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  • REVIEWS
    GAO Pengxia, GONG Mengqiang, LI Zhi, MA Bo, CHEN Aibing, XU Hua, WANG Lili, XIE Jianwei
    Chinese Journal of Pharmacology and Toxicology. 2024, 38(9): 710. https://doi.org/10.3867/j.issn.1000-3002.2024.09.008
    Human beings are inevitably exposed to toxic substances as a result of influences of potential contamination factors in the environment, food and medicines, which poses a threat to human health. In order to effectively screen and prevent the exposure or intake of such substances, it is necessary to develop in vitro assays for the detection and toxicity evaluation of toxic substances. High content screening (HCS) has been recognized as an important tool for toxicity testing and risk assessment of compounds due to its high throughput and automation advantages, and has been widely used in in vitro toxicology research. In this review, we described the system components of HCS and its workflow in toxicity screening and toxicity evaluation by focusing on cases of their application in toxicity detection and evaluation studies, including the cytotoxicity, hepatotoxicity, nephrotoxicity, genotoxicity, neurotoxicity, cardiotoxicity, and developmental toxicity. In addition, the applications and developments of 
    machine learning in HCS were explored, especially to the advantages of supervised and unsupervised machine learning strategies for high throughput image screening and data analysis. Finally, the future applications of HCS in toxicity screening and evaluation are outlined, especially in terms of binding new models and gene editing technology.
  • REVIEWS
    XIE Zhen, YE Kang, KUANG Rong, LU Jingxian, CHEN Bilian
    Chinese Journal of Pharmacology and Toxicology. 2024, 38(8): 619. https://doi.org/10.3867/j.issn.1000-3002.2024.08.007
    Ganoderma lucidum is one of the widely-used traditional Chinese medicines. Ganoderma lucidum extract and Ganoderma spore powder are also widely used in foods, health care and cosmetics, and are highly favored by consumers. Ganoderic acid A is one of the main effective components of Ganoderma lucidum triterpenoids. In recent years, a large number of studies have proved that ganoderic acid A has anti-tumor, anti-inflammatory, hepatoprotection,hypolipidemic, renoprotective properties, and has therapeutic potential in psychiatric and neurological disorders., which has high medicinal value and good prospects for development. Based on review of domestic and foreign literatures in recent years, the new research progress in pharmacology of ganoderic acid A is summarized in this paper in order to provide references for its further development and clinical applications.
  • REVIEWS
    ZHAO Cuimei, WU Yajing, LI Yingran, LONG Xiuzhen, ZHOU Xun, ZHANG Wenyuan
    Chinese Journal of Pharmacology and Toxicology. 2024, 38(12): 952. https://doi.org/10.3867/j.issn.1000-3002.2024.12.007
    Metabolism-related diseases are chronic diseases caused by genetic and environmental factors. The symptoms include insulin resistance, abnormal blood glucose and lipid levels, and elevated blood pressure. This type of illness has become a major threat to human health, and there is an urgent need to find effective treatments. Advanced glycation end products (AGE) are a group of complex and heterogeneous compounds that result from reduced interactions between the carbonyl groups of  sugar and the free amino groups of proteins, lipids, and nucleic acids. Increasing evidence shows that AGE and its receptor (RAGE) are involved in the occurrence and development of such metabolism-related diseases as hypertension, diabetes, and atherosclerosis. AGE can have adverse effects on tissues through non-receptor and receptor-mediated mechanisms. In the receptor-mediated mechanism, AGE interacts with RAGE to increase the production of oxygen free radicals and activate NF-κB so that more pro-inflammatory cells are expressed and released, leading to cell damage. This article reviews the research progress in interventions with AGE and RAGE in the treatment of hypertension, diabetes, and atherosclerosis from a metabolic perspective in the hope of exploring the potential of AGE and RAGE as therapeutic targets for metabolism-related diseases.
  • Special Issue of New Approach Methodologies (NAMs)
    LI Min, LIN Jun, WU Weiliang, SUI Haixia, YANG Xingfen
    Chinese Journal of Pharmacology and Toxicology. 2024, 38(10): 796. https://doi.org/10.3867/j.issn.1000-3002.2024.10.10
    OBJECTIVE  To explore the applicablity of ′BlueScreen HC′(BSHC), a high throughput genotoxicity screening system based on human growth arrest and DNA damage inducible 45α(GADD45α) gene, in detecting the genotoxicity of migrants mixtures from food contact materials (FCM). METHODS  The 2000 bp sequence upstream of the open reading frame of human GADD45α gene was used as the promoter to construct the lentiviral plasmid pEZX-LvPG04, which was double labeled by purinamycin and Gausluciferase (Gluc), and the lentiviral plasmid was infected with human lymphoblastocyte TK6 to obtain a stable transmutation cell line TK6-Gluc.  Methyl methylate (MMS) at concentrations of 0, 1.56, 3.13, 6.25, 12.5, 25.0 and 50.0 mg·L-1 was selected as the genotoxin without liver S9, cyclophosphamide (CTX) 0, 0.78, 1.56, 3.13, 6.25, 12.5, 25.0 mg·L-1 was selected as the pre-genotoxin with liver S9, and dimethyl sulfoxide (DMSO) 0, 0.35, 0.69, 1.38, 2.75, 5.5 and 11.0 g·L-1 was selected as the non-genotoxin. The constructed BSHC was verified with the above known genetic positive and negative substance respectively. Polybutyleneadipate-co-terephthalate (MS/PBAT) was tested using 4% (V/V) acetic acid, and 10%, 20%, 50% and 95% (V/V) ethanol as food simulants at 40 ℃ for 24 hours to obtain 5 multi-component migrants of MS/PBAT that were obtained by using DMSO as a solvent. TK6-Gluc cells were treated with 5 multi-component migrants of MS/PBAT at concentrations of 0, 0.38, 0.76, 1.53, 3.05, 6.10 and 12.20 g·L-1 with or without liver S9. Cells were treated without liver S9 for 48 h. Cells treated with liver S9-mix were incubated for 3 h at a final concentration of 1% (V/V) liver S9 before being washed and re-suspended in fresh recovery media for another 45 h. After exposure, the cell viability was detected using the CCK-8 cell activity kit, and the Gluc Luminescence in the medium was detected with Secrete-PairTM Gaussia Luciferase Assay Kit. In addition, the mutagenicity on Salmonella typhimurium TA98 and TA100 was detected by micro-fluctuation Ames test with 5 multi-component migrants of MS/PBAT at concentrations of 3.05 and 12.20 g·L-1. The in vitro mammalian cell chromosome aberration test was performed on CHL cells with 5 multi-component migrants of MS/PBAT at concentrations of 3.05 and 12.20 g·L-1 to detect the chromosomal aberration. The results of genotoxicity were compared with those of BSHC. RESULTS  The lowest effect centration (LEC; <80% relative cell viability) and the coytotoxicity (<30% relative cell viability) was defined. A positive genotoxicity result threshold was determined at 1.8-fold relative induction. For the liver S9 protocol, the same process was followed, and the decision threshold derived was 1.5-fold relative Gluc induction. It is considered as genetic substance only when a positive genotoxicity result was reached and there was no cytotoxicity. Compared with the vehicle control group, no genotoxicity was observed at all concentration of DMSO by BSHC. MMS 12.5, 25.0 and 50.0 mg·L-1 produced genotoxicity without liver S9 while CTX 6.25, 12.5 and 25.0 mg·L-1 produced genotoxicity with liver S9. Significant cell growth inhibition was observed in 95% ethanol migrants of MS/PBAT at concentrations of 6.10 and 12.20 g·L-1, and in 50% ethanol migrants of MS/PBAT at a concentration of 12.20 g·L-1 without liver S9. No cytotoxicity with a relative cell viability below 30% was observed in any of the treatment groups, and no high expression of Gluc was observed. Therefore, none of the 5 multi-component migrants produced genotoxicity without liver S9. Significant cell growth inhibition was observed in 95% ethanol migrants of MS/PBAT at a concentration of 12.20 g·L-1, and in 4% acetic acid migrants of MS/PBAT at concentrations of 6.10 and 12.20 g·L-1 with liver S9. No cytotoxicity with a relative cell viability below 30% was observed in any of the treatment groups. No high expression of Gluc was observed. Therefore, none of the 5 multi-component migrants produced genotoxicity with liver S9. In the micro fluctuation Ames test, when 5 multi-component migrants of MS/PBAT were treated with concentrations of 3.05 and 12.20 g·L-1 on TA98 and TA100 strains, there was no significant difference in the number of mutagenic positive wells compared with DMSO control group with or without liver S9,  indicating that no mutagenic effect was produced.  When CHL cells were treated with 5 multi-component migrants of MS/PBAT at concentration of 3.05 and 12.20 g·L-1, compared with DMSO control group, there was no significant difference in chromosome aberration rate of CHL cells with or without liver S9. CONCLUSION  BSHC based on GADD45α gene has been established, which can be used for in vitro genotoxicity evaluation of migrants mixtures of FCM, but further exploration of its minimum effective concentrations is still needed, and more types of mixtures need to be applied for further validation.
