Experimental Hematology & Oncology
·
2025
·Vol. 14
·期 1
·1-19
·
IF 13.5
Shan Guangyao,Bian Yunyi,Ren Shencheng,Hu Zhengyang,Pan Binyang,Zeng Dejun,Zheng Zhaolin,Fan Hong,Bi Guoshu,Yao Guangyu,Zhan Cheng
Background Ferroptosis, a regulated cell death driven by iron-dependent lipid peroxidation, is associated with chemoresistance in lung adenocarcinoma (LUAD). This study aims to investigate the role of sarcosine in ferroptosis and its underlying mechanisms.Methods An RSL3-induced ferroptosis model was used to screen a library of 889 human endogenous metabolites and metabolomic profiling was harnessed to identify metabolites associated with ferroptosis. Cell viability, lipid-reactive oxygen species (ROS), ferrous iron, malondialdehyde (MDA), and mitochondrial integrity were assessed to evaluate sarcosine’s effects on ferroptosis. Metabolic fate was studied using 15N-labeled sarcosine. Next, we used untargeted metabolomic profiling and next-generation sequencing to dissect metabolic and transcriptomic changes upon sarcosine supplementation. The effects of sarcosine on ferroptosis and chemotherapy were further validated in patient-derived organoids (PDOs), xenograft models, and LUAD tissues.Results Sarcosine emerged as a potent ferroptosis inducer in the metabolic library screening, which was further confirmed via cell viability, lipid-ROS, ferrous iron, and MDA measurements. Metabolic flux analysis showed limited conversion of sarcosine to other metabolites in LUAD cells, while untargeted metabolomic profiling and seahorse assays indicated a metabolic shift from glycolysis to oxidative phosphorylation. Sarcosine enhanced pyruvate dehydrogenase activity to generate more ROS by interacting with PDK4, reducing PDHA1 phosphorylation. As a co-activator of N-methyl-D-aspartate receptor (NMDAR), sarcosine also exerted its pro-ferroptosis effect via regulating ferrous export through the NMDAR/MXD3/SLC40A1 axis. Given the significance of ferroptosis in chemotherapy, we validated that sarcosine enhanced the sensitization of cisplatin by promoting ferroptosis in LUAD cells, PDOs, and xenograft models.Conclusion Sarcosine promotes ferroptosis and enhances chemosensitivity, suggesting its potential as a therapeutic agent in treating LUAD.
研究领域:
肿瘤学
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代谢组学
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细胞生物学
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DOI
PubMed
高影响因子
Heliyon
·
2023
·
IF 4
Chuan Jiang,Chaonan Wang,Weizhong Qu,Yuanyuan Wang,Hua Wang,Xin Wei,Mingyan Wang,Qianqian He,Yihan Wang,Lirong Yuan,Yonggang Gao
Depression is a complex and prevalent mental illness. Cherry leaf is a traditional Chinese herbal medicine, which has confirmed to exert a certain antidepressant effect, but its potential neural regulation mechanism is not clear. This paper aims to investigate the improved action of cherry leaf decoction (CLD) on chronic unpredictable mild stress (CUMS) rats and its potential neural regulation mechanism by verifying the role and function of NMDAR regulatory target α2δ-1 in depression due to CUMS. Male SD rats were subjected to random stressors persisting for 5 weeks to establish the CUMS depression rat model. CLD could effectively alleviate depression-like behaviors of CUMS rats in behavioral tests including sucrose preference test, forced swimming test, tail suspension test and open field test. After the administration of the CLD, the expression of corticotropic-releasing hormone (CRH) in the hypothalamus was inhibited. Moreover, the levels of CRH, adrenal cortical hormone (ACTH) and corticosterone (CORT) in serum also decreased significantly. CUMS upregulated the expressions of α2δ-1, N-methyl- d -aspartate receptor 1 (NR1), NR2A and NR2B, and enhanced the binding ability to of α2δ-1 and NR1, which were reversed by CLD. The results demonstrated that CLD could ameliorate depression-like behaviors due to CUMS, which was related to the fact that CLD down-regulated α2δ-1 level and interfered with α2δ-1 binding to NR1, thereby reducing NMDAR expression and ultimately inhibiting HPA axis activity.
