CELLULAR SIGNALLING
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2025
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IF 3.7
Xiaoshan Wang,Mengding Chen,Yuwei Wu,Feixu Chen,Tong Shen,Zhengguang Wang
Background Abnormal glycolysis and lipid metabolism play important roles in the occurrence and development of gastric cancer (GC). Moreover, dysregulation of circadian genes is associated with metabolic reprogramming in the tumor microenvironment. This study aimed to determine the role of retinoic acid-related orphan receptor alpha (RORα) in glucose and lipid reprogramming in GC. Methods The effects on cell proliferation and chemoresistance in vitro and in vivo were studied using gain- and loss-of-function experiments. Glycolytic activity and lipid synthesis were assessed using a Seahorse assay and reagent kits. Moreover, the regulatory mechanisms were explored using half-life, coimmunoprecipitation (Co-IP), chromatin immunoprecipitation (ChIP), luciferase reporter and immunofluorescence colocalization assays in GC cells. In addition, the relationships of RORα with E47 and AKR1A1 were analyzed using public databases and retrospective clinicopathological analyses. Results RORα deletion promoted cell proliferation and fluorouracil (5-FU) chemoresistance by increasing glycolytic activity and lipid synthesis. In contrast, SR1078, an RORα activator, reversed these changes and had a synergistic inhibitory effect on cell proliferation in combination with 2-deoxygulose glucose (2-DG) or atorvastatin. Mechanistically, aldo-keto reductase family 1 member A1 (AKR1A1), is the key driver of RORα-mediated glucose and lipid reprogramming. Specifically, E47 is an AKR1A1 transcription factor, and its stability is affected by β-catenin. RORα deletion indirectly promoted E47 protein stability through the up-regulation of β-catenin, leading to increased AKR1A1 transcriptional activity. Moreover, RORα, E47 and AKR1A1 expression was dysregulated, and associated with clinicopathological parameters and prognosis in patients with GC. These expression patterns including RORα-low, E47-high and AKR1A1-high expression patterns alone or in combination were correlated with reduced responsiveness, poor prognosis, increased standard uptake value (SUV) levels and lipid droplet formation. Conclusions These findings reveal a novel mechanism by which RORα regulates glucose and lipid reprogramming and may be a promising target for GC treatment.
研究领域:
肿瘤学
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分子生物学
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代谢组学
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产品关联
DOI
PubMed
高影响因子
BIOCHEMICAL PHARMACOLOGY
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2022
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IF 6.1
Min Chen,Yifei Xiao,Fugui Zhang,Jianhao Du,Li Zhang,Yifang Li,Danyi Lu,Zhigang Wang,Baojian Wu
Delirium is a common and serious neuropsychiatric syndrome characterized with acute cognitive and attentional deficits, however, the effective therapies are lacking. Here, using mouse models of delirium, we investigated the effects of tangeretin (TAN, a natural flavonoid) on cognitive impairment by assessing object preference with novel object recognition (NOR) test and spontaneous alternation with Y maze test. We found that TAN, as a RORα/γ agonist, prevented cognitive decline in delirious mice as evidenced by a normal novel object preference and increased spontaneous alternation. This was accompanied by decreased expression of ERK1/2, TNFα and IL-1β as well as diminished microglial activation in delirious mice. The protective effect of TAN on delirium was mainly attributed to increased hippocampal E4BP4 expression (a known target of RORs and a regulator of cognition in delirium through modulating the ERK1/2 cascade and microglial activation) via activation of RORα/γ. In addition, TAN treatment modulated the expression of RORα/γ target genes (such as E4bp4 and Bmal1 ) and inhibited the expression of TNFα and IL-1β in lipopolysaccharide (LPS)-stimulated cells, supporting a beneficial effect of TAN on delirium. In conclusion, TAN is identified as a RORα/γ agonist which promotes E4BP4 expression to prevent cognitive decline in delirious mice. Our findings may have implications for drug development of TAN for prevention and treatment of various diseases associated with cognitive deficiency.
研究领域:
神经科学
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药理学
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免疫学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
PHYTOMEDICINE
·
2026
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IF 11.3
Hongdan Chu,Yichen Li,Zheng Liang,Yanwei Wang,Yuqi Luo,Jing Gan,Gang Li,Zhenhua Wang,Bo Xu
The decrease of bone mineral density in zebrafish larvae caused by continuous light is closely related to circadian rhythm gene disorder. • LG improved the circadian rhythm gene disorder of zebrafish larvae caused by continuous light. • LG alleviated the decrease of bone mineral density in zebrafish larvae caused by continuous light. • LG reversed the inhibition of osteogenic differentiation of MC3T3-E1 cells caused by circadian rhythm gene disorder. • Circadian rhythm genes play a key role in LG intervention in osteogenic differentiation. Circadian rhythm disorders can destroy the balance of bone metabolism and hence closely related to bone metabolic diseases. To further explore the relationship between circadian rhythm and bone metabolism, the sleep deprivation model of zebrafish induced by continuous light and the MC3T3-EI cell model induced by Nr1d1-specific agonist STL1267 (STL1267) were used to study the intervention mechanism of liquiritigenin on bone metabolism imbalance mediated by circadian rhythm. Molecular docking, behavioral studies, calcein staining, alizarin red staining, alkaline phosphatase and osteocalcin activity, qRT-PCR, Western blotting, and other methods were adopted to screen and study the effects of licorice flavonoids on circadian rhythm disorder and its induced decrease of bone mineral density in zebrafish, osteogenic differentiation, and mineralization inhibition of MC3T3-EI cells. The results showed that liquiritigenin significantly alleviated the expression disorders of zebrafish circadian rhythm genes brain and muscle ARNT-like 1 (Bmal1), circadian locomotor output cycles kaput (Clock), period (Per), cryptochrome (Cry), retinoic acid receptor-related orphan receptor α (Rorα), and nuclear receptor subfamily 1 group D member (Nr1d1) induced by continuous light and caused zebrafish behavioral defects, decreased alkaline phosphatase and osteocalcin activity, and bone mineral density as well. Similarly, liquiritigenin effectively improved the expression of circadian rhythm-related genes at mRNA and protein levels in MC3T3-EI cells induced by STL1267 and enhanced cell viability, alkaline phosphatase and osteocalcin activity, and bone matrix mineralization. Therefore, this work reveals the key role of circadian rhythm in bone metabolism homeostasis, and proves that liquiritigenin can effectively alleviate the imbalance of bone homeostasis caused by circadian rhythm disorders, providing research basis for the application of natural small molecule components to improve circadian rhythm disorders and bone metabolism imbalance. Download: Download high-res image (338KB) Download: Download full-size image
✓ 已验证
DOI
PubMed
高影响因子
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