging and interference with the serotonin system. Hence, WA may serve as promising candidate to treat depression.
Date of acceptance
2021
Autoren
Autoren-URL
https://www.ncbi.nlm.nih.gov/pubmed/33611213
DOI
10.1016/j.phymed.2021.153482
eISSN
1618-095X
Zeitschrift
Phytomedicine
Schlüsselwörter
  • Ageing
  • C. elegans
  • Depression
  • Phytotherapy
  • Solanaceae
  • Stress
  • Withania somnifera
  • Animals
  • Caenorhabditis elegans
  • Caenorhabditis elegans Proteins
  • Fluoxetine
  • Gene Knockout Techniques
  • Longevity
  • Molecular Docking Simulation
  • Oxidative Stress
  • Plant Extracts
  • Reactive Oxygen Species
  • Receptors, Serotonin
  • Withania
  • Withanolides
Sprache
eng
Country
Germany
Paginierung
153482
PII
S0944-7113(21)00024-6
Datum der Veröffentlichung
2021
Status
Published
Datum, an dem der Datensatz öffentlich gemacht wurde
2021
Titel
Induction of stress resistance and extension of lifespan in Chaenorhabditis elegans serotonin-receptor knockout strains by withanolide A.
Sub types
  • Journal Article
Ausgabe der Zeitschrift
84

Data source: PubMed

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