Chinese Journal of Pharmacology and Toxicology

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    2025, 39(8): 0.
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    • ORIGINAL ARTICLES
  • ORIGINAL ARTICLES
    Regulation effect of orbitofrontal cortex-dorsomedial striatum neural circuits on addiction motivation in susceptible mice
    ZHU Huimin, CUN Xingfang, WU Ning, LI Jin, SONG Rui
    2025, 39(8): 561. https://doi.org/10.3867/j.issn.1000-3002.2025.08325
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    OBJECTIVE  To study the neural circuits involved in regulating the strong drug-taking motivation in susceptible mice, and provide novel insights into the intervention and treatment of drug addiction. METHODS  A heroin intermittent-access (Int A) self-administration model was established. Mice were divided into susceptible, unsusceptible, and non-learnt subgroups based on parameters, such as the number of times of drug infusions, effective lever presses, and breakpoints (BP) in the progressive ratio schedule during the drug acquisition phase. Using chemogenetic techniques, the neural projection from the orbitofrontal cortex (OFC) to the dorsomedial striatum (DMS) was selectively manipulated in the progressive ratio schedule, and its impact on drug motivation was assessed across the three subgroups. RESUITS  Selectively inhibiting the OFC-DMS circuit significantly reduced the BP in susceptible mice, with no significant effect on the other two subgroups. Conversely, selective activation of this pathway significantly increased BP in susceptible mice, but had no impact on the other subgroups. CONCLUSION  The OFC-DMS circuit specifically modulates drug motivation behavior in susceptible mice, but not in the unsusceptible, and non-learnt subgroups.
  • ORIGINAL ARTICLES
    Inhibition effect of perillyl alcohol on pulmonary vascular remodeling in hypoxia-induced pulmonary hypertension rats and its mechanism
    WANG Yiwen, BAI Haijun, LI Zhanqiang, LU Dianxiang, NAN Xingmei, YANG Zhanting
    2025, 39(8): 569. https://doi.org/10.3867/j.issn.1000-3002.2025.08444
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    OBJECTIVE  To investigate the impact of perilla alcohol on pulmonary vascular remodeling in hypoxia-induced pulmonary hypertension (HPH) rats and to assess its regulatory effects on the angiotensin-converting enzyme 2 (ACE2)-angiotensin (1-7) [Ang (1-7)]-mas proto-oncogene receptor (Mas) and ACE-angiotensinⅡ(AngⅡ)-angiotensin type 1 receptor (AT1R) axes. METHODS  An HPH rat model was established by keeping them in a hypobaric chamber that simulated an altitude of 5 000 m for 28 d. Male SD rats were randomly divided into the control group, hypoxia group, hypoxia+sildenafil group (ig administration of 30 mg·kg-1), and hypoxia+perillyl alcohol groups (ig administration of 25, 50 and 100 mg·kg-1 respectively). After 28 d, the levels of glutamic-oxaloacetic transaminase (GOT), glutamic-pyruvic transaminase (GPT), and blood urea nitrogen (BUN) in rat serum were measured to evaluate the toxic effects of perillyl alcohol on rat organs. Mean pulmonary artery pressure (mPAP) was measured via right ventricular catheterization. HE staining was used to observe the patho morphological changes of pulmonary vessels in HPH rats and measure the percentages of the vascularwall area [WA(%)], wall thickness [WT(%)], lumen area [LA(%)]. The right ventricular hypertrophy level and α-smooth muscle actin (α-SMA) expression level were detected by immunohistochemistry and immunofluorescence. Western blotting was used to detect the protein expression levels of α-SMA, ACE, AT1R, AngⅡ, ACE2 and Mas in lung tissues of rats. Enzyme-linked immunosorbent assay (ELISA) was employed to measure the content of Ang (1-7) in lung tissues. RESULTS Compared with the control group, the serum levels of GOT, GPT and BUN in the hypoxia group rats were significantly increased, but were significantly decreased by perillyl alcohol and sildenafil intervention. Compared with the control group, mPAP, WA (%), WT (%), right ventricular inner diameter (RVID), right ventricular free wall thickness (RVFWT) and fibrosis levels were significantly increased in the hypoxia group, while LA (%) was significantly decreased. Besides, the protein expression levels of α-SMA, ACE, AT1R and AngⅡ in lung tissues were significantly elevated while those of ACE2 and Mas, as well as Ang(1-7) content were significantly decreased in hypoxia group compared to the control group. Following intervention with perillyl 
    alcohol and sildenafil, the protein expression levels of ACE and AngⅡ in lung tissues of HPH rats were significantly decreased compared to the model group while those of ACE2 and Mas receptor, along with the content of Ang (1-7), were significantly increased. Perillyl alcohol significantly reduced the protein expression level of AT1R while sildenafil had no significant effect. CONCLUSION  Perillyl alcohol can lower mPAP levels by improving pulmonary vascular remodeling and reducing pulmonary vascular fibrosis in HPH rats. The mechanism may be related to the regulatory effects on the ACE-AngⅡ-AT1R and ACE2-Ang (1-7)-Mas axes.
