Chinese Journal of Pharmacology and Toxicology

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    2025, 39(3): 0.
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    • ORIGINAL ARTICLES
  • ORIGINAL ARTICLES
    Effect of N-methyl-D-aspartic acid receptor in secondary visual cortex on methamphetamine-associated contextual learning and memory
    SUN Chu, CAO Danni, SONG Rui, LI Jin
    2025, 39(3): 161. https://doi.org/10.3867/j.issn.1000-3002.2025.03.001
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    OBJECTIVE  To investigate the effect of N-methyl-D-aspartic acid (NMDA) receptor in the secondary visual cortex (V2) on methamphetamine-associated contextual learning and memory. METHODS  With male C57BL/6J mice as subjects and using the mouse conditioned place preference (CPP) experiment, the scores of CPP were observed after microinjection of NMDA receptor selective antagonist D-AP5 (0.5 μg per side) into the bilateral V2 during the formation phase, single microinjection of D-AP5 (0.5 μg per side) into the bilateral V2 prior to the expression test, and methamphetamine (0.5 mg∙kg-1, ip)-induced reactivation test and methamphetamine-associated contextual-induced reactivation test, to evaluate the effect of NMDA receptors on the formation, expression and reinstatement of methamphetamine-induced CPP. RESULTS  Compared with the control group, microinjection of D-AP5 (0.5 μg per side) into the bilateral V2 during the formation phase did not have significant inhibitory effect on CPP scores, nor did single microinjection of D-AP5 (0.5 μg per side) into the bilateral V2 prior to the expression test, single microinjection of D-AP5 (0.5 μg per side) into the bilateral V2 prior to methamphetamine (0.5 mg∙kg-1, ip)-induced reactivation test or single microinjection of D-AP5 (0.5 μg per side) into the bilateral V2 prior to methamphetamine-associated contextual-induced reactivation test. CONCLUSION  The NMDA receptor in the V2 is not involved in the formation, expression and reactivation of methamphetamine-associated contextual learning and memory.
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    Effects of forkhead box protein A1 knockout on microRNA expression profiles of benzo[a]pyrene malignant transformed cells THBEc1
    LIU Zhiyu, FU Yujin, LIN Yitong, FU Juanling, YAO Biyun, ZHAO Peng
    2025, 39(3): 169. https://doi.org/10.3867/j.issn.1000-3002.2025.03.002
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    OBJECTIVE  To explore the potential mechanisms of forkhead box protein A1 (FOXA1) in benzo[a]pyrene (BaP)-induced carcinogenesis by investigating the effect of FOXA1 by knockout on microRNA (miRNA) expression profiles in BaP malignant transformed cells THBEc1 and establishing regulatory networks between FOXA1, miRNA and their target genes. METHODS  FOXA1 knockout THBEc1 cells THBEc1-ΔFOXA1-c34 and control cells THBEc1-ctrl were used as study models. Western blotting was employed to determine FOXA1 protein expression levels. Next-generation sequencing (NGS) technology was used to identify differentially expressed miRNAs between THBEc1-ΔFOXA1-c34 and THBEc1-ctrl cells, with subsequent validation by RT-qPCR. Five databases (ENCORI, miRDB, mirDIP, miRWalk and TargetScan 8.0) were used in conjunction with NGS results of mRNA between THBEc1-ΔFOXA1-c34 and THBEc1-ctrl to predict different expressed genes (DEGs) regulated by the identified differentially expressed miRNAs. GO and KEGG enrichment analyses were conducted on the DEGs using the DAVID database. Interaction network analysis of the proteins encoded by the DEGs was performed using STRING 12.0 and Cytoscape 3.10.2 software. RESULTS  No FOXA1 expression was detected in THBEc1-ΔFOXA1-c34 cells. A differential analysis of miRNA expressions revealed 33 miRNAs with a fold change of >2 or <0.5 and a false discovery rate of <0.05 between THBEc1-ΔFOXA1-c34 and THBEc1-ctrl cells, 13 of which were down-regulated and 20 were up-regulated in THBEc1-ΔFOXA1-c34 cells. A regulatory network was formed by 11 down-regulated miRNAs and 32 up-regulated mRNAs, while a second network included 16 up-regulated miRNAs and 56 down-regulated mRNAs. The 27 differentially expressed miRNAs participated in various biological processes through the regulation of 88 DEGs, primarily associated with cell growth, proliferation, migration, apoptosis, angiogenesis, epithelial-mesenchymal transition, and signal transduction (TGF-β, Hippo, NF-kappa B and MAPK pathways). CONCLUSION  The miRNA expression profile in BaP-malignant transformed THBEc1 cells is altered following FOXA1 knockout that may disrupt TGF-β and MAPK signaling pathways by changing miRNA expression levels, thereby inhibiting cell proliferation and migration.
