FREE RADICAL BIOLOGY AND MEDICINE
·
2023
·
IF 7.4
Peng-Zhou Hang,Feng-Qin Ge,Man-Ru Zhang,Qi-Hang Li,Hua-Qing Yu,Yu-Chen Song,Dan-Dan Guo,Jing Zhao,Hua Zhu
The relationship between mitochondrial dysfunction and cardiovascular disease pathogenesis is well recognized. 7,8-Dihydroxyflavone (7,8-DHF), a mimetic of brain-derived neurotrophic factor, inhibits mitochondrial impairments and improves cardiac function. However, the regulatory role of 7,8-DHF in the mitochondrial function of cardiomyocytes is not fully understood. To investigate the potential mito-protective effects of 7,8-DHF in cardiomyocytes, we treated H9c2 or HL-1 cells with the mitochondrial respiratory complex I inhibitor rotenone (Rot) as an in vitro model of mitochondrial dysfunction. We found that 7,8-DHF effectively eliminated various concentrations of Rot-induced cell death and reduced lactate dehydrogenase release. 7,8-DHF significantly improved mitochondrial membrane potential and inhibited mitochondrial reactive oxygen species . Moreover, 7,8-DHF decreased routine and leak respiration, restored protein levels of mitochondrial complex I-IV, and increased ATP production in Rot-treated H9c2 cells. The protective role of 7,8-DHF in Rot-induced damage was validated in HL-1 cells. Nuclear phosphorylation protein expression of signal transducer and activator of transcription 3 (STAT3) was significantly increased by 7,8-DHF. The present study suggests that 7,8-DHF rescues Rot-induced cytotoxicity by inhibiting mitochondrial dysfunction and promoting nuclear translocation of p-STAT3 in cardiomyocytes, thus nominating 7,8-DHF as a new pharmacological candidate agent against mitochondrial dysfunction in cardiac diseases.
研究领域:
心血管疾病
·
分子生物学
·
细胞生物学
·
药理学
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Scientific Reports
·
2025
·Vol. 15
·期 1
·1-12
·
IF 3.9
Cheng Chunfang,Zhang Shasha,Chen Chong,Gong Yanchun,Ding Kaizhi,Li Guoyin,Jiang Wei,Zhang Zhenyu,He Bin,Hu Zhihong,Li Yuhua,Yao Lihua
Excessive exercise can lead to physical fatigue and disruption of the antioxidant system, resulting in neurological damage and cognitive decline. Cordycepin, the main component of Cordyceps militaris , has anti-inflammatory, antioxidant and neuroprotective effects. In this study, the anti-fatigue effect and potential mechanism of action of cordycepin were investigated using a forced exercise mouse model. The results showed that oral administration of cordycepin enhanced exercise endurance, increased liver and muscle glycogen content, and simultaneously decreased serum levels of lactic acid, lactate dehydrogenase, creatine kinase, and blood urea nitrogen ( p < 0.05). In addition, cordycepin had antioxidant effects, increasing superoxide dismutase activity and decreasing serum malondialdehyde (MDA) levels ( p < 0.01). In vitro experiments further demonstrated the antioxidant and anti-fatigue effects of cordycepin. Behavioral tests showed that the learning and memory ability of mice in the excessive exercise model group decreased to 40% compared with the control group. Cordycepin alleviated the learning and memory deficits in the over-exercised mice, significantly reduced the levels of fatigue metabolites and oxidative stress in vivo ( p < 0.05), and altered the levels of neurotransmitters levels ( p < 0.05). Furthermore, cordycepin modulated Keap1/Nrf2/HO-1-mediated oxidative stress and enhanced BDNF levels ( p < 0.05). These findings suggest that cordycepin can alleviate excessive exercise-induced fatigue by modulating the Keap1/Nrf2/HO-1 signaling pathway and BDNF expression, providing strong supporting evidence for the development of cordycepin-functional foods or anti-fatigue drugs.