  • ORIGINAL ARTICLES
    QIN Hongqian, WANG Xiayi, ZHANG Shu, LI Xiaochuan, XU Hui, YANG Xuechao, SUN Jianmin
    Chinese Journal of Pharmacology and Toxicology. 2024, 38(8): 604. https://doi.org/10.3867/j.issn.1000-3002.2024.08.005
    OBJECTIVE  To study the pharmacodynamics and pharmacokinetics of semaglutide (Sem) capsules in type 2 diabetic model rats. METHODS  Male SD rats were divided into the normal control group, type 2 diabetic model group and model+Sem capsules (0.839, 1.678 and 2.517 mg·kg-1) groups. A type 2 diabetic rat model was induced by high sugar and high fat diet feeding combined with ip given streptozotocin (STZ) injection. Seven days after modeling, the model+Sem capsules group was  ig given Sem capsules  at the corresponding dose in a fasting state, once a day, for 14 d. Body mass, fasting blood glucose (FBG), and glycosylated hemoglobin (HbA1c) levels were regularly measured in each group of rats. Plasma from rats in the model+Sem capsules 0.839, 1.678 and 2.517 mg·kg-1 groups at different time points was collected at the end of the continuous administration of Sem capsules, and the content of Sem in the plasma of rats was determined by liquid chromatography-tandem mass spectrometry. Concentration-time curves were plotted, and the main pharmacokinetic 
    parameters were fitted by the WinNonlin non-atrial model method. RESULTS  Compared with the model group, the body mass of rats in model+Sem capsules dosing groups decreased significantly after 7 and 14 d of Sem capsules intervention (P<0.05, P<0.01), so did FBG (P<0.01) and the HbA1c level (P<0.01). Meanwhile, FBG and HbA1c levels of rats in model+Sem capsules 1.678 and 2.517 mg·kg-1 groups were not significantly different from those of the normal control group after 14 d of Sem capsules intervention, suggesting that FBG and HbA1c levels were basically restored to normal. Pharmacokinetic results showed that the elimination half-life (t1/2) of Sem in plasma after ig administration of Sem capsules 0.839, 1.678, and 2.517 mg·kg-1 for 14 d in rats was 7.40±1.34, 7.48±0.33 and (8.23±0.90) h, respectively, the peak concentration (Cmax) was 18±9, 81±23 and (256±53) μg·L-1, time to peak (Tmax) was 0.06±0.13, 1.56±0.88, (1.50±1.00) h, respectively, the area under the curve (AUC0-t) was 158±76 μg·h·L-1, 858±310 and (3795±1539) μg·h·L-1, and the accumulation index was 1.12±0.05, 1.12±0.01 and 1.15±0.04, respectively. CONCLUSION  Sem capsules ig administrated can effectively reduce body mass, FBG and HbA1c levels in type 2 diabetic model rats, and lead to glucose reduction and by mass loss. After 14 d of continuous administration of Sem capsules, there is no accumulation of semaglutide in rats in the dose range of 0.839-2.517 mg·kg-1, and the exposure increases with the dose.
  • ORIGINAL ARTICLES
    LIAO Hanjing, LUO Yanggan, LU Zihan, LIU Zhenqing, HAO Doudou, HUANG Manjing, ZHU Zhixiang
    Chinese Journal of Pharmacology and Toxicology. 2024, 38(9): 661. https://doi.org/10.3867/j.issn.1000-3002.2024.09.003
    OBJECTIVE  To optimize hematopoietic stem cell transplantation therapy and provide support for drug research by investigating the dynamic process of hematopoietic and immune system reconstitution after bone marrow transplantation (BMT) in mice. METHODS  CD45.2+ C57BL/6 mice were used as recipient mice and randomly divided into the normal control group and transplantation group, with 30 mice in each. The transplantation group was irradiated by a lethal dose of cobalt-60 rays. Bone marrow cells were prepared from CD45.1+ C57BL/6 mice and transfused into recipient mice through the tail vein. Peripheral blood, spleens, lymph nodes, thymuses and bone marrow were collected at 1, 2, 4, 8 and 16 weeks after transplantation. Blood routine examination was performed with peripheral blood and total cell numbers in suspensions of other organs were counted by an automated cell counter. Cell classification analysis of white blood cells in peripheral blood, cell suspensions of other organs was performed by flow cytometry. RESULTS  Four weeks after BMT, the numbers of white blood cells and red blood cells in peripheral blood of recipient mice returned to the same level of or higher level than normal control (P<0.05). Although the number of platelets recovered significantly, it was still markedly lower than that of normal control until 16 weeks post BMT (P<0.05). In addition, the percentages of myeloid leukocytes and B cells in peripheral blood, spleens, lymph nodes, and bone marrow, as well as megakaryocytes and erythrocyte progenitor cells in bone marrow also returned to normal, and the majority of myeloid leukocytes and B cells were CD45.1+ cells from the donors. Eight weeks after BMT, T cells in peripheral blood, spleens, lymph nodes, thymuses, and bone marrow of recipient mice returned to normal, and CD45.1+ T cells were dominating. CONCLUSION  The hematopoietic and immune reconstitution of recipient mice is nearly completed eight weeks after BMT. However, the reconstruction speed of different kinds of cells and the reconstruction status of same kind of cell in different organs vary widely.
  • REVIEWS
    MA Yingkai, WANG Yongan, LUO Yuan
    Chinese Journal of Pharmacology and Toxicology. 2024, 38(11): 859. https://doi.org/10.3867/j.issn.1000-3002.2024.11.007
    The Hippo/YAP signaling pathway is an evolutionarily conserved protein kinase cascade that plays an important role in a variety of biological processes, such as cell proliferation and differentiation, organ growth and tissue regeneration. Fibrosis is a continuous and highly dynamic process characterized by excessive deposition of extracellular matrix, resulting in irreversible pathological changes that eventually lead to the failure of multiple tissues and organs. Targeted therapeutic strategies to ameliorate or reverse fibrosis are lacking. Studies have shown that the aberrantly activated Hippo/YAP signaling pathway may play a role in the development of fibrosis by regulating collagen deposition, fibroblast overproliferation, and epithelial cell differentiation, but the specific mechanism of action has not been fully elucidated. Targeting the Hippo/YAP signaling pathway involves two mechanisms: one is to target the upstream molecules of the Hippo/YAP signaling pathway, which is mainly achieved by inhibiting the activity of the core kinase or blocking the interaction with other molecules; the other is to target the downstream activities of YAP/TAZ and YAP/TAZ-TEAD in the Hippo/YAP signaling pathway. Studies have shown that the phosphorylation and subcellular localization of YAP/TAZ are significantly altered when tissue and organ damage occurs. This article is intended to review the current research on Hippo/YAP signaling pathway and its mediation of fibrosis in the lung, heart, liver, kidney, pancreas and skin in hopes of providing new ideas for studies on the pathogenesis of fibrosis and targeted therapeutic drugs.
