NEUROCHEMICAL RESEARCH
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2026
·Vol. 51
·期 4
·237
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IF 4.5
Han Zhipeng,Li Xing,Yang Li,Li Jinglin,Zhao Kaiyang,Xie Junxiong,Zhou Siyuan,Shi Wenli,Zhang Xiaolina
Neuropathic pain (NP) is chronic pain caused by injury or disease affecting the nervous system. SIN@Lip-HA was prepared and characterised for particle size, zeta potential, encapsulation efficiency and morphology. Sprague-Dawley rats with spared nerve injury (SNI) were randomly divided into the six groups. Analgesic effects were assessed via behavioural tests. Histopathological changes were examined using H&E staining. Astrocyte polarisation was detected using immunofluorescence, and Western blotting was used to assess related protein expression. qRT-PCR measured mRNA level of genes, while ELISA evaluated inflammatory cytokines and oxidative stress markers. The study showed that the particle size of SIN@Lip-HA was 111 ± 5.13 nm, with an encapsulation efficiency of 85.47% and a zeta potential of -24.86 ± 1.20 mV. The in vitro release profile showed sustained drug release, and the formulation remained stable for 3 months. Compared with the model group, SIN@Lip-HA significantly increased PWT and PWL, alleviated spinal cord pathology and was associated with a shift in astrocyte reactivity, as indicated by a reduction in A1-related markers and an increase in A2-related markers. SIN@Lip-HA downregulated CGRP/SP and GFAP. It was also found to inhibit JAK2/STAT3 pathway activation by reducing p-JAK2/p-STAT3 expression and decrease TNF-α, IL-1β and IL-6 whilst increasing IL-10. It also mitigated oxidative stress. Concomitant use with gabapentin markedly enhanced therapeutic efficacy. These findings suggest that sinomenine liposomes alleviate NP in SNI rats in a manner associated with inhibition of JAK2/STAT3 signaling and correlated with astrocyte reactivity, and reduced pain mediators.
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JOURNAL OF ETHNOPHARMACOLOGY
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2026
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IF 6.8
Shuxian Zang,Ziyun Ban,Lingchen Hou,Yuxuan Zhang,Yuanyuan Wang,Yuanyuan Zhang,Chaonan Wang,Depei Li,Feiyu An,Yuqi Liu,Yunyun Geng,Yonggang Gao
Ethnopharmacological relevance The herbal combination of Bupleurum chinense DC (Chaihu) and Paeonia lactiflora Pall (Baishao), collectively referred to as Chaihu-Baishao (CB), has been historically utilized in traditional Chinese medicine for the treatment of depression. However, the mechanisms underlying its therapeutic benefits have not been clearly defined. Aim of the study This study investigated whether CB alleviates depressive symptoms by modulating the interaction between the voltage-gated calcium channel subunit α2δ-1 and the N-methyl-D-aspartate receptor (NMDAR) subunit NMDAR2B (NR2B), thereby restoring hippocampal synaptic plasticity. Materials and methods In vivo , the chronic social defeat stress (CSDS) mouse model was employed to assess the impact of CB on depression-like behaviors, hyperactivity of the hypothalamic-pituitary-adrenal (HPA) axis, impairments in hippocampal neuronal and synaptic plasticity, as well as the expression and interaction of α2δ-1 and NR2B. In vitro , corticosterone (CORT) was utilized to induce cellular injury. In PC12 cells, the therapeutic effects of CB-containing serum and the α2δ-1 inhibitor gabapentin (GBP) were assessed, focusing on the interaction between α2δ-1 and NR2B, as well as the expression levels of synaptic proteins postsynaptic density protein 95 (PSD95) and synaptophysin (SYN). The role of CB was further corroborated using Cacna2d1 gene knockout cells. Molecular docking techniques were employed to predict the key active components within CB that target α2δ-1 and NR2B, hereby exerting antidepressant effects. Results In vivo studies demonstrated that CB significantly alleviated depression-like behaviors in mice, decreased levels of adrenocorticotropic hormone (ACTH) and CORT. Furthermore, CB relieved structural damage to hippocampal neurons and synapses, downregulated the expression of α2δ-1 and NR2B, inhibited their interaction and restored synaptic protein expression. In vitro experiments revealed that CB mitigated CORT-induced cellular damage, suppressed the α2δ-1-NR2B interaction, and enhanced synaptic proteins expression. Additionally, studies involving GBP treatment and Cacna2d1 -knockout confirmed that α2δ-1 plays a regulatory role in NR2B expression and synaptic plasticity. Molecular docking analyses identified Saikosaponin C, Saikosaponin B4, and Bupleuroside I as potential key components. Conclusion The findings of this study elucidate a novel mechanism through which CB exerts its antidepressant effects, specifically by modulating the α2δ-1-NR2B interaction and restoring of synaptic plasticity within the hippocampus.