研究领域:
运动生理学
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药理学
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神经科学
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PHYTOMEDICINE
·
2026
·
IF 8.3
Jian Liu,Yeqing Liu,Changtie Liu,Jing Wang,Yuanyi Zhang,Yuxing Yang,Si Peng,Rongrong Xu,Lingxiang Xu,Xingchen Wang,Wei Xiong,Yun Gao
Visceral pain is frequently accompanied by depression, a comorbidity involving central neuroinflammation and abnormal neuronal plasticity. The P2×7 receptor (P2×7R) plays a crucial role in neuroinflammation and pyroptosis, while Jujuboside A (JuA), a major saponin extracted from Ziziphus jujuba seeds, has been reported to exert significant antidepressant and analgesic effects. In this study, we systematically evaluated the regulatory effects of JuA on the P2×7R-brain-derived neurotrophic factor (BDNF) pathway and on pyroptosis and apoptosis using a rat model of colorectal distension (CRD) and primary neuron/astrocyte cultures. JuA markedly alleviated visceral hypersensitivity and depressive-like behaviors in CRD rats and reduced P2×7R expression in both the spinal cord (SC) and hippocampus (HPC). Further investigations in vitro revealed that JuA inhibited excessive P2×7R activation in SC astrocytes, thereby decreasing the expression of NLRP3, Caspase-1, GSDMD, IL-1β and TNF-α, indicating suppression of pyroptosis. Similarly, JuA exerted an anti-pyroptotic effect in HPC astrocytes and inhibited neuronal apoptosis by reducing Caspase-3 and Bax levels while increasing Bcl-2 expression, leading to upregulation of HPC BDNF. Collectively, JuA targets P2×7R and suppresses downstream pyroptotic and apoptotic signaling in vitro, which may contribute to its neuroprotective effects. These findings provide experimental evidence supporting the potential of JuA as a therapeutic agent for comorbid visceral pain and depression.
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ACTA PHARMACOLOGICA SINICA
·
2022
·Vol. 43
·期 8
·1955-1969
·
IF 7.169
Gao Zhi-ying,Chen Tian-yu,Yu Ting-ting,Zhang Li-ping,Zhao Si-jie,Gu Xiao-yang,Pan Ying,Kong Ling-dong
Paternal stress exposure-induced high corticosterone (CORT) levels may contribute to depression in offspring. Clinical studies disclose the association of depressive symptoms in fathers with their adolescent offspring. However, there is limited information regarding the intervention for intergenerational inheritance of depression. In this study we evaluated the intervention of cinnamaldehyde, a major constituent of Chinese herb cinnamon bark, for intergenerational inheritance of depression in CORT- and CMS-induced mouse models of depression. Depressive-like behaviors were induced in male mice by injection of CORT (20 mg·kg −1 ·d −1 , sc) for 6 weeks or by chronic mild stress (CMS) for 6 weeks. We showed that co-administration of cinnamaldehyde (10, 20, or 40 mg·kg −1 ·d −1 , ig) for 6 weeks in F0 males prevented the depressive-like phenotypes of F1 male offspring. In addition, co-administration of cinnamaldehyde (20 mg·kg −1 ·d −1 , ig) for 4 weeks significantly ameliorated depressive-like behaviors of chronic variable stress (CVS)-stimulated F1 offspring born to CMS mice. Notably, cinnamaldehyde had no reproductive toxicity, while positive drug fluoxetine showed remarkable reproductive toxicity. We revealed that CMS and CORT significantly reduced testis glucocorticoid receptor (GR) expression, and increased testis and sperm miR-190b expression in F0 depressive-like models. Moreover, pre-miR-190b expression was upregulated in testis of F0 males. The amount of GR on miR-190b promoter regions was decreased in testis of CORT-stimulated F0 males. Cinnamaldehyde administration reversed CORT-induced GR reduction in testis, miR-190b upregulation in testis and sperm, pre-miR-190b upregulation in testis, and the amount of GR on miR-190b promoter regions of F0 males. In miR-190b-transfected Neuro 2a (N2a) cells, we demonstrated that miR-190b might directly bind to the 3′-UTR of brain-derived neurotrophic factor (BDNF). In the hippocampus of F1 males of CORT- or CMS-induced depressive-like models, increased miR-190b expression was accompanied by reduced BDNF and GR, which were ameliorated by cinnamaldehyde. In conclusion, cinnamaldehyde is a potential intervening agent for intergenerational inheritance of depression, probably by regulating GR/miR-190b/BDNF pathway.