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    Effect and mechanism of hydroxytyrosol on mouse chondrocyte injury induced by H2O2
    YU Haichao, WANG Wenchao, DUAN Junzhao, WANG Hua, ZHANG Xuesong
    2025, 39(3): 183. https://doi.org/10.3867/j.issn.1000-3002.2025.03.003
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    OBJECTIVE  To investigate the effect and underlying mechanism of hydroxytyrosol (HT) on mouse chondrocyte injury induced by oxidative stress. METHODS  Mouse chondrocytes were incubated with varying concentrations of HT 0-400 μmol·L-1 for 24 h, and the viability of the mouse chondrocytes was assessed using CCK-8 kit. An oxidative stress model of chondrocytes was established by the addition of H2O2 200 μmol·L-1. The experimental groups included the cell control group, H2O2 group, and H2O2+HT 10, 50 and 250 μmol·L-1 groups. After 24 h, the mRNA expression levels of interleukin-6 (IL-6), cyclooxygenase-2 (COX-2), prostaglandin E2 (PGE2), inducible nitric oxide synthase (iNOS), matrix metalloproteinase-3 (MMP-3 ), MMP-13, a disintegrin and metalloproteinase with thrombospondin motifs-4 (ADAMTS-4 ), ADAMTS-5, SRY-box transcription factor-9 (SOX-9 ) and aggrecan (ACAN ) in mouse chondrocytes were detected by real-time quantitative PCR, the intracellular reactive oxygen species (ROS) level in chondrocytes was measured with 2, 7-dichlorodihydrofluorescein diacetate (DCFH-DA) staining, while the mitochondrial membrane potential was evaluated using JC-1 staining. After 48 h, the protein expression levels of iNOS, COX-2, MMP-13, and typeⅡcollagen (Col-2) in mouse chondrocytes were detected using Western blotting. RESULTS  HT at concentrations≤350 μmol·L-1 had no significant effect on the survival of mouse chondrocytes. Compared with the cell control group, after 24 h, the mRNA expression levels of IL-6, COX-2, PGE2, iNOS, MMP-3, MMP-13, ADAMTS-4 and ADAMTS-5 in the chondrocytes of mice in the H2O2 group were increased, while the mRNA expression levels of SOX-9 and ACAN were decreased. Additionally, there was an elevation in the ROS level and a significant loss of mitochondrial membrane potential in the chondrocytes of mice. Compared with the H2O2 group, after treatment with HT 10, 50 and 250 μmol·L-1, there were significant decreases in mRNA expression levels of IL-6, COX-2, PGE2, iNOS, MMP-3, MMP-13, ADAMTS-4 and ADAMTS-5, the mRNA expressions of SOX-9 and ACAN were increased, the ROS level was lowered. After treatment with HT 50 and 250 μmol·L-1, the loss of mitochondrial membrane potential was ameliorated. Compared to the cell control group, the protein expressions of iNOS, COX-2 and MMP-13 were upregulated in the H2O2 group, while the protein expression of Col-2 was downregulated after 48 h. Compared to the H2O2 group, treatment with HT at concentrations of 10, 50 and 250 μmol·L-1 resulted in decreased protein expressions of iNOS, COX-2 and MMP-13 in mouse chondrocytes, but the protein expression of Col-2 increased following treatment with HT 50 and 250 μmol·L-1. CONCLUSION  HT can ameliorate H2O2-induced chondrocyte injury by reducing intracellular ROS levels and alleviating the loss of mitochondrial membrane potential, suppressing the release of inflammatory cytokines, inhibiting catabolic processes, and promoting anabolic activities.
