BIOCHEMICAL PHARMACOLOGY
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2025
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IF 5.6
Tian-tian Wang,Meng-yuan Zhou,Xue-na Gong,Yan Huang,Fei-long Li,Sheng-long Gu,Man-yu Zhang,Ling-ling Li,Ze-shan Xu,Rong Li,Li Cai
Eupalinolide B (EB), a primary bioactive compound isolated from Eupatorium lindleyanum DC ., has exhibited various pharmacological properties, such as antitumor, anti-inflammatory, and notably, neuroprotective effects in neurodegenerative diseases. However, the in-depth studies on the antidepressant potential of EB and its underlying mechanisms are still lacking. Herein, we investigated the therapeutic effects of EB on corticosterone (CORT)-induced neurotoxicity in PC12 cells and its antidepressant-like effects in rats subjected to chronic unpredictable mild stress (CUMS). In particular, we focused on the molecular mechanisms related to modulating the GSK-3β/β-catenin pathway. Our findings revealed that EB promoted cell proliferation while decreasing apoptosis and oxidative stress in CORT-induced PC12 cells. In vivo, EB alleviated the depressive-like behaviors in CUMS rats, as assayed by the sucrose preference test, open field test, and forced swim test. Additionally, EB attenuated the hippocampal pathological damage and increased Ki67- and doublecortin-positive cell numbers in hippocampal dentate gyrus, thus restoring hippocampal neurogenesis in CUMS rats. The binding of EB to GSK-3β was confirmed using molecular docking and cellular thermal shift assays. Overexpression of GSK-3β diminished the therapeutic effects of EB on CORT-induced PC12 cells, further indicating that GSK-3β is the target of EB. Mechanistically, EB hindered GSK-3β activity and thus activated β-catenin signaling in both CORT-induced PC12 cells and CUMS rat hippocampus, as demonstrated by increased p-GSK-3β (Ser9), reduced p-β-catenin, and elevated β-catenin expression. Collectively, this study offers new insights into the antidepressant mechanisms of EB, highlighting its potential as a candidate for depression treatment.
研究领域:
神经科学
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药理学
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分子生物学
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PubMed
高影响因子
BIOORGANIC CHEMISTRY
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2026
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IF 5.1
Man Li,Yuxin Jiang,Yongkang Xue,Yuanqi Duan,Yanan Liu,Xianghao Xin,Xiaoyu Wei,Zhengyu Hu,Pengcheng Yang,Shengbao Diao,Wei Zhou,Jinfeng Sun,Gao Li
Ischemic stroke (IS) is the leading cause of prevalence and mortality in China and a major global public health problem. Eupalinolide B (EB) stands as the main biologically active constituent extracted from Eupatorium lindleyanum , exhibits diverse pharmacological activities, with particular emphasis on its neuroprotective potential in neurodegenerative disorders. Nevertheless, the precise therapeutic outcomes and the specific molecular pathways mediating the protective effects of EB against cerebral ischemia-reperfusion injury (CIRI) are still not fully elucidated. This study systematically explores the potential therapeutic targets and regulatory networks of EB in CIRI treatment through an integrative approach combining network pharmacology analysis with in vitro oxygen-glucose deprivation/reoxygenation (OGD/R) modeling in PC12 cells and in vivo middle cerebral artery occlusion/reperfusion (MCAO/R) modeling in mice. Our findings demonstrate that EB modulates a network composed of 54 core therapeutic targets, including apoptosis regulators (Bcl-2) and components of the PI3K/Akt signaling cascade. In vitro experiments indicate that EB significantly improves the viability of PC12 cells induced by OGD/R, while attenuating intracellular reactive oxygen species (ROS) accumulation and restoring mitochondrial membrane potential. Complementary in vivo studies reveal that the administration of EB activates the PI3K/Akt/GSK3β(Ser9) signaling pathway in MCAO/R mice, leading to reduced neurological deficits, decreased cerebral infarction area, and a mitigation of neuronal pathological changes. Collectively, these findings indicate that EB inhibits neuronal apoptosis by activating the PI3K/Akt/GSK3β(Ser9) signaling pathway, thereby exerting a preventive effect against CIRI. This provides robust experimental evidence for the potential of EB as a new anti-IS therapy.
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高影响因子
RSC Chemical Biology
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2026
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IF 3.9
Zheng Chu,Liting Xu,Honglin Chen,Tianyun Fan,Xueqian Hu,Yin Kwan Wong,Qiaoli Shi,Junzhe Zhang,Chengchao Xu,Jigang Wang,Huan Tang
Treatment of acute promyelocytic leukemia (APL) remains challenged by toxicities associated with current regimens, highlighting the need for novel and safer therapeutic agents. Here, we identify Eupalinolide B (EB), a natural sesquiterpene lactone isolated from Eupatorium lindleyanum DC., as a potent anti-leukemic compound targeting the human APL-derived HL-60 cell line. Through integrated chemoproteomic profiling and functional validation, we demonstrate that EB covalently binds and inhibits 26S proteasome non-ATPase regulatory subunit 14 (PSMD14), a deubiquitinase enzyme (DUB) within the 19S proteasome regulatory particle. This inhibition disrupts PSMD14-mediated stabilization of key oncoproteins RAC-alpha serine/threonine-protein kinase 1 (AKT1) and cyclin-dependent kinase 4 (CDK4), promoting their proteasomal degradation. As a result, EB induces G2/M cell cycle arrest and apoptosis in leukemia cells. Both genetic knockdown and pharmacological inhibition of PSMD14 recapitulate EB's effects, confirming its essential role in leukemia cell survival and proliferation. Collectively, these findings uncover a previously unrecognized PSMD14–AKT1/CDK4 regulatory axis in leukemia and position EB as a promising chemical probe and lead compound for the development of targeted covalent inhibitors against oncogenic DUBs.
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Frontiers in Pharmacology
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2023
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IF 5.6
Li Yingzi,Liu Xiaoyan,Li Ludi,Zhang Tao,Gao Yadong,Zeng Kewu,Wang Qi
Eupalinolide A (EA; Z-configuration) and eupalinolide B (EB; E-configuration) are bioactive cis-trans isomers isolated from Eupatorii Lindleyani Herba that exert anti-inflammatory and antitumor effects. Although one pharmacokinetic study found that the metabolic parameters of the isomers were different in rats, metabolic processes relevant to EA and EB remain largely unknown. Our preliminary findings revealed that EA and EB are rapidly hydrolyzed by carboxylesterase. Here, we investigated the metabolic stability and enzyme kinetics of carboxylesterase-mediated hydrolysis and cytochrome P450 (CYP)-mediated oxidation of EA and EB in human liver microsomes (HLMs). We also explored differences in the hydrolytic stability of EA and EB in human liver microsomes and rat liver microsomes (RLMs). Moreover, cytochrome P450 reaction phenotyping of the isomers was performed via in silico methods (i.e., using a quantitative structure-activity relationship model and molecular docking) and confirmed using human recombinant enzymes. The total normalized rate approach was considered to assess the relative contributions of five major cytochrome P450s to EA and EB metabolism. We found that EA and EB were eliminated rapidly, mainly by carboxylesterase-mediated hydrolysis, as compared with cytochrome P450-mediated oxidation. An inter-species difference was observed as well, with faster rates of EA and EB hydrolysis in rat liver microsomes. Furthermore, our findings confirmed EA and EB were metabolized by multiple cytochrome P450s, among which CYP3A4 played a particularly important role.
研究领域:
药理学
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生物化学
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分子生物学
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高影响因子
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