  • ORIGINAL ARTICLES
    LI Jiajia, WANG Jiao, XIAO Wenyi, WEI Donghui, ZHANG Yongxiang, JIANG Ning, ZHOU Wenxia
    Chinese Journal of Pharmacology and Toxicology. 2024, 38(8): 561. https://doi.org/10.3867/j.issn.1000-3002.2024.08.001
    OBJECTIVE  To investigate the damage effect and mechanisms of cyclophosphamide (CTX) and its active metabolite derivative 4-hydroperoxycyclophosphamide (4-HC) to human neuroblastoma SH-SY5Y cells. METHODS  SH-SY5Y cells were treated with CTX [0 (cell control), 0.01, 0.1, 1, 5, 10, 20, 40 and 80 mmol·L-1] and 4-HC [0 (cell control), 0.01, 0.1, 1, 5, 10, 20, 40 and 80 μmol·L-1 ] for 48 h. Cell  confluence and morphology were observed by the IncuCyte ZOOM system. Cell viability was assessed by CCK-8 assay. Lactate dehydrogenase (LDH) release was measured by  LDH assay kit. SH-SY5Y cells were treated with CTX (0, 1, 5, 10 and 20 mmol·L-1) and 4-HC (0, 1, 5, 10 and 20 μmol·L-1) for 48 h before cell proliferation was analyzed by 5-ethynyl-2′-deoxyuridine (EdU) staining assay. Immunofluorescence was employed to assess the levels of the DNA double-strand break marker γ-H2AX and to evaluate changes in mitochondrial membrane potential. SH-SY5Y cells were treated with CTX (0, 1, 5 and 10 mmol·L-1) and 4-HC (0, 1, 5 and 10 μmol·L-1) for 48 h, and the alterations in glycolysis and oxidative phosphorylation levels were analyzed using the Seahorse XFe96 Analyzer. RESULTS  Compared with the cell control group, cell confluence and cell viability were significantly reduced in the CTX and 4-HC groups (P<0.01), and the half-maximal inhibitory concentrations (IC50) for CTX and 4-HC were 4.44 mmol·L-1 and 4.78 μmol·L-1, respectively. The release rate of LDH was significantly increased while the percentage of EdU+ cells was significantly reduced in the CTX and 4-HC groups (P<0.01). The percentage of γ-H2AX+ cells was significantly increased and mitochondrial membrane potential significantly decreased in the CTX and 4-HC group (P<0.05). Treatment with CTX and 4-HC resulted in reduced levels of maximum glycolytic capacity, glycolytic reserve, maximal respiration, and ATP production (P<0.05). CONCLUSION  CTX and 4-HC exert significant cytotoxic effects on SH-SY5Y cells by disrupting cell membrane structure, impeding cell proliferation, and reducing cell viability. The mechanisms underlying these effects may involve intracellular DNA damage, disturbance of energy metabolism and mitochondrial dysfunction.
  • Special Issue of New Approach Methodologies (NAMs)
    FENG Chiyuan, SHOU Yingqing, JIN Yuan, YU Dianke
    Chinese Journal of Pharmacology and Toxicology. 2024, 38(10): 773. https://doi.org/10.3867/j.issn.1000-3002.2024.10.007
    With the emergence of high-throughput technology and massive toxicology data, toxicology research has entered the era of big data. How to efficiently integrate existingtoxicological data, clarify the toxic effects of chemicals, and use these patterns to providenew information, in order to achieve efficient prediction of the toxicity of new chemicalsubstances, is one of the cutting-edge issues in toxicology. In view of the high cost, low throughput and difficulty in revealing the mechanism information of traditional chemical toxicity testing methods, high throughput prediction models are urgently needed. Machine learning methods have been applied to toxicity testing, such as supervised learning models, unsupervised learning models, deep learning models, reinforcement learning models, and transfer learning models. Chemical characteristic data commonly used in machine learning models include chemical structure data, text data, toxicological genome data and image data. There is huge potential for applying machine learning to toxicity testing and machine learning methods have made some progress. However, current research focuses on the processing of data and development of  models, which has failed to produce a widely used and accepted method. In addition, the prediction accuracy of machine learning models is not only dependent on algorithms, but also affected by data quality, and the mutual promotion and development of algorithms and data quality remains a big challenge. In short, data 
    processing and model construction in the field of toxicology require interdisciplinary cooperation and technological innovation. With the increasing perfection of toxicology databases and the continuous optimization of various model algorithms, the toxicity prediction of new chemicals based on machine learning models will become increasingly efficient and accurate, playing an important role in ensuring human health and environmental safety.
  • REVIEWS
    LI Yuehan, HAN Lu, ZHOU Wenxia
    Chinese Journal of Pharmacology and Toxicology. 2024, 38(8): 610. https://doi.org/10.3867/j.issn.1000-3002.2024.08.006
    The relationship between glycolysis and viral infectious diseases is close, and the interaction between viral and host glycolysis is a common mechanism found in a wide range of viruses. Therefore, the regulation of glycolysis may be an important antiviral strategy. The coronavirus diseases 2019 pandemic has brought about a tremendous disaster to humanity, compelling us to seek effective solutions from various perspectives. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection can induce an increase in host glycolysis, the level of which plays an important role in virus replication and infection, associated with the progression of the disease and a variety of clinical symptoms and complications. The study on the interaction between host glycolysis and SARS-CoV-2 infection can shed light on the pathogenic mechanism of SARS-CoV-2 and promote the research on related drugs. This article reviews the interactions between SARS-CoV-2 infection and host glycolysis in the hopes of providing a new perspective to understand the relationships between viral infections and disease in terms of metabolic regulation and formulate countermeasures.
  • Special Issue of New Approach Methodologies (NAMs)
    PENG Hui, ZONG Youjia, PENG Shuangqing, GUO Jiabin
    Chinese Journal of Pharmacology and Toxicology. 2024, 38(10): 742. https://doi.org/10.3867/j.issn.1000-3002.2024.10.003
    Integrated Approaches to Testing and Assessment (IATA) is a toxicological assessment decision-making method that integrates existing information from various sources, including physical and chemical properties, animal testing, and non-animal testing. Through the evaluation and analysis of a series of iterative strategies, it ultimately obtains risk assessment conclusions, thereby providing a basis for risk management decisions regarding chemical substances. The use of IATA is becoming increasingly prevalent in such areas as ocular irritation and genotoxicity. This paper introduces the conceptual connotation of IATA, sorts out the framework elements and sequential processes, explains the commonly used framework construction methods, shares cases of application in various exposure scenarios, and finally envisions future research directions in order to provide better methodological support for the risk assessment of chemical substances.
  • Contents
    Chinese Journal of Pharmacology and Toxicology. 2025, 39(3): 0.
  • REVIEWS
    LIU He, YUE Liang, WU Chengjun, TAN Yingxia
    Chinese Journal of Pharmacology and Toxicology. 2024, 38(8): 633. https://doi.org/10.3867/j.issn.1000-3002.2024.08.008
    Kidney organoids are induced and differentiated from human pluripotent stem cells (PSCs) or adult stem cells (ASCs) derived from tissue sources, primarily composed of nephron structures. However, due to the absence of a supporting vascular network, kidney organoids often exhibit immature tissue structures and limited growth. Therefore, vascularization in kidney organoids remains a pressing challenge in this field. Currently, the methods such as transplantation into immunodeficient animals, alterations in induced differentiation protocols, utilization of microfluidic chips, and manipulation of extracellular matrix and oxygen concentrations may facilitate vascularization of kidney organoids, which  provides a new perspective for the scientific study and clinical application of kidney organoids.
  • Special Issue of New Approach Methodologies (NAMs)
    XU Feifei, ZHAO Xiaohan, ZHOU Meng, WAN Siyu, XIAO Xiaoxuan, SONG Jia, YANG Xingfen
    Chinese Journal of Pharmacology and Toxicology. 2024, 38(10): 723. https://doi.org/10.3867/j.issn.1000-3002.2024.10.001
    With the rapid development of industry and economy, the emergence of a large number of chemicals has made of risk management more difficult. Traditional risk assessment relies on animal experiments for toxicity testing. However, animal experiments are time-consuming, costly, and unable to meet the practical needs of risk assessment. The increasing maturity of toxicity testing alternative technologies signifies the possibility of rapid, sensitive, and accurate identification of chemical toxicity. This article focuses on the research and applications of alternative toxicity testing by reviewing the background, developments, and current research at home and abroad. It also discusses the progress in alternative testing methods in such areas as cosmetics and food safety risk assessment and explores the problems with the development of alternative testing technologies and risk assessment in China. This review aims to provide a reference for the system construction of cosmetics health risk assessment in China.