  • ORIGINAL ARTICLES
    Ameliorative effect of ursolic acid against acute liver injury induced by carborn tetrachloride in mice
    LI Hanwei, ZHAO Hui, SONG Yagang, ZHU Pinsheng, MIAO Mingsan, QIAO Jingyi
    2025, 39(3): 191. https://doi.org/10.3867/j.issn.1000-3002.2025.03.004
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    OBJECTIVE To explore the ameliorative effect of ursolic acid on carbon tetrachlorideinduced acute liver injury in mice, and the feasibility of multispectral optoacoustic tomography (MSOT) for characteristic structural and functional imaging of liver tissues. METHODS Kunming mice were randomly divided into the normal control group, model group, model+ursolic acid 30, 60 mg·kg-1 groups and model+bifendate 5.625 mg·kg-1 group, with 14 mice in each. Each group was given the corresponding drug once daily for 7 days. An acute liver injury model was established in mice by intraperitoneal injection of 0.2% carbon tetrachloride in olive oil solution after the last administration. Blood was collected, liver tissues were taken 24 h after modeling, and the liver index was calculated, 8 mice from each group and the levels of serum glutamic pyruciv transaminase (GPT) and glutamic oxaloacetic transaminase (GOT), as well as superoxide dismutase (SOD) activity and malondialdehyde (MDA) content in liver tissues were measured. The enzyme-linked immunosorbent assay (ELISA) method was used to detect the level of α - glutathione S-transferase (α -GST) in serum. The histopathological changes of the liver were observed under a light microscope. The remaining 6 mice in each group underwent MSOT technique was used for characteristic structural and functional imaging of liver tissue. Levels of oxygenated hemoglobin (HbO2) and deoxygenated hemoglobin (Hb) were analyzed, oxygen saturation was calculated, and the extent of liver injury was assessed by examining the intrahepatic distribution of indocyanine green (ICG). RESULTS Compared with the normal group, the levels of GPT, GOT and α-GST in serum, content of MDA in liver tissues and the liver index in the model control group were significantly increased while the activity of SOD in liver tissues were significantly decreased. Compared with the model group, ursolic acid in each dose group significantly reduced the liver index of mice, lowered the serum levels of GPT and GOT as well as the level of α- GST, decreased the content of MDA in liver tissues, and elevated the activity of SOD in liver - injured mice. Hematoxylin-eosin staining showed that significant steatosis and hepatocyte necrosis and inflammatory cell infiltration in hepatocytes of mice in the model group. Ursolic acid significantly attenuated the degree of hepatocellular lesions and markedly reduced steatosis in mice. MSOT imaging showed that the HbO2 level and oxygen saturation were significantly lower while the Hb level was remarkably higher in the liver of mice in the model group. In each administration group, the level of HbO2 significantly increased, the level of Hb was significantly decreased, oxygen saturation was significantly increased in the liver of model mice and the accumulation of ICG dye probe was atten⁃ uated in the body after hepatocyte injury. CONCLUSION Ursolic acid can elevate the hepatic oxygen saturation, improve the metabolism of ICG, reduce the degree of hepatic necrosis in mice, and help protect against carbon tetrachloride-induced hepatic injury in mice. The mechanism is probably related to the inhibition of oxidative stress.