研究领域:
神经科学
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中药学
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精神医学
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DOI
高影响因子
EUROPEAN JOURNAL OF PHARMACOLOGY
·
2023
·
IF 5
Mo-li Zhu,Jie Zhang,Li-juan Guo,Rui-zhu Yue,Shan-shan Li,Bao-yue Cui,Shuang Guo,Qian-qian Niu,Ya-nan Yu,Huan-huan Wang,Lin Yang,Ya-ling Yin,Shuang-xi Wang,He-qin Zhan,Zhi-tao Gao,Peng Li
Vascular dementia (VD) is one of the most common causes of dementia, taking account for about 20% of all cases. Although studies have found that selenium supplementation can improve the cognitive ability of Alzheimer's patients, there is currently no research on the cognitive impairment caused by VD. This study aimed to investigate the role and mechanism of Amorphous selenium nanodots (A SeNDs) in the prevention of VD. The bilateral common carotid artery occlusion (BCCAO) method was used to establish a VD model. The neuroprotective effect of A SeNDs was evaluated by Morris water maze , Transcranial Doppler TCD, hematoxylin–eosin (HE) staining , Neuron-specific nuclear protein (Neu N) staining and Golgi staining. Detect the expression levels of oxidative stress and Calcium-calmodulin dependent protein kinase II (CaMK II), N-methyl-D-aspartate receptor subunit NR2A, and postsynaptic dense protein 95 (PSD95). Finally, measure the concentration of calcium ions in neuronal cells. The results showed that A SeNDs could significantly improve the learning and memory ability of VD rats, restore the posterior arterial blood flow of the brain, improve the neuronal morphology and dendritic remodeling of pyramidal cells in hippocampal CA1 area, reduce the level of oxidative stress in VD rats, increase the expression of NR2A, PSD95, CaMK II proteins and reduce intracellular calcium ion concentration, but the addition of selective NR2A antagonist NVP-AAMO77 eliminated these benefits. It suggests that A SeNDs may improve cognitive dysfunction in vascular dementia rats by regulating the NMDAR 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
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产品关联
DOI
PubMed
高影响因子
NEUROCHEMICAL RESEARCH
·
2024
·Vol. 50
·期 1
·1-16
·
IF 3.7
Lao Dayuan,Gong Zhuowei,Li Taiyan,Mo Xuean,Huang Wen
The clinical manifestations of anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis may be closely related to the integrity of the blood–brain barrier (BBB). The P38 mitogen-activated protein kinase (P38MAPK) pathway plays a protective role in neurodegenerative diseases. However, whether the P38MAPK pathway is involved in the underlying mechanism of tight junction (TJ) protein disruption and neuronal damage has not been elucidated. Therefore, in this study, a mouse model of anti-NMDAR encephalitis was established by active immunization with NMDAR NR1 356-385 peptides. The critical pathways of P38MAPK were screened by interaction network and co-enrichment analysis. The role of P38MAPK pathways was investigated by the injection of P38MAPK inhibitor SB203580 (10 mg/kg, i.p.). Compared with the control group, the expression of occludin and zonula occludens (ZO)-1 in NMDAR NR1 356-385 group mice was downregulated, and the structure and function of BBB were damaged. However, after the intervention of SB203580, the activation of the P38MAPK was inhibited, the expression of matrix metalloproteinase 9 (MMP9) was reduced, and the function of BBB was improved. Meanwhile, inhibiting the P38MAPK pathway reversed the degradation of NMDAR NR1, while reducing the expression of the glial fibrillary acidic protein (GFAP) and pro-inflammatory factor tumor necrosis factor (TNF-α). It also relieved the damage of neuron-specific nucleus (NeuN), thus alleviating psychobehavioral symptoms. In conclusion, our results suggested that the P38MAPK pathway is involved in BBB destruction and neurobehavioral change in mice with anti-NMDAR encephalitis. Targeting the P38MAPK pathway may be a promising option for the treatment of anti-NMDAR encephalitis.