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Chinese Medicine
·
2026
·
IF 7.4
Qing Zhang,Ziyun Chen,Qingyong Yu,Hanwen Wang,Yucui Jiang,Lan Zhou,Guang Yu,Zongxiang Tang,Changming Wang
Background Cancer-induced bone pain (CIBP) remains a debilitating clinical challenge due to its complex pathogenesis and limited therapeutic options. Tetrahydropalmatine (THP), an active alkaloid from Corydalis tuber , has shown analgesic potential, but its specific mechanisms in mitigating CIBP- especially its interactions with neural factors and immune cells-remain incompletely understood. This study aimed to investigate the efficacy of THP in alleviating CIBP and clarify its underlying mechanisms, with a focus on the roles of transient receptor potential vanilloid 1 (TRPV1), substance P (SP), and macrophage dynamics in a mouse model of CIBP. Methods Using a multidisciplinary approach, we established a CIBP model in male C57BL/6 mice (and TRPV1-knockout mice) via intramedullary injection of lung cancer cells. Behavioral assessments were performed to evaluate mechanical, thermal, and cold allodynia, as well as spontaneous pain, following daily oral administration of THP (80 mg/kg) from day 7 post-modeling. Molecular and cellular analyses included immunofluorescence staining, real-time PCR, ELISA (to quantify SP, cytokines, and Tac1 expression), calcium imaging (to measure TRPV1-mediated calcium influx in DRG neurons), scratch assays (to assess macrophage migration), and flow cytometry (to analyze macrophage polarization in RAW 264.7 cells). Results THP significantly alleviated CIBP-related allodynia and spontaneous pain in mice. Mechanistically, THP directly inhibited TRPV1 function in the primary phase (≤ 14 days post-modeling) (with an IC 50 of 77.9 µM), reducing SP release from DRG neurons and suppressing macrophage recruitment to DRG and sciatic nerve via the TRPV1-SP pathway. Importantly, THP directly promoted the polarization of recruited macrophages toward the anti-inflammatory M2 phenotype, as evidenced by downregulated iNOS, TNF-α, IL-1β and upregulated CD206, IL-4, IL-10 in vitro (RAW264.7 cells) and in vivo. These effects were abrogated in TRPV1-knockout mice, confirming TRPV1 as a critical mediator in the primary phase. Conclusion In conclusion, THP mitigates CIBP through a dual mechanism: regulating macrophage recruitment via the TRPV1-SP pathway in the early stage to inhibit CIBP initiation and directly modulating the migrated macrophage polarization. This study provides novel insights into THP’s analgesic mechanisms and supports its potential as a preclinical candidate for CIBP treatment. Graphical Supplementary Information The online version contains supplementary material available at 10.1186/s13020-026-01359-3.