研究领域:
神经科学
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药理学
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分子生物学
·
行为科学
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JOURNAL OF ENZYME INHIBITION AND MEDICINAL CHEMISTRY
·
2023
·
IF 5.6
Hao Zhou,Mengjiao Li,Hui Liu,Zheng Liu,Xuekun Wang,Shiben Wang
In this study, four series of piperazine derivatives were designed, synthesised and subjected to biological test, and compound 6a with potential antidepressant activity was obtained. An affinity assay of compound 6a with 5-hydroxytryptamine (serotonin, 5-HT)1A receptor (5-HT1AR) was undertaken, and the effects on the 5-HT level in the brains of mice were also tested. The results showed that compound 6a had the best affinity with 5-HT1AR (Ki = 1.28 nM) and significantly increased the 5-HT level. The expression levels of 5-HT1AR, BDNF, and PKA in the hippocampus were analysed by western blot and immunohistochemistry analyses. The results showed that the expression of 5-HT1AR, BDNF, and PKA in the model group was reduced compared to that of the control group, and compound 6a could reverse this phenomenon. Molecular docking was performed to investigate the interactions of the studied compound 6a with 5-HT1AR on the molecular level.
研究领域:
药理学
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神经科学
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药物化学
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JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY
·
2026
·Vol. 74
·期 29
·22784-22797
·
IF 6.7
Cheng Xin,Wang Jiaxing,Tan Haoyang,Ji Yaxin,Yu Xiaoqing,Hu Jiahuan,Li Siyao,Kang Huijie,Zhang Shuai,Xuanpan Ding,Jiao Wenjing,Fan Honggang,Zhao Yuan
Chronic
stress (CS) represents a pivotal environmental trigger
for depression. It induces depression-like behaviors primarily by
disrupting hypothalamic–pituitary–adrenal (HPA) axis
homeostasis and impairing hippocampal synaptic plasticity. Flavonoids
are abundant in human diet and possess significant neuroprotective
potential. We screened a library of 339 flavonoid compounds. Daidzein
(DAI) was identified as the lead compound. Subsequently, in rats subjected
to chronic restraint stress (CRS), DAI administration effectively
ameliorated depression-like behaviors, and attenuated hippocampal
histopathological damage. Network pharmacology and molecular docking
analyses suggested that ERK-related signaling may be involved in the
protective effects of DAI, and molecular dynamics simulations supported
the stability of the DAI-ERK2 complex. Furthermore, DAI activated
the ERK/CREB/BDNF signaling cascade, an effect that was partially
reversed by ERK inhibitor intervention. Notably, DAI also enhanced
dendritic complexity and spine density in hippocampus. In summary,
our study demonstrates that DAI alleviates stress-induced synaptic
plasticity damage through the ERK/CREB/BDNF signaling pathway.
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JOURNAL OF PHARMACY AND PHARMACOLOGY
·
2026
·Vol. 78
·期 2
·
IF 3.7
Wang Baoying,Liu Hui,Zhang Changjing,Yan Xiangli,Xu Erping,Bai Ming,Li Yucheng
ObjectivesFormononetin (FMN) is known for its significant neuroprotective effects, this study aims to investigate the antidepressant potential and underlying mechanisms of FMN.MethodsAntidepressant efficacy was evaluated in corticosterone (CORT)-induced depression models. In vivo, CORT-exposed mice received FMN to assess behavioral and hippocampal changes (dendritic spine density, synaptic markers: MAP-2/GAP-43). In silico, network pharmacology and molecular docking predicted FMN’s binding affinity and enriched pathways. In vitro, HT22 cells pretreated with FMN (10 μM, 6 h) were subjected to CORT injury, with mechanistic validation via ERα antagonist (MPP) and ERK inhibitor (PD98059).Key findingsFMN alleviated depressive-like behaviors and preserved hippocampal integrity in mice. Bioinformatics analysis revealed FMN’s strong binding to ER subtypes and enrichment in estrogen/MAPK pathways. In vitro, FMN pretreatment activated the ERK-CREB-BDNF axis in CORT-injured HT22 cells, enhancing neuronal survival and synaptic function. The activation was ERα/ERK-dependent, as evidenced by the abolition of protective effects following pharmacological inhibition with MPP (ERα antagonist) or PD98059 (ERK inhibitor). Concomitantly, in vivo FMN treatment restored hippocampal p-ERK/ERK ratios in mice, directly corroborating the ERK-CREB-BDNF pathway activation and highlighting its efficacy in reversing CORT-induced signaling deficits.ConclusionFMN exerts antidepressant effects via ERα-mediated neurotrophic signaling (ERK-CREB-BDNF), offering a mechanistic foundation for natural antidepressant development.