  • VSV-G modification enhances engineered exosome SARS-CoV-2 vaccine to respiratory mucosal immunity
    CHEN Zehong, XING Haonan, LU Mei, WANG Xiwei, LI Meng, GAO Xiuli, ZHENG Aiping
    2025, 39(8): 581. https://doi.org/10.3867/j.issn.1000-3002.2025.08370
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    OBJECTIVE  To investigate the impact of vesicular stomatitis virus envelope glycoprotein-G (VSV-G) modification on the mucosal immune efficacy of antigen-loaded engineered exosome vaccines. METHODS  In vitro experiments: Dendritic cells (DCs) were divided into three groups: cell- control (treated with culture medium), receptor binding domain (RBD) (transfected with plasmid RBD), and RBD+VSV-G (co-transfected with plasmids RBD and VSV-G). Expression levels of RBD and VSV-G were assessed using Western blotting, flow cytometry, and immunofluorescence. Exosomes were extracted via ultracentrifugation, whose morphology, size distribution, and marker proteins were analyzed using transmission electron microscopy, nanoparticle tracking analysis, and Western blotting that confirmed the expressions of RBD and VSV-G in the exosomes. In vivo experiments: ① Female BALB/c mice were divided into the control group Mock exosomes (Mock-Exo) (derived from the supernatant of cell-control), RBD decorated exosomes (RBD-Exo) (derived from the RBD cell supernatant), and RBD and VSV-G decorated exosomes (RBD+VSV-G-Exo) (derived from RBD+VSV-G cell supernatant). Following intranasal immunization with the respective vaccines, the nasal retention effects were evaluated using in vivo imaging. Flow cytometry was used to assess the ability to recruit immune cells to the nasal tissue. Serum RBD-specific immunoglobulin G (IgG) and mucosal immunoglobulin A (IgA) (bronchoalveolar lavage fluid/nasal wash) were quantified at 7 and 21 d post-immunization by enzyme-linked immunosorbent assay. Body weight changes were monitored and key serum biochemical parameters along with histopathological damage to major organs were analyzed following immunization. ② Female BALB/c mice were divided into the Mock-Exo group (intranasally inoculated with Mock-Exo), RBD+VSV-G-Exo group (intranasally inoculated with RBD+VSV-G-Exo), and RBD+VSV-G-Exo (im) group (intramuscularly injected with RBD+VSV-G-Exo). RESULTS  In vitro experiments: RBD and VSV-G were successfully expressed in cells, with positive rates of RBD+ and VSV-G+ cells at 64.4% and 31.2%, respectively. The extracted exosomes exhibited regular morphology and qualified purity, with a particle size of approximately 138 nm and successfully loaded RBD and VSV-G proteins. In vivo experiments: Compared to Mock-Exo and RBD-Exo, RBD+VSV-G-Exo prolonged nasal retention time to 96 h and markedly increased the numbers of CD49B+ natural killer cells, CD11c+ dendritic cells, and F4/80+ macrophages in nasal tissues. RBD+VSV-G-Exo induced robust RBD-specific immune responses, with serum IgG titers, BALF IgA titers, and nasal wash IgA titers reaching 1∶5 215, 1∶2 560, 1∶1 114, respectively. In contrast, no RBD-specific IgA antibody titers were detected in the BALF and nasal wash of mice treated with RBD+VSV-G-Exo  (im). Mice showed stable body weight gain during 30 d post-immunization. Major serum biochemical indices were within normal reference ranges, and no obvious pathological changes were observed in major organs or olfactory bulbs 7 d after immunization. CONCLUSION  VSV-G modification extends the retention time of engineered exosome vaccines in nasal tissues, enhance their ability to recruit immune cells, and induce a high-level antigen-specific respiratory mucosal immune response.