  • ORIGINAL ARTICLES
    Pharmacokinetics/pharmacodynamics (PK/PD) of meropenem during continuous renal replacement therapy in a septic rabbits model based on microdialysis technology
    SHAO Ying, WANG Dan
    2025, 39(3): 199. https://doi.org/10.3867/j.issn.1000-3002.2025.03.005
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    OBJECTIVE  To study the pharmacokinetics/pharmacodynamics (PK/PD) profiles of meropenem in the plasma, lung, muscle and skin tissues of rabbits, and to explore the effects of sepsis and continuous renal replacement therapy (CRRT) on the probability of target attainment (PTA) of meropenem. METHODS Twenty-four New Zealand rabbits were randomly divided into four equal groups: sepsis-CRRT group, sepsis group, normal-CRRT group and normal control group. Six hours after a rabbit model of sepsis was established via cecal ligation and puncture (CLP) surgery, an automatic infusion pump with meropenem [(1 000/60)×3.27=54.5 mg·kg-1, converted from that of humans (1 g) to that of rabbits] was used to administer the drug to the animals for 0.5 h, while CRRT was started simultaneously with drug administration in the CRRT group. Microdialysis samples were collected from 4 target sites of each group once every 30 min for 480 min. The concentration of meropenem was determined using liquid chromatography-tandem mass spectrometry (LC-MS/MS) before a concentration-time curve was constructed. Pharmacokinetic parameters such as the peak concentration (Cmax), time to reach peak concentration (Tmax), area under the concentration-time curve (AUC), and elimination half-life (t1/2) were calculated using a non-atrioventricular model. Monte Carlo simulation (MCS) was performed at various minimum inhibitory concentrations (MICs) using pharmacokinetic parameters of meropenem to assess the probability of target attainment (PTA). The predefined PK/PD target was %fT>4MIC>40%, where the percentage of time that the free drug concentration [f] exceeded 4 times that of the MIC during a dosing interval was above 40% and Cmax /MIC exceeded 4. RESULTS  The results indicated no statistically significant differences between the PK parameters of skin tissue in the normal control group and sepsis group, whereas Cmax of other tissues was significantly lower in the sepsis group than in the normal control group (P<0.01). AUCplasma and AUCskin were significantly increased (P<0.01), while AUClung and AUCmuscle were significantly decreased (P<0.01) when the sepsis-CRRT group was compared with the sepsis group. With a target value of %fT>4MIC>40%, the plasma and skin tissues of the sepsis-CRRT group, the muscle tissues of the normal-CRRT group and the lung, muscle and skin tissues of the normal control group achieved a PTA of over 90% (MIC=1 mg·L-1). The skin tissues of the sepsis-CRRT group and the lung tissues of the normal control group achieved an efficacy target of more than 90% (MIC=2 mg·L-1). However, our results did not indicate that either AUC or Cmax was involved in the changes of PTA in the normal control group. For all tissues except skin tissues (MIC=4 mg·L-1), PTA decreased with Cmax in the sepsis group. The PTA of plasma and skin tissues increased with the AUC, while the PTA of lung (MIC=2, 4 mg·L-1) and muscle tissues (MIC=1, 2, 4 mg·L-1) decreased with the AUC in the sepsis-CRRT group. CONCLUSION  Sepsis has little effect on the distribution of meropenem in skin tissues. Sepsis may reduce the efficacy of meropenem in various tissues, and CRRT can improve the efficacy of plasma and skin tissues in sepsis. This method of collecting target samples with microdialysis probes is accurate and reliable, which can be used in therapeutic drug monitoring.