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CELL PROLIFERATION
·
2025
·Vol. 58
·期 10
·e70057
·
IF 5.6
Yiyang Wang,Xinyi Du,Chenxi Duan,Miaomiao Wang,Ying Zhu,Lihua Wang,Jun Hu,Yanhong Sun
Effective treatment of depression poses a major clinical challenge, accompanied by considerable social and emotional burdens. Electroacupuncture, a non-pharmacological modality derived from traditional Chinese medicine, offers a promising alternative for depression treatment due to its safety and efficacy. However, its underlying molecular mechanisms remain unclear. In this study, a corticosterone-induced depression model in C57BL/6 mice was employed and electroacupuncture was applied to stimulate at Zusanli (ST36) acupoint. The results demonstrated that electroacupuncture effectively alleviated depression-like symptoms and restored the structural morphology and plasticity of neurons in the hippocampal CA1 region. Further analysis revealed a significant upregulation of brain-derived neurotrophic factor (BDNF) and β-type calmodulin-dependent protein kinase II (CaMKIIβ), which are associated with neuronal plasticity regulatory pathways. This study elucidates the potential molecular mechanisms by which electroacupuncture alleviates depression through the regulation of neuroplasticity, providing an experimental basis for its clinical application.
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BRITISH JOURNAL OF PHARMACOLOGY
·
2022
·Vol. 179
·期 16
·4078-4091
·
IF 9.473
Hailou Zhang,Yan Sun,Suk-yu Yau,Yanmeng Zhou,Xinxin Song,Han-Ting Zhang,Boran Zhu,Haoxin Wu,Gang Chen
Background and Purpose Current mainstream antidepressants have limited efficacy with a delayed onset of action. Yueju, a herbal medicine, has a rapid antidepressant action. Identification of the active ingredients in Yueju and the mechanism/s involved was carried out. Experimental Approach Key molecule/s and compounds involved in this antidepressant action was identified by transcriptomic and HPLC analysis, respectively. Antidepressant effects were evaluated using various behavioural experiments. The signalling involved was assessed using site-directed pharmacological intervention or optogenetic manipulation. Key Results Transcriptomic analysis showed that Yueju up-regulated pituitary adenylate cyclase activating polypeptide (PACAP) expression in the hippocampus. Two iridoids, geniposide and shanzhiside methyl ester, were identified and quantified from Yueju. Only co-treatment with both, at an equivalent concentrations found in Yueju, increased PACAP expression and elicited a rapid antidepressant action, which were blocked by intra-dentate gyrus infusion of a PACAP antagonist or optogenetic inactivation of PACAP expressing neurons. Geniposide and shanzhiside methyl ester co-treatment rapidly inhibited CaMKII phosphorylation and enhanced mTOR/4EBP1/P70S6k/BDNF ignalling, while intra-dentate gyrus infusions of a CaMKII activator blunted the rapid antidepressant action and BDNF expression up-regulation induced by the co-treatment. A single co-treatment of them rapidly improved depression-like behaviours and up-regulated hippocampal PACAP signalling in the repeated corticosterone-induced depression model, further confirming the involvement of PACAP. Conclusion and Implications Geniposide and shanzhiside methyl ester co-treatment had a synergistic rapid onset antidepressant action by triggering hippocampal PACAP activity and associated CaMKII–BDNF signalling. This mechanism could be targeted for development of fast onset antidepressants. Graphical
研究领域:
药理学
·
神经科学
·
中药
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PHYTOMEDICINE
·
2026
·
IF 11.3
Wei Ye,Ze Lin,Zihan You,Zijian Zhu,Zhengzhong Yuan
Background Jiao-tai-wan (JTW) is a classic formula for Heart-Kidney Disharmony insomnia, yet its mechanism in hippocampal neurons remains unclear. Purpose To investigate whether JTW ameliorates insomnia-induced hippocampal neuronal damage by inhibiting ferroptosis and elucidate the underlying mechanisms. Methods UPLC-Q-TOF/MS analyzed JTW constituents. Network pharmacology and molecular docking predicted core targets. A mouse insomnia model was established using PCPA combined with MMPM. Behavioral tests, pathological examinations, and ferroptosis markers were evaluated. In vitro, HT22 cells underwent IKE-induced ferroptosis to validate Jiao-tai-wan drug-containing serum (JTWS) and the PDE4D inhibitor Zatolmilast (ZAT). Results 413 compounds were identified in JTW, with 47 predicted to penetrate the blood-brain barrier. Network pharmacology, molecular docking, and molecular dynamics simulations predicted PDE4D and