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Materials Today Bio
·
2025
·
IF 10.2
Han Shi,Zhiqiang Xie,Junrong Zhang,Fengchun Lu,Haoteng Luo,Pengfei Guo,Meichen Jiang,Zongqi Weng,Xin Luo,Bing Chen,Heguang Huang,Tianhong Teng
Reprogramming of branched-chain amino acid (BCAA) metabolism is a key mechanism promoting pancreatic cancer progression. While gabapentin (Gp) can inhibit BCAA catabolism by targeting branched-chain amino acid aminotransferase 1 (BCAT1), its efficacy is limited by inefficient delivery and compensatory mitochondrial metabolism. To address this, we developed a novel copper ionophore-functionalized mesoporous silica nanoplatform (XQ/Gp@CMSNs) for synergistic cuproptosis and tumor-starvation therapy. The designed nanoparticles exhibit excellent pancreatic cancer-targeting capability via XQ-2d aptamer modification and acid-responsive drug release within the tumor microenvironment. Upon internalization, XQ/Gp@CMSNs simultaneously induce mitochondrial copper overload and disrupt BCAA metabolism, leading to dihydrolipoamide S-acetyltransferase (DLAT) oligomerization, ferredoxin 1 (FDX1) downregulation, and tricarboxylic acid (TCA) cycle suppression. Both in vitro and in vivo studies demonstrated potent antitumor efficacy with minimal systemic toxicity. Metabolomic analyses further confirmed synergistic BCAA metabolic inhibition and copper-induced mitochondrial dysfunction. This work presents a promising metabolic intervention strategy for pancreatic cancer through targeted nanomedicine.
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RSC Advances
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2018
·Vol. 8
·期 40
·22777-22784
·
IF 2.936
Xiuwen Li,Shuangxi Zhou,Yuting Qian,Zhuoran Xu,Yang Yu,Yanhua Xu,Yide He,Yongjun Zhang
Gabapentin (GAB) is an emerging contaminant that is frequently detected in water bodies across the globe. The present study used zebrafish as a model organism to investigate the effects of GAB on the early development of zebrafish and on its antioxidant system. Acute toxicity tests indicated that the 96 h LC50 value of GAB for zebrafish embryos was 59.9 g L−1. Further, it was observed that GAB causes malformation of embryos such as hemagglutination and pericardial edema. Compared to the control group, a significant enhancement (p < 0.05) of heartbeat rates was found at GAB concentrations exceeding 50 mg L−1, while the swimming frequency was clearly increased upon exposure to GAB at a concentration of 100 mg L−1 (p < 0.05). Additionally, the development of the zebrafish embryo was also negatively impacted after exposure to GAB as demonstrated by significantly decreased body lengths. Exposure to GAB at concentrations exceeding 50 mg L−1 significantly influenced the development of zebrafish, leading to malformation of organs and abnormal movements. Although no significant developmental effects of GAB were observed at environmentally relevant concentrations (0.1 and 10 μg L−1), further research about the antioxidant system confirmed that severe oxidant injury happened inside the organisms. catalase (CAT), lactate dehydrogenase (LDH), glutathione S-transferase (GST), glutathione (GSH) and the ability of inhibition of hydroxyl radicals (IHR) were used as biomarkers in the present study to illustrate GAB toxicity at environmentally relevant concentrations. The results showed that activities of CAT, LDH and GST as well as IHR were all elevated after GAB exposure, which proved that ROS were formed in the body as derived from GAB exposure. Among all of these biomarkers, CAT was the most sensitive one to evaluate the influence of GAB, and showed a significant increase even at a very low exposure concentration (0.1 μg L−1).