研究领域:
神经科学
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免疫学
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药理学
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DOI
高影响因子
Neuropsychiatric Disease and Treatment
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2022
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IF 2.989
Kun Zhang,Ran Liu,Yuan Gao,Wen Ma,Weidong Shen
Background Neuroinflammation is an important pathological mechanism of depression that leads to an increase in indoleamine-2,3-dioxygenase (IDO) activity and NMDAR activation. This study aimed to observe the effects of electroacupuncture on depression-like behaviour in lipopolysaccharide (LPS)-treated rats and the underlying mechanism.Methods Wistar rats were intraperitoneally administered LPS (0.5 mg/kg) for 7 consecutive days to establish a depression model. Electroacupuncture treatment was administered 1 hour after daily LPS injection. The open field test (OFT), forced swimming test (FST), and sucrose preference test (SPT) were used to evaluate the depressive-like behaviours. IL-1β, IL-6, and TNF-α levels were determined by enzyme-linked immunosorbent assay (ELISA); Trp, 5-hydroxytryptamine (5-HT), kynurenine (Kyn) and quinolinic acid (Quin) were detected by ultra-high-performance liquid chromatography-tandem mass spectrometry; and N-methyl-D-aspartate receptor (NMDAR) protein and mRNA were assessed by Western blot and real-time qPCR.Results The results showed that electroacupuncture treatment successfully corrected LPS-induced depressive-like behaviour, reduced the inflammatory factor (IL-1β, IL-6 and TNF-α) levels in the blood and hippocampus, prevented IDO over-activation and recovered NR2B expression after challenge by LPS.Conclusion Electroacupuncture treatment provided protection against LPS-induced depressive-like behaviour, and the associated mechanisms may be related to inhibiting the inflammatory response, regulating the IDO-mediated tryptophan-degrading pathway, and inhibiting NR2B activation.
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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行为科学
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产品关联
DOI
PubMed
高影响因子
CELL BIOCHEMISTRY AND BIOPHYSICS
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2025
·
IF 2.5
Ma Qi,Ma Yu,Sun Shizhuo,Yang Lei,Shi Tian,Zhang Boxi,Shang Bo,Zhou Ruiyuan,Liu Jingyuan,He Jiao,Hu Jing,Cao Yanjun
Geniposide (GE), an iridoid glycoside from Gardenia jasminoides J.Ellis , exhibits anti-inflammatory, antioxidant, antidepressant, and neuroprotective properties. The excessive presence of corticosterone (CORT) can lead to neurotoxicity and inflict harm upon nerve cells. This study aimed to examine GE’s neuroprotective effects on CORT-induced damage in PC12 cells. Cells were pre-treated with GE for 3 h, then exposed to CORT for 24 h. Cell viability and lactate dehydrogenase (LDH) leakage were measured, apoptosis was assessed via flow cytometry, and immunofluorescence was used to detect MAP2 and PSD95 expression. The detection of glutamate (Glu) receptor, BDNF pathway, synaptic plasticity-related protein, and apoptosis pathway were performed using Western blot. The findings indicated that GE effectively prevented the reduction in cell viability, apoptosis, and LDH release caused by CORT. In PC12 cells, the expression of MAP2 and PSD95 were significantly enhanced by GE. Furthermore, GE reduced NR1, NR2A, NR2B, and Bax levels, increased EAAT2/3, Bcl-2, and proteins linked to BDNF and synaptic plasticity, and inhibited Caspase-3 and Caspase-9. GE shows neuroprotective and anti-apoptotic properties against CORT-induced cellular damage through BDNF pathway activation and Bax/Bcl-2 pathway suppression.
