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Cell communication and signaling : CCS
05 25, 2021;19 (1): 61.

Hyoscyamus albus nortropane alkaloids reduce hyperglycemia and hyperinsulinemia induced in HepG2 cells through the regulation of SIRT1/NF-kB/JNK pathway.

Anna Kowalczuk, Nabila Bourebaba, Katarzyna Kornicka-Garbowska, Eliza Turlej, Krzysztof Marycz, Lynda Bourebaba
Author Information
  1. Anna Kowalczuk: National Medicines Institute, Chełmska 30/34, 00-725, Warsaw, Poland.
  2. Nabila Bourebaba: International Institute of Translational Medicine, Jesionowa 11, 55-114, Malin, Wisznia Mała, Poland.
  3. Katarzyna Kornicka-Garbowska: International Institute of Translational Medicine, Jesionowa 11, 55-114, Malin, Wisznia Mała, Poland.
  4. Eliza Turlej: Department of Experimental Biology, Faculty of Biology and Animal Science, Wrocław University of Environmental and Life Sciences, Norwida 27B, 50-375, Wrocław, Poland.
  5. Krzysztof Marycz: International Institute of Translational Medicine, Jesionowa 11, 55-114, Malin, Wisznia Mała, Poland.
  6. Lynda Bourebaba: International Institute of Translational Medicine, Jesionowa 11, 55-114, Malin, Wisznia Mała, Poland. lynda.bourebaba@upwr.edu.pl. ORCID
PMID: 34034759 DOI: 10.1186/s12964-021-00735-w

Abstract

BACKGROUND: Chronic superphysiological glucose and insulin concentrations are known to trigger several tissue and organ failures, including insulin resistance, oxidative stress and chronic low-grade inflammation. Hence, the screening for molecules that may counteract such conditions is essential in current existing therapeutic strategies, thereby the use of medicinal plant derivatives represents a promising axis in this regard.
METHODS: In this study, the effect of a selected traditional medicinal plant, Hyoscyamus albus from which, calystegines have been isolated, was investigated in an experimental model of hyperinsulinemia and hyperglycemia induced on HepG2 cells. The mRNA and protein expression levels of different insulin signaling, gluconeogenic and inflammatory pathway- related molecules were examined. Additionally, cell viability and apoptosis, oxidative stress extent and mitochondrial dysfunctions were assayed using flow cytometric and qRT-PCR techniques.
RESULTS: Treatment of IR HepG2 cells with calystegines strongly protected the injured cells from apoptosis, oxidative stress and mitochondrial integrity loss. Interestingly, nortropane alkaloids efficiently regulated the impaired glucose metabolism in IR HepG2 cells, through the stimulation of glucose uptake and the modulation of SIRT1/Foxo1/G6PC/mTOR pathway, which is governing the hepatic gluconeogenesis. Furthermore, the alkaloidal extract restored the defective insulin signaling pathway, mainly by promoting the expression of Insr at the mRNA and protein levels. What is more, treated cells exhibited significant mitigated inflammatory response, as evidenced by the modulation and the regulation of the NF- κB/JNK/TLR4 axis and the downstream proinflammatory cytokines recruitment.
CONCLUSION: Overall, the present investigation demonstrates that calystegines from Hyoscyamus albus provide cytoprotection to the HepG2 cells against insulin/glucose induced insulin resistance and apoptosis due to the regulation of SIRT1/Foxo1/G6PC/mTOR and NF-κB/JNK/TLR4 signaling pathways. Video Abstract.

Keywords

Calystegines HepG2 Hyoscyamus albus Hyperglycemia Insulin Resistance NF-κB Sirt1

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Grants

  1. 2018/29/B/NZ7/02662/Narodowe Centrum Nauki

MeSH Term

Apoptosis
Caspases
Cell Proliferation
Cell Survival
Cytokines
Gluconeogenesis
Glucose
Hep G2 Cells
Humans
Hyoscyamus
Hyperglycemia
Hyperinsulinism
Inflammation
Inflammation Mediators
Insulin
Insulin Resistance
MAP Kinase Signaling System
Mitochondria
NF-kappa B
Nortropanes
Oxidative Stress
Plant Extracts
Seeds
Signal Transduction
Sirtuin 1
TOR Serine-Threonine Kinases

Chemicals

Cytokines
Inflammation Mediators
Insulin
NF-kappa B
Nortropanes
Plant Extracts
TOR Serine-Threonine Kinases
Caspases
Sirtuin 1
Glucose
Journal Article Research Support, Non-U.S. Gov't
Article has an altmetric score of 1

Word Cloud

Created with Highcharts 10.0.0cellsHepG2insulinHyoscyamusalbusglucoseoxidativestresscalysteginesinducedsignalingapoptosispathwayregulationresistancemoleculesmedicinalplantaxishyperinsulinemiahyperglycemiamRNAproteinexpressionlevelsinflammatorymitochondrialIRnortropanealkaloidsmodulationSIRT1/Foxo1/G6PC/mTORBACKGROUND:Chronicsuperphysiologicalconcentrationsknowntriggerseveraltissueorganfailuresincludingchroniclow-gradeinflammationHencescreeningmaycounteractconditionsessentialcurrentexistingtherapeuticstrategiestherebyusederivativesrepresentspromisingregardMETHODS:studyeffectselectedtraditionalisolatedinvestigatedexperimentalmodeldifferentgluconeogenicpathway-relatedexaminedAdditionallycellviabilityextentdysfunctionsassayedusingflowcytometricqRT-PCRtechniquesRESULTS:TreatmentstronglyprotectedinjuredintegritylossInterestinglyefficientlyregulatedimpairedmetabolismstimulationuptakegoverninghepaticgluconeogenesisFurthermorealkaloidalextractrestoreddefectivemainlypromotingInsrtreatedexhibitedsignificantmitigatedresponseevidencedNF-κB/JNK/TLR4downstreamproinflammatorycytokinesrecruitmentCONCLUSION:Overallpresentinvestigationdemonstratesprovidecytoprotectioninsulin/glucosedueNF-κB/JNK/TLR4pathwaysVideoAbstractreduceSIRT1/NF-kB/JNKCalysteginesHyperglycemiaInsulinResistanceNF-κBSirt1

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