BDNF as core targets. In vivo, JTW ameliorated cognitive deficits, attenuated hippocampal neuronal damage, and restored mitochondrial ultrastructure. Mechanistically, JTW downregulated Ptgs2 expression, upregulated Gpx4, Fth1, and Acsl3 expression, reduced lipid peroxidation and iron accumulation, while simultaneously suppressing Pde4d and restoring Bdnf levels. In vitro, ZAT mimicked the anti-ferroptotic effects of JTW. Conclusion JTW inhibits hippocampal neuronal ferroptosis through multi-target regulation, ameliorating insomnia-related neuronal damage and providing a molecular basis for its traditional efficacy in restoring Heart-Kidney communication. Download: Download high-res image (282KB) Download: Download full-size image
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CURRENT GENE THERAPY
·
2018
·
IF 1.943
Li Li-Ming,Huang Ling-Ling,Jiang Xin-Chi,Chen Jia-Chen,OuYang Hong-Wei,Gao Jian-Qing
Introduction: Mesenchymal Stem Cells (MSCs) are promising candidates for nerve tissue engineering. Brain Derived Neurotrophic Factor (BDNF) secreted by MSCs can function to increase neural differentiation and relieve inflammation response. Gene transfection technology is an efficient
strategy to increase the secretion levels of cytokines and enhance cellular functions. However, transfection and in vivo gene expression of environmentally sensitive stem cells have been one of the most challenging subjects due to the requirement in both safety and transfection efficiency.
In this study, gene transfection technology was applied to prepare BDNF gene recombinant MSCs based on our previously reported liposomal vector ScreenFect® A. To improve cellular survival and gene expression after in situ implantation of MSCs, an adhesive peptide modified hydrogel scaffold
was constructed using hyaluronic acid. The scaffold was optimized and modified with an adhesive peptide PPFLMLLKGSTR. The transfected MSCs exhibited improved cellular survival and sustained gene expression in the three-Dimentional (3D) scaffold in vitro. Compared to untransfected MSCs, gene
recombinant MSCs effectively improved spinal tissue integrity, inhibited glial scar formation and alleviated inflammatory response. These effects were found discounted when cells were implanted without the scaffold. Conclusion: The study developed a promising implantation system for therapy
of severe spinal cord injury and provided the first understanding of Screenfect® A about its functions on stem cell therapy for nerve tissue repair as well as three-dimentional gene expression.
研究领域:
干细胞治疗
·
组织工程
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神经科学
·
基因治疗
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Drug and Alcohol Dependence Reports
·
2026
·
IF 3.5
Tianqi Wang,Shu Tian,Mengru He,Siyu Tang,Xinyu Ji,Qixin Deng,Wenjuan Zhang,Ge Jin,Jian Mao,Haifeng Zhang
Nicotine withdrawal-induced anxiety is a key contributor to cigarette smoking relapse. Cordycepin, an adenosine analogue, is hypothesized to counteract the withdrawal-induced decline in hippocampal AMP/ATP ratios and consequent AMP-activated protein kinase (AMPK) dephosphorylation, as its monophosphate derivative structurally mimics AMP and directly activates AMPK. In this study, a mouse model of chronic nicotine exposure followed by withdrawal was used to investigate whether cordycepin mitigates nicotine withdrawal-induced anxiety and its underlying mechanisms. Our results revealed that chronic nicotine exposure significantly elevated hippocampal AMPK phosphorylation, whereas nicotine withdrawal led to a sharp decline in p-AMPK levels (p-AMPK/t-AMPK: F = 23.11, P < 0.001), concomitant with pronounced anxiety-like behaviors in the elevated plus maze (open-arm time: F = 16.18, P < 0.01) and open field tests (center time: F = 6.63, P < 0.01). Pretreatment with cordycepin (10 mg/kg) effectively alleviated nicotine withdrawal-induced anxiety-like behaviors (open-arm time: F = 11.74, P < 0.01; center time: F = 5.79, P < 0.01), an effect that was counteracted by the AMPK inhibitor Compound C. Further mechanistic studies via Western blot and immunohistochemical analyses further demonstrated that cordycepin activated the hippocampal AMPK/CREB/BDNF signaling pathway, restoring withdrawal-induced reductions in p-AMPK, p-CREB, and BDNF expression. This effect was further validated in PC12 cell experiments. In conclusion, cordycepin alleviates nicotine withdrawal-induced anxiety by activating the AMPK/CREB/BDNF pathway, offering preliminary experimental evidence for its potential as an adjunctive therapy for smoking cessation.
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