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JOURNAL OF HAZARDOUS MATERIALS
·
2025
·
IF 11.3
Yide He,Xiang Li,Yan Yang,Rosa Freitas,Jiansheng Zhu,Guixiang Ji,Yongjun Zhang
Gabapentin (GBP), a pharmaceutical widely used for seizures and neuropathic pain, has emerged as a contaminant in global aquatic environments, raising concerns about its ecological impact. This study investigated the effects of environmentally relevant concentrations of GBP (0, 1, 10, 1000 μg/L) on visual development in zebrafish ( Danio rerio ). Behavioral assays showed that GBP exposure enhanced light sensitivity, as indicated by a significant increase in total travel distance (TTD) in all exposure groups compared to controls. The 1 μg/L and 1000 μg/L exposure groups demonstrated a 41 % and 37 % increase in TTD, respectively ( p < 0.05). Apoptosis assays revealed dose-dependent retinal cell death, with fluorescence intensity rising by 15 % at 1000 μg/L ( p < 0.05). Visual acuity, measured through optokinetic response (OKR) tests, decreased significantly across all color stimuli. Angular velocity under white light decreased from 4.0 °/s in controls to 1.6 °/s at 1000 μg/L ( p < 0.01) in a dose-de p endent manner. Retinal histopathology showed a 17 % increase in ganglion cell layer thickness at 1000 μg/L ( p < 0.05) in a dose-dependent manner. Thyroid hormone assays indicated significant reductions in T3 and T4 levels ( p < 0.001), with a 22 % increase in the T3/T4 ratio at 1000 μg/L. Gene expression analysis revealed dysregulation in apoptosis ( casp3a , ifi27 ), thyroid ( tshr , dio1 ), and retinal development ( atoh7 , pax6a ) pathways. These findings demonstrate that GBP disrupts visual development in zebrafish through retinal apoptosis and thyroid hormone dysregulation, highlighting the ecological risks posed by pharmaceutical pollutants. GBP exposure increased light-driven locomotor activity, indicating heightened light sensitivity due to apoptosis in the retina. Visual acuity was assessed through the optokinetic response (OKR) test, retinal morphology, and thyroid hormone (TH) levels. Even at concentrations as low as 1 µg/L, GBP exposure led to significant reductions in OKR across various colors, likely due to changes in retinal thickness linked to thyroid hormone disruption. These effects were consistent with alterations in gene expression related to apoptosis, the thyroid system, and retinal development. Our findings enhance understanding of how GBP exposure impairs vision in fish and highlight the need to evaluate the ecological risks of pharmaceutical contaminants in aquatic environments.
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eLife
·
2024
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IF 6.4
Lu Yang,Zijin Lin,Ruijing Mu,Wenhan Wu,Hao Zhi,Xiaodong Liu,Hanyu Yang,Li Liu
Blood–brain barrier (BBB) prevents neurotoxins from entering central nervous system. We aimed to establish and characterize an in vitro triple co-culture BBB model consisting of brain endothelial cells hCMEC/D3, astrocytoma U251 cells, and neuroblastoma SH-SY5Y cells. Co-culture of SH-SY5Y and U251 cells markedly enhanced claudin-5 and VE-cadherin expression in hCMEC/D3 cells, accompanied by increased transendothelial electrical resistance and decreased permeability. Conditioned medium (CM) from SH-SY5Y cells (S-CM), U251 cells (U-CM), and co-culture of SH-SY5Y and U251 cells (US-CM) also promoted claudin-5 and VE-cadherin expression. Glial cell line-derived neurotrophic factor (GDNF) levels in S-CM and US-CM were significantly higher than CMs from hCMEC/D3 and U-CM. Both GDNF and US-CM upregulated claudin-5 and VE-cadherin expression, which were attenuated by anti-GDNF antibody and GDNF signaling inhibitors. GDNF increased claudin-5 expression via the PI3K/AKT/FOXO1 and MAPK/ERK pathways. Meanwhile, GDNF promoted VE-cadherin expression by activating PI3K/AKT/ETS1 and MAPK/ERK/ETS1 signaling. The roles of GDNF in BBB integrity were validated using brain-specific Gdnf silencing mice. The developed triple co-culture BBB model was successfully applied to predict BBB permeability. In conclusion, neurons enhance BBB integrity by upregulating claudin-5 and VE-cadherin expression through GDNF secretion and established triple co-culture BBB model may be used to predict drugs’ BBB permeability.