  • REVIEWS
    JIA Jingyi, ZHANG Zhibo, WEN Ruiting, ZENG Linggao, WANG Zhongrui, LIANG Jianhui
    Chinese Journal of Pharmacology and Toxicology. 2024, 38(9): 681. https://doi.org/10.3867/j.issn.1000-3002.2024.09.005
    Animal models are powerful tools for studying the mechanism of depressive disorders and screening antidepressants, but so far there is no model which can stimulate the clinical status of patients ideally. Here, we briefly introduced the research advances in classic animal models of depressive disorders, and focused on stress-related animal models, especially those induced by physical and social psychological stressors. The tests for evaluating animal depression behavior were reviewed. In this article, the strengths and weaknesses of each model were analyzed, and the precautions in its application were recommended. Finally, given the high heterogeneity of depressive disorders, this article elaborated on the research progress in models for subtypes of depressive disorders, such as treatment resistant depression, bipolar disorder, peripartum depression, and premenstrual syndrome.
  • REVIEWS
    ZOU Jianping, YAO Xinxin, WEN Chun, ZHU Shan, ZHANG Shihui, ZHANG Xiaojing
    Chinese Journal of Pharmacology and Toxicology. 2025, 39(1): 58. https://doi.org/10.3867/j.issn.1000-3002.2025.01.006
    Antibody-based therapies are one of the crucial tumor-targeted therapies, enabling precise elimination of tumor cells by specifically binding to antigens on the tumor cell surface. However, their wide applications in solid tumor therapy are often limited by on-target toxicity. Recent advancements in antibody engineering have led to the development of novel tumor-targeted masking antibodies, which are specifically designed to address these limitations. Masking antibodies typically consist of an antibody domain, a masking domain and a linker. These antibodies are characterized by selective activation and other functional properties. Currently, various masking antibody technologies with distinct characteristics have been developed and have demonstrated favorable safety profiles in animal studies. This review summarizes the structure and characteristics of tumor-targeted masking antibodies outlines common masking technologies and their drug development in order to offer new lines of thought  for the design and development of next-generation tumor-targeted therapeutics.
  • ORIGINAL ARTICLES
    LI Hanwei, ZHAO Hui, SONG Yagang, ZHU Pinsheng, MIAO Mingsan, QIAO Jingyi
    Chinese Journal of Pharmacology and Toxicology. 2025, 39(3): 191. https://doi.org/10.3867/j.issn.1000-3002.2025.03.004
    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.
  • Special Issue of New Approach Methodologies (NAMs)
    YANG Hui, SHI Miaoying, YANG Daoyuan, SUI Haixia, YU Zhou, JIA Xudong
    Chinese Journal of Pharmacology and Toxicology. 2024, 38(10): 734. https://doi.org/10.3867/j.issn.1000-3002.2024.10.002
    Food toxicology plays a crucial role in supporting scientific and technical aspects of food safety risk assessment. However, traditional methods relying on animal testing are becoming increasingly inadequate for identifying and evaluating emerging foods and unknown risks. There is a strong push worldwide towards the development of new approach methodologies (NAMs) based on non-animal testing methods. Policies and regulations related to NAMs are being standardized gradually in the European Union, the United States, and China. Some progress has also been made in applying these methodologies in food toxicology research in China. For instance, within the "Food Toxicology Program" at the National Center for Food Safety Risk Assessment, high-content and high-throughput in vitro hazard identification models employing model organisms like human macrophages, hepatocytes, adipocytes, embryonic stem cells, and zebrafish, as well as Toxicological Thresholds of Concern and quantitative in vitro to in vivo extrapolation based on physiologically-based toxicokinetic models have been established and applied. Nonetheless, new toxicological hazard identification technologies still face challenges such as inadequate elucidation of toxic mechanisms, insufficient collaborative research efforts, and inefficient translation of these findings into practical applications.
  • INSTRUCTIONS FOR AUTHORS
    Chinese Journal of Pharmacology and Toxicology. 2025, 39(1): 79.
  • REVIEWS
    CHANG Yongchun, SHENG Li
    Chinese Journal of Pharmacology and Toxicology. 2024, 38(11): 872. https://doi.org/10.3867/j.issn.1000-3002.2024.11.008
    Special populations such as the elderly, pregnant women, children, and patients with impaired liver and kidney function have different physiological characteristics and drug processes from other patients. As a result during medication, these populations are vulnerable to drug-drug interactions in case of combined medications, which makes it more difficult of optimize drug treatment and develop new drugs. The physiologically based pharmacokinetic (PBPK) model can predict drug-drug interaction in special populations by altering metabolism-related physiological parameters such as metabolic 
    enzymes, transporter activity and clearance. Gene polymorphisms, intestinal metabolism and other 
    factors also affect the accuracy of model results. This review aims to to optimize clinical regimens for special populations and provide references for new drug development.
  • REVIEWS
    JIANG Shuyuan, ZHANG Changhao, WANG Taoran
    Chinese Journal of Pharmacology and Toxicology. 2025, 39(1): 69. https://doi.org/10.3867/j.issn.1000-3002.2025.01.007
    As antibiotic resistance becomes increasingly concerning, antimicrobial peptides, as a new type of antibiotic alternative, have attracted more attention. However, the low enzymatic stability of antimicrobial peptides severely limits their clinical applications. To address this issue, researchers have developed various structural modification strategies, including the introduction of unnatural amino acids, peptide chain cyclization and chemical group modification. This article reviews the basic principles and cases of the above modification strategies analyzes the advantages and disadvantages of different modification strategies and recommends ways these strategies can be optimized. In addition, this article predicts the developments of and potential challenges to strategies for enhancing enzymatic stability of antimicrobial peptides in the hope of providing references for subsequent research and development of antimicrobial peptides.
  • ORIGINAL ARTICLES
    GUAN Yaqi, CUI Kai, WEI Wenyi, TIAN Yajuan, ZHANG Zhao, CHU Shifeng, LI Qinqing, GUO Jilong, ZHANG Li, HE Wenbin
    Chinese Journal of Pharmacology and Toxicology. 2024, 38(12): 897. https://doi.org/10.3867/j.issn.1000-3002.2024.12.002
    OBJECTIVE  To investigate the mechanism by which salvianolic acid A (Sal A) reduces the inflammatory response and oxidative stress of BV2 cells injured by oxygen and glucose deprivation/reperfusion (OGD/R). METHODS  An OGD/R injury model of BV2 cells was established with sugar free Earle solution containing Na2S2O4 10 mmol·L-1. Na2S2O4 sugar free Earle solution was added and cultured in an incubator (37 ℃, 5%CO2) for 1.5 h (oxygen glucose deprivation) before a normal medium was used for 24 h (reperfusion). Then, the cells were divided into the cell control group, OGD/R group, OGD/R+Sal A 1, 5 and 10 μmol·L-1 group, OGD/R+ML385 group, OGD/R+ML385+Sal A 1, 5 and 10 μmol·L-1 group and OGD/R+edaravone (Eda, 50 μmol·L-1) group. After twenty-four hours of culture, the cell survival rate was measured by CCK8 kit. The contents of Interleukin-1β (IL-1β), IL-6, tumor necrosis factor-α (TNF-α), IL-10, IL-4 and transforming growth factor-β (TGF-β) in the cell supernatant were detected by ELISA. Reactive oxygen species (ROS) in cells was detected using the chemical fluorescence method. The contents of malondialdehyde (MDA) and the activities of superoxide dismutase (SOD), glutathione peroxidase (GSH-PX) and chloramphenicol acetyltransferase (CAT) in cells were determined with the colorimetric method. Protein expressions of Kelch like ECH-associated protein 1 (Keap1), nuclear factor erythroid-2 related factor 2 (Nrf2),Heme oxygenase-1 (HO-1), NADPH: quinone oxidoreductase-1 (NQO1) and p-nuclear factor kappa-B p65 (p-NF-κB p65) were detected by Western blotting. RESULTS  ① Compared with the cell control group, the cell survival rate of the OGD/R group was significantly decreased (P<0.01). Compared with the OGD/R group, the survival rates of OGD/R+Sal A 1, 5 and 10 μmol·L-1 groups were significantly increased (P<0.05, P<0.01). ② Compared with the cell control group, the contents of IL-1β, IL-6 and TNF-α were significantly increased, the contents of IL-10, IL-4 and TGF-β were significantly decreased, the contents of ROS and MDA were significantly increased, and the activities of SOD, CAT and GSH-Px were significantly decreased in the OGD/R group (P<0.01). Compared with the OGD/R group, the content of IL-6 was significantly decreased, the contents of IL-10, IL-4 and TGF-β were significantly increased, the contents of ROS and MDA were significantly decreased, and the activities of SOD, CAT and GSH-Px were significantly increased in OGD/R+Sal A 1, 5 and 10 μmol·L-1 and OGD/R+Eda groups (P<0.05, P<0.01). ③ Compared with the cell control group, the protein expression of p-NF-κB P65 in the OGD/R group was significantly increased (P<0.01). Compared with the OGD/R group, the protein expressions of Keap1 and cytoplasmic Nrf2 were significantly decreased, the expressions of nuclear Nrf2, HO-1 and NQO1 proteins were significantly increased, and the expression of p-NF-κB p65 protein was significantly decreased in OGD/R+Sal A 5 and 10 μmol·L-1 and OGD/R+Eda groups (P<0.05, P<0.01). In OGD/R+ML385, OGD/R+ML385+Sal A 1, 5 and 10 μmol·L-1 groups, the protein expression of Keap1 was significantly increased, the protein expressions of cytoplasmic Nrf2, nuclear Nrf2, HO-1 and NQO1 protein were significantly decreased, and the protein expression of p-NF-κB P65 was significantly increased (P<0.01). CONCLUSION  Sal A reduces the inflammatory response and oxidative stress of OGD/R injured BV2 cells possibly by activating the Keap1/Nrf2 pathway and inhibiting the NF-κB pathway.
