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Long-term stress exposure can lead to disturbed homeostasis and cause many life-style diseases. Phloridzin possesses various bioactivities, but the understanding of the effects of phloridzin on stress-related lipid metabolism disorder is limited. Our results demonstrate that phloridzin improved plasma lipoprotein lipase (LPL) activity and triglyceride metabolism in restrained mice. A decrease of angiopoietin-like protein 4 (ANGPTL4) mRNA expression and an increase of AMP-activated protein kinase (AMPK) phosphorylation were observed after phloridzin treatment. After inhibiting AMPK phosphorylation, the effects of phloridzin on the amelioration of plasma LPL activity and suppression of ANGPTL4 expression were blocked. In addition, cardiac AMPK phosphorylation, plasma LPL activity and ANGPTL4 expression were also affected by phloridzin, even if the glucocorticoid receptor was blocked. Taken together, the down-regulation of ANGPTL4 expression by phloridzin was probably via a direct activation of AMPK pathway. This discovery can provide a biochemical and nutritional basis for the use of phloridzin-containing food and beverage in daily life. [ABSTRACT FROM AUTHOR]

Introduction: Chronic stress-associated hormonal imbalance impairs hippocampal neurogenesis, contributing to depressive and anxiety behaviors. Targeting neurogenesis is thus a promising antidepressant therapeutic strategy. Niuhuang Qingxin Wan (NHQXW) is an herbal formula for mental disorders in Traditional Chinese Medicine (TCM) practice, but its anti-depressant efficacies and mechanisms remain unverified. Methods: In the present study, we tested the hypothesis that NHQXW could ameliorate depressive-like behaviors and improve hippocampal neurogenesis by modulating the TrkB/ERK/CREB signaling pathway by utilizing two depression mouse models including a chronic restraint stress (CRS) mouse model and a chronic corticosterone (CORT) stress (CCS) induced mouse model. The depression-like mouse models were orally treated with NHQXW whereas fluoxetine was used as the positive control group. We evaluated the effects of NHQXW on depressive- and anxiety-like behaviors and determined the effects of NHQXW on inducing hippocampal neurogenesis. Results: NHQXW treatment significantly ameliorated depressive-like behaviors in those chronic stress mouse models. NHQXW significantly improved hippocampal neurogenesis in the CRS mice and CCS mice. The potential neurogenic mechanism of NHQXW was identified by regulating the expression levels of BDNF, TrkB, p-ERK (T202/T204), p-MEK1/2 (S217/221), and p-CREB (S133) in the hippocampus area of the CCS mice. NHQXW revealed its antidepressant and neurogenic effects that were similar to fluoxetine. Moreover, NHQXW treatment revealed long-term effects on preventing withdrawal-associated rebound symptoms in the CCS mice. Furthermore, in a bioactivity-guided quality control study, liquiritin was identified as one of the bioactive compounds of NHQXW with the bioactivities of neurogenesis-promoting effects. Discussion: Taken together, NHQXW could be a promising TCM formula to attenuate depressive- and anxiety-like behaviors against chronic stress and depression. The underlying anti-depressant mechanisms could be correlated with its neurogenic activities by stimulating the TrkB/ERK/CREB signaling pathway., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Du, Gao, Tsoi, Wu and Shen.)