A Chemically Characterized Polyherbal Extract Selectively Attenuates Chronic Unpredictable Stress-Induced Redox-Sensitive, Inflammatory, and Metabolic Alterations in Female Rats
- 1Department of Biochemistry, Institute for Biological Research “Siniša Stanković”, National Institute of the Republic of Serbia, University of Belgrade, 142 Despot Stefan Blvd, 11108 Belgrade, Serbia
- 2Department of Neurophysiology, Institute for Biological Research “Siniša Stanković”, National Institute of the Republic of Serbia, University of Belgrade, 142 Despot Stefan Blvd, 11108 Belgrade, Serbia
- 3Department of Plant Physiology, Institute for Biological Research “Siniša Stanković”, National Institute of the Republic of Serbia, University of Belgrade, 142 Despot Stefan Blvd, 11108 Belgrade, Serbia
Abstract
Chronic stress contributes to metabolic and mental disorders, with accumulating evidence suggesting differences in stress responses between females and males. Although Centaurium erythraea, Valeriana officinalis, Melissa officinalis, and Humulus lupulus possess well-documented antioxidant, anti-inflammatory, and neuroactive properties, the biological activity of their combined extract remains largely unexplored. Here, a chemically characterized polyherbal extract was evaluated for in vitro biosafety and its effects on chronic unpredictable stress-induced behavioral, metabolic, and molecular alterations in male and female rats. LC-HRMS/MS identified 121 metabolites, including phenolic acids, iridoid glycosides, flavonoids, and xanthone derivatives, while the extract showed a favorable biosafety profile in HaCaT keratinocytes. Chronic stress-induced alterations were predominantly observed in females, including reduced body mass, serum glucose and insulin levels, enhanced hippocampal glucocorticoid signaling, increased NRF2 and NFκB protein levels, altered IRS1 signaling, and anxiety-like behavior. Treatment with the extract normalized glucose tolerance, restored hippocampal IRS1, phosphorylated IRS1 (Ser307), NRF2, and NFκB protein levels in females. These findings indicate that, under the experimental conditions employed, chronic stress-associated alterations and the effects of the polyherbal extract were predominantly observed in female rats, and suggest that the extract may mitigate stress-induced metabolic disturbances through modulation of redox-sensitive, inflammatory, and hippocampal insulin signaling pathways.
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BibTeX
@article{kovacevic2026chemically,
title = {{A Chemically Characterized Polyherbal Extract Selectively Attenuates Chronic Unpredictable Stress-Induced Redox-Sensitive, Inflammatory, and Metabolic Alterations in Female Rats}},
author = {Sanja Kovačević and Ljupka Gligorovska and Biljana Bursać and Mirna Jovanović and Danijela Vojnović Milutinović and Srdjan Kesić and Branka Petković and Uroš Gašić and Ana Ćirić and Dejan Stojković and Ana Djordjevic},
journal = {International Journal of Molecular Sciences},
year = {2026},
month = sep,
doi = {10.3390/ijms27188298},
url = {https://www.mdpi.com/1422-0067/27/18/8298},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - A Chemically Characterized Polyherbal Extract Selectively Attenuates Chronic Unpredictable Stress-Induced Redox-Sensitive, Inflammatory, and Metabolic Alterations in Female Rats
AU - Sanja Kovačević
AU - Ljupka Gligorovska
AU - Biljana Bursać
AU - Mirna Jovanović
AU - Danijela Vojnović Milutinović
AU - Srdjan Kesić
AU - Branka Petković
AU - Uroš Gašić
AU - Ana Ćirić
AU - Dejan Stojković
AU - Ana Djordjevic
PY - 2026
DA - 2026/09/17
JO - International Journal of Molecular Sciences
DO - 10.3390/ijms27188298
UR - https://www.mdpi.com/1422-0067/27/18/8298
AB - Chronic stress contributes to metabolic and mental disorders, with accumulating evidence suggesting differences in stress responses between females and males. Although Centaurium erythraea, Valeriana officinalis, Melissa officinalis, and Humulus lupulus possess well-documented antioxidant, anti-inflammatory, and neuroactive properties, the biological activity of their combined extract remains largely unexplored. Here, a chemically characterized polyherbal extract was evaluated for in vitro biosafety and its effects on chronic unpredictable stress-induced behavioral, metabolic, and molecular alterations in male and female rats. LC-HRMS/MS identified 121 metabolites, including phenolic acids, iridoid glycosides, flavonoids, and xanthone derivatives, while the extract showed a favorable biosafety profile in HaCaT keratinocytes. Chronic stress-induced alterations were predominantly observed in females, including reduced body mass, serum glucose and insulin levels, enhanced hippocampal glucocorticoid signaling, increased NRF2 and NFκB protein levels, altered IRS1 signaling, and anxiety-like behavior. Treatment with the extract normalized glucose tolerance, restored hippocampal IRS1, phosphorylated IRS1 (Ser307), NRF2, and NFκB protein levels in females. These findings indicate that, under the experimental conditions employed, chronic stress-associated alterations and the effects of the polyherbal extract were predominantly observed in female rats, and suggest that the extract may mitigate stress-induced metabolic disturbances through modulation of redox-sensitive, inflammatory, and hippocampal insulin signaling pathways.
SN - 1422-0067
ER -