  • ORIGINAL ARTICLES
    GU Yongfang, Li Jincao, XUE Rui, LI Shuo, ZHANG Yang, FANG Qiongyin, WANG Yanxin, ZHANG Youzhi
    Chinese Journal of Pharmacology and Toxicology. 2025, 39(5): 321. https://doi.org/10.3867/j.issn.1000-3002.2025.08327
    OBJECTIVE  To investigate the role of Bai Ling Long Zao An Shen formula (BLLZ) in sleep improvement in an environmental stress-induced insomnia rat model and explore its underlying mechanisms. METHODS  (1) Component analysis: the chemical constituents of the BLLZ extract were analyzed using ultra-high performance liquid chromatography-mass spectrometry (UPLC-MS). (2) Evaluation of the sedative and hypnotic effect: ① Mice: 50 ICR mice were randomly divided into normal control group, BLLZ-L group (5, 10 and 20 g·kg-1) and diazepam group (DZP, 3 mg·kg-1). After five days of intragastric administration, pentobarbital sodium-induced righting reflex and locomotor activity tests were performed. ② Rats: 8 SD rats were implanted with electrodes and allowed to recover for seven days before baseline EEG data was collected over 24 h. A crossover design (7 d washout period) was employed,  with rats randomly assigned to the DZP (3 mg·kg-1) and BLLZ (20 g·kg-1) group. After five days of treatment, 24 h EEG recordings were obtained. (3) Insomnia model and interventions: ① 8 SD rats were allowed to recover for seven days post-surgery, followed by 6 h (14:00-20:00) baseline EEG recording. A 3×3 crossover design was used to assign rats to model (environmental stress-induced insomnia), model+DZP, or model+BLLZ groups. After five days of treatment, insomnia was induced by frequent cage changes (14:00, 16:00 and 18:00), and EEG changes were monitored. (4) Mechanistic study: 32 SD rats were randomly divided into the normal control group, model group, and model+DZP group. After five days of treatment, hypothalamic tissues were collected for biochemical analysis. γ-aminobutyric acid (GABA), glutamate (Glu), and dopamine (DA) levels were measured 
    using biochemical kits while γ aminobutyric acid receptor subunit alpha-1 (GABAA1), core clock proteins period circadian regulator 2 (PER2) and circadian locomotor output cycles (CLOCK) protein expressions were assessed by Western blotting. RESULTS  (1) Compared with the normal control group, the sleep latency of BLLZ 10 and 20 g·kg-1 and DZP groups was significantly shortened, and the locomotor activity of BLLZ 20 g·kg-1 and DZP groups was significantly reduced; BLLZ 20 g·kg-1 significantly increased the total sleep time, slow-wave sleep time, and average duration of sleep in normal rats, and significantly reduced the wakefulness time. (2) The total sleep time and slow-wave sleep time of the model group significantly decreased and the wakefulness time significantly increased compared with baseline. (3) Compared with the model group, the total sleep time and slow-wave sleep time of the model+BLLZ group and the model+DZP group were significantly increased, and the wakefulness time significantly shortened. (4) Compared with the normal control group, the Glu/GABA ratio, DA content and CLOCK protein expression were significantly increased and GABAA1 and PER2 protein expression were significantly decreased in the model group; compared with the model group, the Glu/GABA ratio, DA content and CLOCK protein expression were significantly decreased, and the expression of GABAA1 and PER2 were significantly increased in the model+BLLLZ group and the model+DZP group. CONCLUSION  BLLZ has sedative and hypnotic effects. It can prolong the total slow-wave sleep time by increasing the average duration of slow-wave sleep episodes, thereby increasing the total sleep time and improving environmental stress-induced insomnia. The mechanism may be related to the downregulation of the Glu/GABA ratio and DA levels as well as the enhancement of GABAA1 
    expressions and the regulation of hypothalamic core clock protein expressions.
  • Special Issue of New Approach Methodologies (NAMs)
    LING Min, BIAN Qian
    Chinese Journal of Pharmacology and Toxicology. 2024, 38(10): 787. https://doi.org/10.3867/j.issn.1000-3002.2024.10.009
    The quality of toxicological data is critical to toxicity assessment and risk prediction. Integrating multiple streams of evidence and enhancing the quality of toxicological data are indispensable for more efficient and precise health risk assessment. There are several commonly used toxicology data quality evaluation systems abroad, which include Klimisch rating system, ToxRTool evaluation tool, the SciRAP evaluation tool and the integrated risk information system tool. The TRAM reliability evaluation tool is developed in China for toxicology data in food safety risk assessment.  These evaluation tools have different backgrounds and applicability of evaluation standards. Each evaluation system also has its advantages and disadvantages.
  • ORIGINAL ARTICLES
    SUN Chu, CAO Danni, SONG Rui, LI Jin
    Chinese Journal of Pharmacology and Toxicology. 2025, 39(3): 161. https://doi.org/10.3867/j.issn.1000-3002.2025.03.001
    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.
  • REVIEWS
    WANG Mengran, ZHUANG Xiaomei
    Chinese Journal of Pharmacology and Toxicology. 2025, 39(2): 138. https://doi.org/10.3867/j.issn.1000-3002.2025.02.007
    Sleep disorders are becoming a social problem that poses a danger to human health and an obstacle to economic development. As an endogenous hormone, melatonin plays an important role in regulating circadian rhythm. Research has shown that exogenous melatonin holds promising prospects in the treatment of insomnia disorders and thus merits in-depth exploration and development. Given the close relationship between pharmacokinetic properties and drug efficacy as well as toxicity, this paper reviews the quantitative analysis methods for melatonin and its major metabolites, especially the  pretreatment methods for biological samples and the related LC-MS/MS analysis methods. Studies related to the absorption, distribution, metabolism, excretion and drug-drug interactions of melatonin both in vivo and in vitro, as well as the level and species differences of endogenous melatonin are also outlined. Meanwhile, the druggability of melatonin and corresponding solutions are explored in the hope of providing data for the development of exogenous melatonin into novel sleep-regulating drugs.