研究领域:
神经药理学
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细胞生物学
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植物化学
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分子生物学
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神经科学
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产品关联
DOI
PubMed
高影响因子
SCHIZOPHRENIA BULLETIN
·
2025
·
IF 4.8
Fan Rui,Pu Jianlin,Zhang Jin,Yu Minglan,Wang Tingting,Geng Xiaoqi,Dong Wei,Ma Rong,Wang Binglong,Wu Jianfei,Liu Kezhi,Hashimoto Kenji,Xiang Bo
BackgroundSocial withdrawal is a core symptom of schizophrenia (SCZ), yet its underlying molecular mechanisms remain unclear. Gα13 (GNA13), a G protein alpha subunit, has been implicated in SCZ susceptibility. This study investigated the role of Gα13 in social behavior by overexpressing it in the medial prefrontal cortex (mPFC) pyramidal neurons of mice.Study DesignIn this study, we first constructed CRE recombinase overexpressing Gα13 gene mice using CRISPR/Cas9 technology, tested the social behaviors by three-box socialization test, detected the changes of neuronal activities during social activities in mice by calcium signal fiber-optic recordings, observed the changes of dendritic spines by Golgi staining, applied RNA sequencing (RNA-Seq) to find the relevant targets, and observed whether it could reverse the abnormalities by pharmacological experiments social behavior. The electrophysiological characteristics of Gα13 overexpression were investigated using the whole-cell membrane clamp technique, followed by assessment of the severity of SCZ patients and social withdrawal using the PANSS scale and measurement of human plasma Gα13 protein levels using the ELISA technique, and the clinical correlation between the two was assessed.Study ResultsGα13 overexpression (Gα13-OE) mice exhibited significant social deficits in the three-chamber test, showing reduced sociability but normal social novelty recognition. Fiber photometry recordings revealed decreased neuronal activity during social interactions, and Golgi staining showed reduced dendritic spine density in mPFC pyramidal neurons. RNA-Seq identified downregulation of Adcyap1, affecting the cAMP/PKA signaling pathway and NMDA receptor (NMDAR) function. Pharmacological activation of Adcyap1 with PACAP-38 or NMDAR with D-cycloserine rescued the social deficits and restored synaptic function. Conversely, knockdown of Gα13 in an MK-801-induced SCZ mouse model ameliorated social behavior abnormalities. Clinically, patients with SCZ exhibited elevated plasma levels of Gα13, which positively correlated with the severity of social withdrawal symptoms measured by the PANSS G16 item.ConclusionsThese findings suggest that overexpression of Gα13 in the mPFC impairs social behavior by disrupting neuronal function and synaptic plasticity via the Adcyap1/cAMP/PKA/NMDAR pathway. Targeting Gα13 may offer a novel therapeutic strategy for addressing social deficits in SCZ.
研究领域:
神经生物学
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精神病学
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分子神经科学
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信号转导
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行为神经科学
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转化医学
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突触生物学
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产品关联
DOI
PubMed
高影响因子
JOURNAL OF HAZARDOUS MATERIALS
·
2026
·
IF 10.6
Xinchao Guan,Lijie Xie,Guoliang Li,Yujie He,Shilin Chen,Han Wang,Wenke Yuan,Huan Gao,Ming Chen,Xiaoge Yang,Yingxia Luo,Xiaojian Shao,Wen Chen,Lili Liu,Qing Wang
NCM exposure is associated with lower Mini-Cog scores and higher NfL. • NCM may induce rat cognitive deficits, neuronal damage, and NMDAR downregulation. • CTCF is implicated in NCM metal ion induced impairment of NMDAR and synaptogenesis. • 4.Current Ni/Mn OELs may exceed the neurotoxicity threshold of NCM. Lithium nickel cobalt manganese oxide (NCM) is the predominant cathode material for lithium-ion batteries (LIBs); however, its occupational health risks remain insufficiently understood. In this study, we found that in occupationally NCM‑exposed workers, urinary levels of Li, Ni, Co, and Mn were negatively associated with Mini‑Cog test scores and positively associated with serum neurofilament light chain (NfL, as neuronal injury marker). In an intratracheal instillation rat model, NCM-exposed rats exhibited learning and memory deficits, neuronal injury, and reduced synaptic complexity. RNA‑seq analysis revealed