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CNS Neuroscience & Therapeutics
·
2024
·
IF 4.8
Mingyan Wang,Xin Wei,Yugai Jia,Chaonan Wang,Xinliu Wang,Xin Zhang,Depei Li,Yuanyuan Wang,Yonggang Gao
Background Depression is a serious mental disorder and the most prevalent cause of disability and suicide worldwide. Chronic unpredictable mild stress (CUMS) can lead to a significant acceleration of depression development. Quercetin (Que) is a flavonoid compound with a wide range of pharmacological effects. Recent studies have shown that quercetin can improve CUMS‐induced depression‐like behavior, but the mechanism of its improvement is still unclear. α2δ‐1 is a regulatory subunit of voltage‐gated calcium channel, which can interact with N‐methyl‐D‐aspartate receptor (NMDAR) to form a complex. Objective In this study, we found that Que could inhibit the increase of α2δ‐1 and NMDAR expression in rat hypothalamus induced by CUMS. In pain, chronic hypertension and other studies have shown that α2δ‐1 interacts with the NMDAR to form a complex, which subsequently affects the expression level of NMDAR. Consequently, the present study aimed to investigate the antidepressant effect of Que in vivo and in vitro and to explore its mechanism of action in terms of the interaction between α2δ‐1 and NMDAR. Methods Rats were randomly exposed to two stressors every day for 4 weeks to establish a CUMS rat model, then sucrose preference test (SPT), forced swimming test (FST), tail suspension test (TST), and open field test (OFT) were performed to detect the behavior of CUMS rats, so as to evaluate whether the CUMS rat model was successfully established and the improvement effect of Que on CUMS‐induced depression‐like behavior in rats. Experimental techniques such as serum enzyme‐linked immunosorbent assay (ELISA), immunofluorescence, Western blot, and co‐immunoprecipitation, as well as in vitro experiments, were used to investigate the mechanisms by which Que exerts its antidepressant effects. Results Behavioral and ELISA test results showed that Que could produce a reduction in the excitability of the hypothalamic–pituitary–adrenal (HPA) axis in CUMS rats and lead to significant improvements in their depressive behavior. Western blot, immunofluorescence, and co‐immunoprecipitation experiments showed that Que produced a decrease in NMDAR1 and α2δ‐1 expression levels and interfered with α2δ‐1 and NMDAR1 binding. In addition, the neural regulation mechanism of Que on antidepressant effect in PC12 cells knocked out α2δ‐1 gene was further verified. Cellular experiments demonstrated that Que led to a reversal of up‐regulation of NMDAR1 and α2δ‐1 expression levels in corticosterone‐injured PC12 cells, while Que had no effects on NMDAR1 expression in PC12 cells with the α2δ‐1 gene knockout. Conclusions Que has a good antidepressant effect and can significantly improve the depression‐like behavior caused by CUMS. It exerts antidepressant effects by inhibiting the expression level of α2δ‐1, interfering with the interaction between α2δ‐1 and NMDAR, and then reducing the excitability of the HPA axis.
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RESEARCH ON CHEMICAL INTERMEDIATES
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2024
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IF 2.8
Xiong Neng,Jiang Lin-Li,Chen Jia-Yu,Lin Lei,Huang Jin-Rong,Shen Qi,Xue Ya-Ping,Zheng Yu-Guo
Hydrogenation plays an important role in the production of bulk and fine chemicals. In the present work, the hydrogenation process of 1-cyanocyclohexaneacetic acid (1-CA), a key intermediate in the chemo-enzymatic synthesis of the antiepileptic drug gabapentin, was investigated. The catalysts were screened, the operating parameters for the 1-CA hydrogenation were determined by response surface methodology, and the effects of biological impurities on the reaction and catalysts were investigated. The reaction temperature, reaction solution pH and reaction time were identified as the main factors for hydrogenation by single-factor experiments. Under the optimal reaction conditions: reaction temperature 110 °C, solution pH 12.33, reaction time 3.74 h, hydrogen pressure 2 MPa and stirring speed 500 rpm, the substrate conversion reached 100%, and the total product yield reached 96.40%, which was very close to the prediction (96.88%). It was demonstrated that biological impurities greatly affect the reaction rate of hydrogenation, as well as the activity and reusability of the catalyst, in which protein impurities lead to catalyst deactivation through cumulative deposition on the catalyst surface and within the pores.