  • REVIEWS
    DONG Huisheng, XING Haoyu, GAO Qianlong, PAN Qifei, MA Qian, LI Ying, SUN Jiefang
    Chinese Journal of Pharmacology and Toxicology. 2024, 38(9): 701. https://doi.org/10.3867/j.issn.1000-3002.2024.09.007
    Over the past 30 years, nano-drug delivery systems (NDDS) have become a promising field of drug research. However, a poor knowledge of the in vivo process of NDDS, the limited methods of pharmacokinetic correlation, and the inability to effectively provide strong support for the construction of upstream drug as well as the evaluation of downstream pharmacology and toxicology have become the technical bottleneck for their clinical transformation. Lipid nanodrug (LND) is the most successful NDDS for industrial transformation with great biocompatibility. Taking LND as an example, this paper reviewed the delivery process and influencing factors in vivo, and summarized the regulatory mechanism of biological environments on drug release in vivo. Based on advanced spectroscopy and mass spectrometry techniques, the spatial and temporal distribution of the dynamic carrier particle/depolymerized molecule ratio and dynamic free/encapsulated drug ratio of LND in biological matrix were analyzed. Finally, the existing problems and future developments in this field were summarized to provide references for the analysis of NDDS in vivo, and stimulate readers' interest in nanomedical research and development. 
  • ORIGINAL ARTICLES
    GAO Zhenna, YOU Xinyue, LIU Weiying, WU Jiaying, XI Jing, CAO Yiyi, ZHANG Xiaohong, ZHANG Xinyu, LUAN Yang
    Chinese Journal of Pharmacology and Toxicology. 2024, 38(9): 641. https://doi.org/10.3867/j.issn.1000-3002.2024.09.001
    OBJECTIVE  To investigate whether aldo-keto reductases (AKRs) can act as a nitroreductase (NR) and bioactivate aristolochic acid Ⅰ (AA-Ⅰ) to produce AA-Ⅰ-DNA adducts. METHODS  ① Human-induced hepatocytes (hiHeps) and human bladder RT4 cells were used as tool cells and treated with AA-Ⅰ 0, 0.5, 1.0 and 2 μmol·L-1 for 24 h. Cell viability was detected using the CCK-8 method, and the half maximal inhibition concentration (IC50) was calculated using the CCK-8 method and the level of DNA adduct production was calculated. ② hiHeps and RT4 cells were treated with AKR inhibitor luteotin (0, 5, 10 and 25 μmol·L-1)+AA-Ⅰ 0.2 and 1.0 μmol·L-1 for 24 h, respectively, and the levels of DNA adducts were detected by a liquid chromatography-tandem mass spectrometer (LC-MS/MS). ③ hiHeps cells were incubated with 80 nmol·L-1 small interfering RNAs (si-AKRs) for 48 h and treated with AA-Ⅰ1.0 μmol·L-1 for 24 h. Real-time qualitative PCR (RT-qPCR) method was used to detect the mRNA expression of AKRs gene and LC-MS/MS technology was used to investigate the effect of specific AKR gene knockdown on DNA adduct levels. ④ 500 nmol·L-1 human AKR recombinant proteins AKR1A1 and AA-Ⅰ were incubated in vitro under anaerobic conditions and the formation of AA-Ⅰ-DNA adducts was detected. RESULTS  ① The IC50 of AA-Ⅰ to hiHeps and RT4 cells was 1.9 and 0.42 μmol·L-1, respectively. The level of DNA adduct production of the two cell lines was significantly different (P<0.01). ② Luteolin≥5 μmol·L-1 significantly inhibited the production of AA-Ⅰ-DNA adducts in both cells (P<0.05), and there was a concentration-dependent effect in hiHeps cells (P<0.01, R=0.84). ③ In the AKR family, the knockdown of AKR1A1 gene up to 80% inhibited the generation of AA-Ⅰ-DNA adducts by 30%-40%. ④ The AA-Ⅰ-DNA adducts were detected in the incubation of recombinant protein AKR1A1 and AA-Ⅰ under anaerobic conditions in vitro, approximately 1 adduct per 107 nucleotides. CONCLUSION  AKR1A1 is involved in AA-Ⅰ bioactivation, providing a reference for elucidation of the carcinogenic mechanism of AA-Ⅰ.
  • ORIGINAL ARTICLES
    LIANG Jiahong, GONG Jiamin, DU Zuo
    Chinese Journal of Pharmacology and Toxicology. 2024, 38(9): 652. https://doi.org/10.3867/j.issn.1000-3002.2024.09.002
    OBJECTIVE  The inhibitory effect of active ingredients of Tripterygium wilfordii Hook. F. (TWHF) (celastrol, triptolide, triptonide, wilforlide A, wilforgine and wilforine) on human carboxylesterase 1 (CES1) and CES2 was detected to investigate the herb-drug interactions (HDIs) of TWHF. METHODS  Human liver microsomes catalysed hydrolysis of 2-(2-benzoyl-3-methoxyphenyl) benzothiazole (BMBT) and fluorescein diacetate (FD) were used as the probe reaction to phenotype the activity of CES1 and CES2, respectively. The residual activities of CES1 and CES2 were detected by ultra-high performance liquid chromatography (UPLC) after intervention with celastrol, triptolide, triptonide, wilforlide A, wilforgine and wilforine (100 μmol·L-1). Kinetics analysis, involving half inhibitory concentration (IC50), inhibition type and kinetic parameter (Ki), and in vitro-in vivo extrapolation (IVIVE), was carried out to predict the HDIs between these compounds and CES-metabolizing drugs. Molecular docking was performed to analyze the ligand-enzyme interaction. RESULTS  Out of the six main constituents of TWHF, only celastrol exhibited strong inhibition towards both CES1 and CES2, with the inhibitory rates of 97.45% (P<0.05) and 95.62% (P<0.05) , respectively. The IC50 was 9.95 and 4.02 mol·L-1, respectively, and the types of inhibition were all non-competitive inhibition. Based on the kinetics analysis, the Ki  values were calculated to be 5.10 and 10.55 μmol·L-1 for the inhibition of celastrol on CES1 and CES2, respectively. IVIVE indicated that celastrol might disturb the metabolic hydrolysis of clinical drugs in vivo by inhibiting CES1. Molecular docking results showed that hydrogen bonds and hydrophobic contacts contributed to the interaction of celastrol and CESs. CONCLUSION  The inhibitory effect of celastrol on CES1 and CES2 might cause HDIs with clinical drugs hydrolysed by CESs.
  • FRONTIER VIEWS
    LI Chen, HASEN Bilige, WANG Yun
    Chinese Journal of Pharmacology and Toxicology. 2025, 39(1): 1. https://doi.org/10.3867/j.issn.1000-3002.2025.01.001
    Peptide nanomedicines have been rapidly developed in the field of tumor treatment and the discovery of new drugs due to their strong stability, precise targeting and high bioavailability. The administration methods of peptide nanomedicines include intravenous injection, oral administration, respiratory administration and transdermal administration, among which intravenous administration is the most commonly used. Once inside the body, peptide nanomedicines can be transported everywhere via the blood circulation, accumulating in large quantities at the target site. Effective drug tracking analysis methods can help to obtain accurate pharmacokinetic data, while a comprehensive understanding of the in vivo distribution and pharmacokinetic characteristics of peptide nanomedicines can contribute to the development of new drugs and promote the progress of cancer therapy. This paper reviews the advantages and disadvantages of analytical methods for peptide nanomedicines and the research progress in their metabolism and transport in order to provide references for subsequent research on peptide nanomedicines.
  • ORIGINAL ARTICLES
    YUN Wenxin, HE Zhen, XU Fanxing, LI Fei, WU Ning
    Chinese Journal of Pharmacology and Toxicology. 2024, 38(8): 575. https://doi.org/10.3867/j.issn.1000-3002.2024.08.002
    OBJECTIVE  To investigate the transcriptomal charactersistics of the striatum in the chronic social defeat stress (CSDS) model mice by using spatial transcriptome analysis and to address the underlying mechanism of the striatum in regulating depressive states. METHODS  The CSDS paradigm was employed to establish a depression-like mouse model. The depressive indicators of behavioral despair, anhedonia, and social disorders were assessed through a battery of tests, including the tail suspension test, forced swim test, sucrose preference test, and social interaction experiments. The control mice and the mice exhibiting CSDS-sensitive depression-like behaviors were selected for spatial transcriptome sequencing of the striatal region. This sequencing aimed to identify highly expressed genes, followed by KEGG and GO enrichment analyses using the DAVID database. RESULTS  The CSDS mouse model effectively induced behavioral despair, anhedonia and social avoidance (P<0.05, P<0.01). Spatial transcriptome analysis revealed 193 differentially expressed genes in the striatum of normal mice. KEGG and GO analyses indicated that these genes were primarily associated with striatal development, locomotor behaviors, and drug addiction. They were strongly implicated in signaling pathways such as cyclic adenosine monophosphate, cyclic guanosine monophosphate-protein kinase G, calcium signaling, Ras-related protein 1, and mitogen-activated protein kinase, and synaptic linked to GABAergic and dopaminergic neurons. In contrast, CSDS modeling mice led to the identification of 298 differentially expressed genes in the striatum compared with the normal control mice. These genes were significantly enriched in pathways related to neurodegenerative diseases, including Huntington disease, Alzheimer disease, and Parkinson disease. CONCLUSION  Depressive states induced by CSDS are associated with the pathological processes underlying neurodegenerative diseases in the striatum.