suppression of N-methyl- D -aspartate receptors (NMDAR)‑dependent synaptogenesis pathways in rat hippocampus, along with downregulation of NMDAR subunits (GluN2A and GluN2B) and postsynaptic proteins such as CaMKII‑α, MAP2, PSD‑95, and Synapsin‑1. In SH-SY5Y cells, treatment with NCM-derived metals recapitulated these gene expression changes. Bioinformatics analysis identified CCCTC-binding factor (CTCF) as a potential regulator of NMDAR. Cellular thermal shift assays (CETSA) identified the binding of NCM-derived metals to CTCF. Based on in vivo data, human equivalent concentrations (HECs) derived from BMDL 10 of Ni and Mn were below the current OELs of China and America. Collectively, these findings indicate that NCM may induce neurotoxicity and impair learning and memory by disrupting synaptogenesis, and CTCF is implicated in this process. Download: Download high-res image (273KB) Download: Download full-size image
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DOI
高影响因子
TISSUE & CELL
·
2025
·
IF 2.5
Yanfei Yang,Lili Yang,Yabin Li,Yanfen Wang
Background The gut microbiota is essential for the bidirectional communication between the gut and the brain. However, its specific role and underlying mechanisms in anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis remain largely unclear. Methods An anti-NMDAR encephalitis model was induced by GluN1 peptide immunization, and brain histopathology was assessed by hematoxylin-eosin staining. Behavioral performance was assessed through the Y-maze and open field tests. Flow cytometry was employed to quantify T follicular helper (Tfh) and T follicular regulatory (Tfr) cell populations. Enzyme-linked immunosorbent assay and western blot were used to assess inflammatory cytokines and phosphoinositide 3-kinase/protein kinase B (PI3K/AKT) pathway-related protein levels, respectively. 16S rRNA sequencing and Helicobacter rodentium gavage (1.5 mL, 1×10¹¹ CFU/mL) were used to assess microbiota composition and bacterial function. Results 16S rRNA sequencing revealed a trend toward reduced gut microbial diversity in anti-NMDAR encephalitis mice. Helicobacter rodentium colonization further exacerbated behavioral deficits and inflammatory cell infiltration in the cerebral cortex. This was accompanied by a marked increase in tumor necrosis factor alpha (TNF-α) and interleukin (IL)-21 levels and a reduction in IL-10 concentrations in both cerebrospinal fluid and serum. Moreover, the Tfh/Tfr cell ratio was further elevated following Helicobacter rodentium exposure. Targeted suppression of the PI3K/AKT pathway with LY294002 significantly restored Tfh/Tfr balance and alleviated neurobehavioral impairments and cortical inflammation. Conclusion Helicobacter rodentium exacerbates anti-NMDAR encephalitis by inducing PI3K/AKT-mediated Tfh/Tfr imbalance, highlighting a potential therapeutic target in autoimmune encephalitis.
研究领域:
神经免疫学
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微生物组研究
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自身免疫性疾病
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分子信号通路
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炎症生物学
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DOI
PubMed
高影响因子
MOLECULES
·
2018
·Vol. 23
·期 5
·996
·
IF 3.098
Wenchao Li,Jingjian Liu,Minghua Fan,Zhongtang Li,Yin Chen,Guisen Zhang,Zhuo Huang,Liangren Zhang
GLYX-13, a NMDAR glycine-site partial agonist, was discovered as a promising antidepressant with rapidly acting effects but no ketamine-like side effects. However, the reported synthetic process route had deficiencies of low yield and the use of unfriendly reagents. Here, we report a scaled-up synthesis of GLYX-13 with an overall yield of 30% on the hectogram scale with a column chromatography-free strategy, where the coupling and deprotection reaction conditions were systematically optimized. Meanwhile, the absolute configuration of precursor compound of GLYX-13 was identified by X-ray single crystal diffraction. Finally, the activity of GLYX-13 was verified in the cortical neurons of mice through whole-cell voltage-clamp technique.Keywords:GLYX-13;NMDA receptor;chromatography-free synthesis;crystal structure;whole-cell voltage-clamp
研究领域:
药理学
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合成化学
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神经科学
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DOI
PubMed
高影响因子
JOURNAL OF ETHNOPHARMACOLOGY
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2024