  • ORIGINAL ARTICLES
    Evaluation of antimicrobial activity of milk exosomes loaded with rifamycin S derivative
    YANG Zhanqun, LI Xiang, LIU Chenghua, ZHENG Mengzhu, FAN Shiyong, DONG Yuchao, WANG Zihao, LIN Jian, YANG Guang, CHEN Long
    2025, 39(3): 208. https://doi.org/10.3867/j.issn.1000-3002.2025.03.006
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    OBJECTIVE To design and synthesize rifamycin S derivatives and load them into milk exosomes to evaluate their in vitro antimicrobial activity. METHODS Rifamycin S derivatives were synthesized and characterized by mass spectrometry and NMR. Using the dilution assay method, the inhibitory activity of each rifamycin S derivatives molecule against Staphylococcus aureus and Pseudomonas aeruginosa was determined, and the IC50 was calculated. Derivatives molecules with excellent antimicrobial activity were selected and loaded into milk exosomes using the ultrasonication method, resulting in the preparation of milk exosome-loaded rifamycin S derivatives. The antimicrobial activity against Staphylococcus aureus was determined using the dilution assay method. The inhibitory effect of the exosome-loaded rifamycin S derivatives on Staphylococcus aureus residing within macrophages was detected using the plate colony counting method. RESULTS Three rifamycin S derivatives were successfully designed and synthesized, which demonstrated superior antimicrobial activity against Staphylococcus aureus (the parent compound′s antimicrobial activity is merely from 1/20 to 1/80 of that of the three rifamycin S derivatives) and Pseudomonas aeruginosa (the parent compound′s antimicrobial activity is only 1/14 and 1/9 of that of compound 1 and compound 3) compared to the parent compound. The loading of milk exosomes with the rifamycin S derivatives compound 3 was successfully achieved, with a loading efficiency of 10.9%. The antimicrobial activity of the compound after exosome loading was significantly enhanced against Staphylococcus aureus in vitro and against Staphylococcus aureus residing within macrophages (P<0.01). CONCLUSION The designed and synthesized derivatives of rifamycin S possess stronger antimicrobial activity, and their antibacterial efficacy against both extracellular and intracellular bacteria can be further enhanced after loading into exosomes.
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    Influence of peripheral alpha 1-adrenergic receptors on the toxicity of dexmedetomidine
    SHI Beibei, WANG Zhen, WANG Xiaoxuan, ZHOU Peilan, SU Ruibin
    2025, 39(3): 216. https://doi.org/10.3867/j.issn.1000-3002.2025.03.007
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    OBJECTIVE  To investigate α1-adrenergic receptors (α1-AR) distribution in mouse tissues and its function on dexmetomidine (DMED) induced toxic effects. METHODS  ① Real-time fluorescence quantitative PCR was used to detect the relative expression of α1A-AR, α1B-AR, α1D-AR, α2A-AR, α2B-AR and α2C-AR mRNAs in the heart, apical potion of heart, lungs, apical potion of lung, liver, kidneys, abdominal aorta, prefrontal cortex, hippocampus, striatum, brainstem, thalamus, olfactory bulb, and the rest of the brain tissues of the mouse. The relative expression of mRNA were analyzed. ② C57BL/6J mice were pretreated with α2 adrenergic receptor antagonist atipamezole ATI (0.005, 0.010, 0.020, 0.025, 0.040, 0.050 mg·kg-1, im), or α1-adrenoceptor antagonist prazosin (1 mg·kg-1, im) for 15 min, and then DMED (0.20 mg·kg-1, iv) was given to observe the rate of the loss of righting reflex and the immobilization time in mice. ③ C57BL/6J mice were treated with DMED (16.38, 20.48, 25.60, 32.00, 40.00, and 50.00 mg·kg-1, iv) to observe the lethality of the mice in 24 h. The dose-effect relationship curves of the lethality rate and the half lethal-dose (LD50) were detected. ATI (1, 2, 4, and 8 mg·kg-1, im) or prazosin (1 mg·kg-1, im) were pretreated 15 min followed by the administration of DMED (25.60 mg·kg-1, iv). The lethality of the mice were recorded for 24 h. HE staining to observe the lung tissue damage in the mice.  RESULTS  ① The mRNA expression levels of three α1-AR subtype were higher than those of α2-AR subtype. α2A-AR and α2C-AR were highly expressed in the central nervous system. α2B-AR was highly expressed in the brainstem and peripheral tissues. The mRNA expression levels of α1-AR subtypes were higher than those of α2-AR subtypes in heart, apical potion of heart or lung (P<0.05). ② ATI (0.005 to 0.05 mg·kg-1, im) dose dependently antagonized the loss of righting reflex and decreased the immobilization time induced by DMED (0.20 mg·kg-1, iv). In contrast, prazosin (1 mg·kg-1, im) had no effect on the loss of righting reflex induced by DMED (0.20 mg·kg-1, iv). ③ The LD50 of DMED in mice was 26.734 mg·kg-1 (iv) with a 95% CI of 23.606-30.000 mg·kg-1. DMED (25.6 mg·kg-1) was selected for subsequent toxicity. ATI (1, 2, 4, and 8 mg·kg-1, im) did not antagonize the lethality induced by DMED (25.6 mg·kg-1, iv). The high dose of ATI resulted in elevated death rate and accelerated mortality induced by DMED (25.6 mg·kg-1, iv) in the mice. However, prazosin (1 mg·kg-1, im) reduced the lethality of DMED (25.6 mg·kg-1, iv) (P<0.01). After administration of DMED (25.6 mg·kg-1), the mice lungs showed significant congestion. HE staining of lung tissues revealed obvious vascular hemorrhage, alveolar rupture, and erythrocyte spillage. Prazosin (1 mg·kg-1, im) effectively attenuated the tissue damage in the lungs, but ATI (1 mg·kg-1, im) aggravated the pulmonary hemorrhage. CONCLUSIONS  In cardiopulmonary tissues, the high expression levels of α1 adrenoceptor overactivation, might related with the lethality induced by DMED.