  • REVIEWS
    WANG Yuanying, YE Qiao
    Chinese Journal of Pharmacology and Toxicology. 2025, 39(2): 146. https://doi.org/10.3867/j.issn.1000-3002.2025.02.008
    Along with more research into the mechanisms of pulmonary fibrosis, anti-pulmonary fibrosis drugs under development are becoming diversified. Over the past decade, multiple phase Ⅱ/Ⅲ clinical trials have been terminated due to insufficient efficacy, with seven single-target monoclonal antibody drugs failing to meet expectations. In contrast, multi-target drugs such as nintedanib and pirfenidone have been successfully marketed, demonstrating favorable clinical outcomes. However, drugs 
    directly targeting transforming growth factor-β have raised safety concerns. Ongoing phase Ⅲ candidates, such as lysophosphatidic acid receptor 1 antagonists and phosphodiesterase 4B inhibitors, do not directly intervene in the transforming growth factor-β signaling pathway. Given the potential limitations of single-target drugs, future drug development is expected to prioritize multi-target and multi-cell strategies while exploring synergistic multi-drug therapies. This article reviews the current clinical trials for anti-pulmonary fibrosis drugs worldwide and the challenges they face in order to provide references for the research and development of new anti-pulmonary fibrosis drugs.
  • REVIEWS
    XU Chang, YANG Xiaoya, GUO Jiabin, LI Yujie
    Chinese Journal of Pharmacology and Toxicology. 2025, 39(2): 129. https://doi.org/10.3867/j.issn.1000-3002.2025.02.006
    Nanomaterials have been used in a variety of industries recently, involving foods, chemicals and biomedicine. There are multiple routes through which humans are exposed to nanomaterials, and their toxic effects deserve more attention. In vivo studies have confirmed that nanomaterials exposure can lead to toxicity in such target organs as the heart, liver, kidney, skin and nerve. The toxicity mechanism is related to changes in organelles such as the endoplasmic reticulum, lysosomes and mitochondria. Increasing studies suggest that mitochondria are critical targets for the toxicity of nanomaterials. Mitochondrial biogenesis serves as an important mechanism for maintaining mitochondrial homeostasis, which plays a vital role in the process of nanomaterials-induced cellular toxicity. This article summarizes the current research on the effects of nanomaterials on mitochondrial biogenesis, and elaborates the mechanism through which nanomaterials disrupt mitochondrial biogenesis by triggering oxidative stress, upsetting the homeostasis of calcium ion and disturbing toxicity pathways. This article is expected to provide a reference for toxicity testing and risk assessment of nanomaterials.
  • REVIEWS
    LIU Yujia, ZOU Zhengyun
    Chinese Journal of Pharmacology and Toxicology. 2025, 39(3): 233. https://doi.org/10.3867/j.issn.1000-3002.2025.03.009
    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.
  • REVIEWS
    LI Xiong, YANG Genmeng, YAN He, DING Jiameng, HONG Shijun, ZHANG Dongxian
    Chinese Journal of Pharmacology and Toxicology. 2024, 38(12): 959. https://doi.org/10.3867/j.issn.1000-3002.2024.12.008
    Methamphetamine (METH) is a highly addictive synthetic psychoactive drug that is often abused as a psychostimulant. Chronic exposure to METH induces neurotoxic effects through oxidative stress, impairment of mitochondrial function, activation of astrocytes and microglia, and amino acid excitability. METH abuse increases the chance of developing neurodegenerative diseases such as Alzheimer′s disease, Parkinson′s disease, Huntington′s disease. However, the mechanism behind METH-induced neurotoxicity remains incompletely understood. So far, there is no specific treatment for METH-induced neurotoxicity. This paper reviews some of the potential mechanisms of METH-induced neurotoxicity in recent years, such as neuroinflammation, glutamatergic excitotoxicity, oxidative stress, and mitochondrial toxicity, and discusses the current therapeutic strategies related to mitigating the neurotoxic effects of METH in the brain through different pathways.
  • ORIGINAL ARTICLES
    WU Yanyan, WANG Yufei, CHEN Min, ZHANG Xuanping, LUO Le
    Chinese Journal of Pharmacology and Toxicology. 2025, 39(1): 36. https://doi.org/10.3867/j.issn.1000-3002.2025.01.004
    OBJECTIVE  To investigate the protective effect of farrerol against lipopolysaccharide (LPS) induced acute lung injury (ALI) in mice and the mechanisms. METHODS  ① ICR rats were randomly  divided into the normal control group, model group and model+farrerol group, with 6 rats in each. The normal control group and model group were given an equal amount of normal saline intragaically for 4 d. The model+farrerol group was given 20 and 40 mg·kg-1 intragaically for 4 d, while the normal control group was given an equal amount of normal saline intragaically on the 5th day. The model group and model +farrerol group were injected with 3 mg·kg-1 LPS solution for 24 h to construct an animal model of ALI. ② Mouse alveolar macrophages (MH-S) were cultured and randomly divided into the cell control group, model group and model+farrerol group.  Cell control group (conventional culture for 24 h), model group (100 μg·L-1 LPS combined with 40 μg·L-1 IFN-γ co-incubation for 24 h), model+farrerol group (5, 10 and 20 μmol·L-1 farrerol pretreatment of MH-S cells for 24 h, and then 100 μg·L-1 LPS combined with 40 μg·L-1 IFN-γ co-incubation for 24 h), an inflammatory cell model was established in vitro. HE was used to observe the pathological changes of the lungs. The wet-dry weight ratio (W/D) was used to assess pulmonary edema while Evans blue dye (EBD) was used to detect pulmonary vascular permeability. The activity of myeloperoxidase (MPO) was detected by colorimetry. The number of white blood cells in BALF was counted with a blood cell counting plate. Cell proliferation assay (CCK-8) was used to determine the cell viability. The levels of interleukin-1β (IL-1β), tumor necrosis factor α (TNF-α), IL-6 and IL-10 in lung tissue, bronchoalveolar lavage fluid (BALF) and cell supernatants were detected via enzyme-linked immunosorbent assay (ELISA). The protein levels of inducable nitric oxide synthase (iNOS), arginase 1 (ARG1), phosphorylated NF-κB p65, NOD-like receptor protein 3 (NLRP3), cysteinyl aspartate specific proteinase1 (caspase1) and gasdermin family member (GSDMD-N terminal) in lung tissue and MH-S cells were detected with Western blot. RESULTS  ① Compared with the normal control group, the histopathological changes, Injury score, W/D ratio, pulmonary vascular permeability, MPO content, leukocyte count, pro-inflammatory factor IL-1β, TNF-α, IL-6 levels, iNOS, phosphorylated NF-κB p65, NLRP3, caspase1 and GSDMD-N-terminal protein expression in lung tissues were significantly increased in the model group (P<0.05, P<0.01) while the expression levels of anti-inflammatory factors IL-10 and ARG1 were decreased (P<0.05, P<0.01). Compared with the model group, the Injury score, W/D ratio, pulmonary vascular permeability, leukocyte number, MPO content, proinflammatory factor content and iNOS, phosphorylated NF-κB p65, NLRP3, caspase1 and GSDMD-N-terminal protein levels were significantly decreased in the model+farrerol group(P<0.05, P<0.01) while the levels of anti-inflammatory factor IL-10 and ARG1 protein were increased (P<0.05,P<0.01). ② The results of in vitro experiments showed that compared with the cell control group, the contents of IL-1β, TNF-α and IL-6 and the expression levels of iNOS, phosphorylated NF-κB p65, NLRP3, caspase1 and GSDMD-N-terminal protein were increased (P<0.05, P<0.01), and that the content of anti-inflammatory factor IL-10 and expression level of ARG1 protein were decreased (P<0.01). Compared with the model group, the content of proinflammatory factor and the expressions of iNOS, phosphorylated NF-κB p65, NLRP3, caspase1 and GSDMD-N protein in the model+farrerol group were significantly decreased (P<0.05, P<0.01) while the expression levels of IL-10 and ARG1 protein were increased (P<0.05, P<0.01). CONCLUSION  Farrerol can alleviate acute lung injury induced by LPS in mice, possibly by inhibiting the phosphorylation of NF-κB p65 and activation of NLRP3 inflammatome, alleviating pyroptosis of cells and regulating macrophage polarization.