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JOURNAL OF PHARMACEUTICAL AND BIOMEDICAL ANALYSIS
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2025
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IF 3.1
Xiao-han Peng,Yan-lin Zhao,Zhong Huang,Xin-feng Xia,Kun Wang,Peng Jin,Yan Du,Dao-quan Tang
Currently, treatment with antiepileptic drugs (AEDs) is still the first choice for epileptic patients, while monitoring their blood concentrations is undoubtedly beneficial for minimizing their adverse side effects and optimizing their therapeutic effects. In this study, an ultra-high performance liquid chromatography coupled with tandem mass spectrometry with polarity switching was developed and validated for simultaneous determination of 14 AEDs and 2 active metabolites in human serum. Olanzapine was selected as the internal standard. One-step protein precipitation using methanol containing 0.05 % formic acid was used to treat sample, and the supernatant was injected for analysis without further evaporation and reconstitution. Chromatographic separation was performed on an Aglient Zorbax Eclipse Plus C18 (50 mm × 2.1 mm, 1.8 μm) column with gradient methanol and 0.1 % formic acid in water as mobile phase. Multi-reaction monitoring was performed for quantification of 16 analytes in polarity switching mode. Matrix-matched calibration curves of 16 analytes presented good linearity within the test concentration range ( r > 0.99). The intra- and inter-run accuracies and precisions at the lower limit of quantification, and low, medium and high quality control levels were all less than 20 % or 15 %, respectively. The extraction recovery, matrix effect, and stability were all acceptable under detected conditions. Finally, this method was successfully applied in the quantitation of target analytes in the serum of patients received AEDs.
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Advanced Science
·
2025
·
IF 14.1
Zhaoyichun Zhang,Yanran Zhang,Jialin Si,Honghui Mao,Feng He,Jin Ning,Guaiguai Ma,Xiaohua Chen,Haoxiang Xiao,Yuanyuan Zhu,Haifeng Zhang,Yifan Lu,Qian Liu,Meng Nian,Shiquan Sun,Shibin Yu,Shengxi Wu,Ze Fan,Zuolin Jin,Jing Huang
Structural craniofacial abnormalities, particularly mandibular asymmetry (MA), are increasingly recognized as key drivers of orofacial pain and emotional comorbidities, although the underlying neural mechanisms remain unclear. This study aims to develop a preclinical MA model to investigate the dynamic interplay between craniofacial structural defects and neurobehavioral dysfunction. Longitudinal behavioral phenotyping including von Frey filaments test as well as open field and elevated plus maze tests reveals progressive sensory hypersensitivity and anxiety-like behaviors, with computational ethology revealing subtle but consistent alterations in the naturalistic behaviors. Whole-brain activity mapping reveal hyperactivation in the anterior cingulate cortex (ACC), whereas multi-omics profiling reveal cell type-specific transcriptional changes and synaptic reorganization within this region. Functional investigation including sparse labeling, electrophysiology, western blotting, and chemogenetics demonstrate that the ACC modulation regulated both pain and anxiety. These findings establish a causal association between structural craniofacial defects and maladaptive neural circuit remodeling, with the ACC emerging as a critical therapeutic target. The study provides a comprehensive framework for understanding how anatomical abnormalities translate into persistent neurological dysfunction and offers new avenues for mechanistically informed intervention.
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