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IF 4.8
Jingbin Chen,Yali Liu,Yonggui Song,Huihui Liang,Genhua Zhu,Bike Zhang,Liangliang Liao,Jian Luo,Ming Yang,Dan Su
Ethnopharmacological relevance Citri Reticulata Pericarpium Viride (also known Qing-Pi or QP) is a plant in the Rutaceae family, QP is a traditional Qi-regulating medicine in Chinese medicine that is compatible with other Chinese medicine components and has extensive clinical practice in treating anxiety and depression. Reports on the pharmacological effects of QP have demonstrated its neuroprotective effects and antioxidant capacities. Numerous pharmacological benefits of QP are attributed to its antioxidant abilities. Anxiety disorders are a broadly defined category of mental illnesses. Oxidative stress and an imbalance in the antioxidant defense system are typical pathological features of these disorders. Aim of the study The aim of this study was to evaluate the effects of QP essential oil on anxiety using animal models and investigate the underlying neurobiological mechanisms. Materials and methods This study aimed to develop an animal model of anxiety using chronic restraint stress and investigate the effects of inhalation of Citri Reticulata Pericarpium Viride essential oil on anxiety-like behavior, olfactory function, and olfactory bulb neurogenesis in mice with anxiety. Results The results showed that long-term chronic restraint stimulation caused a decrease in olfactory function, significant anxiety-like behavior, and a notable reduction in the number of neurons in the olfactory bulb. However, inhalation of Citri Reticulata Pericarpium Viride essential oil reversed these effects, improving the olfactory function, neuro-stimulating effect, alleviating anxiety-like behavior, and regulating theta (4-12Hz) oscillation in the hippocampus DG area. These effects were associated with changes in the expression levels of glutamate receptor NMDAR and NeuN in olfactory bulb. Conclusions The study revealed that mice with anxiety induced by chronic restraint stress exhibited significant olfactory dysfunction, providing strong evidence for the causal relationship between anxiety disorders and olfactory dysfunction. Moreover, QP essential oil has the potential to be developed as a therapeutic drug for anxiety disorders, in addition to its role as a complementary anxiolytic.
研究领域:
药理学
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神经科学
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民族药理学
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行为科学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
JOURNAL OF HAZARDOUS MATERIALS
·
2024
·
IF 12.2
Jinzhi Ren,Ying Peng,Luhang She,Lu Yan,Jianjun Li,Caixia Gao,Chao Wang,Yimeng Wang,Xiangping Nie,Xiaowei Zhang
The estuarine ecological environment faces significant threats from contaminants of emerging concern (CECs); yet, the risk posed by CECs to resident organisms remains poorly understood. Here, we employed tiered toxicity testing to investigate the adverse effects and potential mechanisms of tris (1-chloro-2-propyl) phosphate (TCPP) on the early life stages of an estuarine fish, Mugilogobius chulae . TCPP affected the development of M. chulae embryos, including survival, morphology, hatching, and behavior. A concentration-dependent transcriptomic analysis showed that TCPP disrupted 12 neurodevelopment-related KEGG pathways in M. chulae embryos, with five of the 30 % top-ranked pathways related to neurotransmitter signaling. Besides the cholinergic synapse signaling pathway, the glutamatergic signaling pathway (including NMDAR and AMPAR subtypes) may also mediate TCPP-induced neurodevelopmental toxicity. The NMDAR subtype GRIN2B was downregulated at high concentrations. Molecular dynamics simulations revealed a strong interaction between TCPP and GRIN2B, with TCPP binding to the residues Ile153 and Ile188. The results suggest that NMDARs play a crucial role in TCPP-induced neurodevelopmental toxicity toward M. chulae. AOP network analysis predicted that TCPP may impact cognitive functions and memory. Our study provides a novel testing strategy for identifying the mechanisms of toxicity of CECs, a crucial component of ecological risk assessment.
研究领域:
环境毒理学
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水生生态学
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分子生物学
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神经科学
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产品关联
DOI
PubMed
高影响因子
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