  • ORIGINAL ARTICLES
    ZHU Xiaohui, ZHAO Yuanyuan, LI Nanxi, GUO Jinnan, TIAN Yunfei, ZHAI Huiting, WANG Shanshan, YANG Dexuan, DOU Guifang, FENG Suxiang, MENG Zhiyun
    Chinese Journal of Pharmacology and Toxicology. 2025, 39(2): 89. https://doi.org/10.3867/j.issn.1000-3002.2025.02.002
    OBJECTIVE  To investigate the effects of ginsenosides as P-glycoprotein (P-gp) substrates in combination with paclitaxel on the proliferation and migration of colon cancer Caco-2 cells.  METHODS  Bio-layer interferometry (BLI) technology was used to detect the constants of ginsenosides and P-gp. Network molecular docking was adopted to predict the binding affinity energy of ginsenosides and P-gp. Caco-2 cells were divided into paclitaxel 0, 6.25, 12.5, 25, 50, 100 and 200 mg·L-1 groups, ginsenoside Rg3 0, 6.25, 12.5, 25, 50, 100 and 200 mg·L-1 groups, and paclitaxel 5 mg·L-1+ginsenoside Rg3 0, 25, 50, 100 and 200 mg·L-1 groups. After 48 h of incubation, the growth inhibition rate of Caco-2 cells was detected by MTT assay, and the interaction between the two drugs was quantitatively evaluated using the "one-belt, one-line" modle. Caco-2 cells were divided into the cell control group, paclitaxel 5 mg·L-1 group, ginsenoside Rg3 50 and 100 mg·L-1 groups, and paclitaxel 5 mg·L-1+ginsenoside Rg3 50 and 100 mg·L-1 groups. After 24 h of incubation, the proliferation and migration ability of the cells were detected by colony assay and Transwell migration assay. Caco-2 cells were then divided into the cell control group, quinidine 12.5 mg·L-1 group, and ginsenoside Rg3 6.25 and 12.5 mg·L-1 groups. After  4 h of incubation, the expression levels of P-gp and total protein were detected by ELISA. RESULTS  The affinity constants of ginsenoside Rb1, Rg3, Rg5 with P-gp were all less than 10-3 mol·L-1, while that of ginsenoside CK with P-gp was 10-2 mol·L-1. There was no typical binding dissociation curve between ginsenoside Re and P-gp. The absolute binding affinities of ginsenosides Rg3 and Rg5 to P-gp were determined to be 8.5 kcal·mol-1 and 7.6 kcal·mol-1, respectively. Ginsenosides mixed with PTX 5 mg·L-1 inhibited the growth of colon cancer cells through synergy and addition, and the dose range of the synergistic effect was [0+5, 43.15+5] mg·L-1; [164.51+5, 200+5] mg·L-1, the additive effect dose ranged from [43.15+5, 164.51+5] mg·L-1. The combination of the two drugs could significantly reduce the proliferation and migration ability of Caco-2 cells (P<0.01). The ELISA results showed a decrease in total protein and P-gp content in both the ginsenoside and quinidine groups (P<0.05). CONCLUSION  Ginsenoside bind to and inhibit the activity of P-gp, synergizing with paclitaxel to reduce the proliferative and migratory abilities of Caco-2 cells. The combination of ginsenosides and paclitaxel enhances the sensitivity of Caco-2 cells to paclitaxel induced inhibition. The combined use of these two substances is expected to achieve better anticancer effects compared to paclitaxel alone.
  • ORIGINAL ARTICLES
    HOU Xiaojuan, ZHANG Yue, BAI Yafan, LI Hailong, YANG Yixin, LI Yunfeng, MA Hui, WANG Henglin
    Chinese Journal of Pharmacology and Toxicology. 2024, 38(11): 807. https://doi.org/10.3867/j.issn.1000-3002.2024.11.001
    OBJECTIVE  To study the way in which hypidone hydrochloride (code: YL-0919) improves motor function after ischemic stroke (IS) and explore the related mechanism. METHODS  Adult male SD rats were used to establish a middle cerebral artery occlusion (MCAO) model that simulated acute IS. All animals were randomly divided into four groups: sham group, MCAO group, MCAO+YL-0919 group, and MCAO+YL-0919+erastin (Era, ferroptosis inducer) group. The drug administration groups received the first ip injection 6 h after operation, followed by continuous ip injection once per day. After 7-10 d of drug administration, the effect of YL-0919 on motor function after IS were evaluated via neurological function test, adhesive-removal test, rotarod test, balance beam test and open field test. After 7 d of drug administration, TTC staining was used to detect the cerebral infarction area while the colorimetry method was used to measure the contents of glutathione (GSH), malondialdehyde (MDA), and ferrous ions (Fe2+) in the penumbra of the cerebral cortex. Western blotting was used to detect the expression levels of glutathione peroxidase 4 (GPX4), solute carrier family 7 member 11 (xCT), acyl-CoA synthetase long-chain family member 4 (ACSL4), and transferrin receptor 1 (TFR1) in the cortical penumbra. RESULTS  Compared with the sham group, the MCAO group showed higher neurological function scores (P<0.01), with notably prolonged time for tape removal and first contact with the right forepaw (P<0.01), spent significantly more time crossing the balance beam (P<0.01) but endured a notably shorter duration on the rotarod (P<0.01), reduced the movement distance in the open field (P<0.01), had a remarkably increased infarct area (P<0.01) but significantly level of GSH in the cortical penumbra region decreased (P<0.01), while MDA and Fe2+ levels were markedly increased (P<0.01). Protein expression levels of GPX4 and xCT were reduced (P<0.05), while those of ACSL4 and TFR1 were elevated (P<0.05). Compared with the MCAO group, these changes were significantly reversed after YL-0919 administration. However, when Era and YL-0919 were administered simultaneously, the reversal effect of YL-0919 was significantly weakened. CONCLUSION  YL-0919 can improve motor function impairment and reduce cerebral infarction areas in rats after IS, and the mechanism may be related to the inhibition of ferroptosis.
  • ORIGINAL ARTICLES
    YU Haichao, WANG Wenchao, DUAN Junzhao, WANG Hua, ZHANG Xuesong
    Chinese Journal of Pharmacology and Toxicology. 2025, 39(3): 183. https://doi.org/10.3867/j.issn.1000-3002.2025.03.003
    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.
  • Special Issue of New Approach Methodologies (NAMs)
    LIU Shengnan, ZHANG Qiang, PI Jingbo
    Chinese Journal of Pharmacology and Toxicology. 2024, 38(10): 766. https://doi.org/10.3867/j.issn.1000-3002.2024.10.006
    New approach methodologies (NAMs) based next generation risk assessment for toxicity testing has quietly emerged globally. As an important component of NAMs, quantitative in vitro to in vivo extrapolation (QIVIVE) has come to be one of the significant technologies for chemical toxicity testing and risk assessment, and has gained rapid development and wide applications in the field of toxicology. The implementation of QIVIVE technology relies on two vital branches of computational toxicology: physiologically based toxicokinetics and physiologically based toxicodynamics. The system integrates population research, in vivo/in vitro testing, and computational toxicology research to quantitatively study the nonlinear quantitative relationship between exposure doses and physiological response, providing an efficient and accurate means of toxicity testing for health risk assessment of chemicals. At the same time, utilizing increasingly mature multi omics technologies to obtain high-throughput and 
    effective toxicology information, and drawing a signal network of toxicity occurrence and development in the context of big data can greatly improve the efficiency and range of toxicology research.