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  • REVIEWS
    Research progress in neuropsychiatric diseases therapy using vagus nerves
    NI Han, HE Dujuan, DUAN Jingyao, CHEN Aibing, ZHANG Liming
    2025, 39(3): 224. https://doi.org/10.3867/j.issn.1000-3002.2025.03.008
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    As the longest and most widely distributed pair of nerves in the brain, the vagus nerve is involved in the regulation of many systems and organs. Recent studies have found that the vagus nerve may be involved in the occurrence of a variety of neuropsychiatric diseases by regulating the release of neurotransmitters (such as norepinephrine, 5-hydroxytryptamine, gamma-aminobutyric acid and acetylcholine) and regulating the immune system and gut-brain axis. This article focuses on the regulatory mechanisms of the vagus nerve on neurotransmitters, immune system function, and the gut-brain axis, as well the therapeutic advances in vagus nerve stimulation for neurological and psychiatric diseases such as epilepsy, depression and anxiety disorders. 
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    Current immunotherapy for acral melanoma and research advances
    LIU Yujia, ZOU Zhengyun
    2025, 39(3): 233. https://doi.org/10.3867/j.issn.1000-3002.2025.03.009
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    Acral melanoma (AM) is a distinct and aggressive subtype of melanoma characterized by high metastatic potential and poor prognosis. The pathogenesis and therapeutic strategies for advanced AM differ significantly from those of other melanoma subtypes, yet AM has received relatively less attention. AM exhibits high heterogeneity and a low tumor mutation burden. Mutations in braf, nras, and the tert promoter occur at much lower frequencies in AM than in cutaneous melanoma, limiting the 
    effectiveness of treatments such as recombinant B-Raf proto oncogene serine/threonine protein kinase(BRAF) inhibitors. Additionally, reduced tumor immunogenicity due to low tumor-infiltrating lymphocyte levels contributes to the limited efficacy of immune checkpoint inhibitors, including anti-programmed death-1 and anti-cytotoxic T-lymphocyte-associated protein 4 therapies. Recent discoveries of novel therapeutic targets, such as receptor tyrosine kinases and cyclin-dependent kinases, along with emerging immune checkpoints, including V-domain immunoglobulin suppressor of T cell activation, adenosine A2A receptor, T cell immunoglobulin and ITIM domain, and T cell immunoglobulin and mucin-domain containing-3, offer new prospects for improving AM patient outcomes. Many AM treatments remain in the experimental stage, with research focusing on small-molecule targeted therapies, immune checkpoint inhibitors, and tumor microenvironment modulation. Combination strategies incorporating next-generation cell therapies, oncolytic virus therapies, and therapeutic vaccines are also gaining prominence. Notably, clinical trials of personalized mRNA cancer vaccines have been promising, while antibody-drug conjugate and radionuclide-conjugated therapies present additional opportunities for enhancing AM prognosis. This article summarizes the cellular immune characteristics, mutation profiles, and tumor microenvironment of AM, as well as the current therapeutic strategies and advancements in the hope of expanding clinical benefits for AM patients.