    • ORIGINAL ARTICLES
  • ORIGINAL ARTICLES
    Screening and preliminary evaluation of nanobodies targeting granulocyte-macrophage colony-stimulating factor
    LIU Jiao, CHEN Lei, QIN Hui, KANG Qinlin, LI Gege, YANG Zhixin, DU Peng, ZHOU Chunyang
    2025, 39(8): 591. https://doi.org/10.3867/j.issn.1000-3002.2025.08222
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    OBJECTIVE  To screen and obtain nanobodies with neutralizing activity against granulocyte-macrophage colony stimulating factor (GM-CSF) to contribute to investigations into the mechanism of inflammation interventions and the development new drugs. METHODS  Recombinant human GM-CSF was subcutaneously injected to immunize camels. Peripheral blood was collected after five immunizations, and mononuclear cells were isolated. Total mRNA was extracted, and the variable domains of the heavy chain of heavy-chain antibody (VHH, also called nanobody) genes were obtained by PCR amplification after reverse transcription. The genes were cloned into the pADSCFV-S phage display vector and electrotransformed into TG1 competent cells to construct a nanobody immune library that was screened with recombinant human GM-CSF immobilized on a solid phase. The VHH genes specifically binding to human GM-CSF were cloned into the pABG eukaryotic expression vector before VHH-Fc samples were prepared by using the human embryonic kidney 293 fibroblast expression system. The binding activity of candidate VHH-Fc molecules to GM-CSF was investigated through ELISA response curves, and binding colorimetric values with different antigens were detected to determine their specificity. The binding affinity between VHH-Fc candidates and GM-CSF was measured using biolayer interferometry (BLI). The inhibition rate curve of VHH-Fc candidates on GM-CSF was detected through cell proliferation assays to determine its neutralization activity. The Uncle system was used to investigate its thermal stability. 100 μg of VHH-Fc was injected into mice via the tail vein, and the serum concentration of VHH-Fc was quantitatively detected by ELISA to examine its pharmacokinetic curve in mice. RESULTS  The camel serum titer of anti-human GM-CSF antibodies was higher than 1:800 000 after the fifth immunization, and the capacity of the constructed nanobody library was about 5.55×107. Following the screening process, five candidate VHH-Fc molecules specifically binding to human GM-CSF were obtained. Among these, 22N10 effectively neutralized the cell proliferation-promoting activity of GM-CSF (the IC50 value was 17.23 nmol·L-1). Subsequent studies revealed that 22N10 interacted with human GM-CSF with an affinity of 1.97×10-8 mol·L-1, blocked the binding of GM-CSF to its receptor CSF2Rα, exhibited good thermal stability (Tm1=59.2 ℃), and showed favorable metabolic characteristics in mice. CONCLUSION  A new candidate nanobody molecule 22N10 targeting human GM-CSF is obtained which is expected to facilitate the drug development and mechanism investigations.
  • ORIGINAL ARTICLES
    Effects of combined silica nanoparticles and high-fat diet exposure on vascular fibrosis
    YIN Jingwen, WANG Fenghong, CHI Baofeng
    2025, 39(8): 600. https://doi.org/10.3867/j.issn.1000-3002.2025.08418
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    OBJECTIVE  To investigate the effects of combined exposure of silica nanoparticles (SiNPs) and a high-fat diet (HFD) on aortic vascular fibrosis in rats and explore the underlying mechanisms. METHODS  Transmission electron microscopy and a particle size analyzer were used to analyze the size and dispersion of SiNPs. Male Wistar rats were randomly divided into four groups: standard diet control group (STD-control), standard diet SiNPs group (STD+SiNPs), high-fat diet control group (HFD-control), and high-fat diet SiNPs group (HFD+SiNPs). The rats received intratracheal instillation of SiNPs (10 mg·kg-1) or saline combined with either an STD or HFD every four days for 90 days. Small animal ultrasound was used to evaluate vascular function and structure. Hematoxylin and eosin (HE) staining and Masson′s staining were performed to analyze aortic pathology and fibrosis. Biochemical assays were conducted to measure superoxide dismutase (SOD) activity, malondialdehyde (MDA) contents, and the ratio of reduced gluta-thione/glutathione disulfide (GSH/GSSG). Immunohistochemistry and Western blotting were used to analyze the expression levels of mitophagy-related proteins phosphatase and PTEN induced kinase 1 (PINK1), E3 ubiquitinligase (Parkin), microtubule-associated protein 1 light chain 3B (LC3B), and P62, as well as vascular fibrosis marker proteins alpha-smooth muscle actin (α-SMA), typeⅠcollagen (Col-Ⅰ), and type Ⅲ collagen (Col-Ⅲ). RESULTS  Transmission electron microscopy analysis showed that SiNPs had a uniform size (51.24±8.54) nm, regular morphology, and good dispersion. Compared with the STD-control group, the STD+SiNPs group exhibited a significant reduction in the end-diastolic diameter of the left common carotid artery and aorta, along with a significant increase in intima-media thickness. Additionally, SOD activity decreased, MDA contents increased, and the GSH/GSSG ratio declined, indicating that SiNPs exposure induced oxidative damage and vascular dysfunction in the aorta. Pathological staining revealed that SiNPs caused inflammatory infiltration and vascular fibrosis in the aortic intima of rats. Notably, HFD exacerbated the vascular toxicity induced by SiNPs, suggesting a synergistic effect of their combined exposure. Mechanistically, immunohistochemistry and Western blotting results showed that the combined exposure to SiNPs and HFD significantly upregulated the expressions of PINK1, Parkin, LC3BⅡ/Ⅰ, P62, α-SMA, Col-Ⅰ, and Col-Ⅲ in the aorta. These findings suggested that SiNPs and HFD co-exposure might activate PINK1/Parkin-mediated mitophagy, contributing to the progression of aortic fibrosis. CONCLUSION  Combined exposure to SiNPs and HFD might induce mitophagy through the PINK1/Parkin signaling pathway, leading to decreased vascular antioxidant capacity and fibrosis. These findings provided new  evidence for the joint impact of SiNPs exposure and metabolic disorders on cardiovascular health.
    • REVIEWS
  • REVIEWS
    Influences of sleep on attention and intervention strategies: current progress
    YIN Yu, WEN Qing, SONG Lun, PENG Hui
    2025, 39(8): 611. https://doi.org/10.3867/j.issn.1000-3002.2025.08412
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    Sleep is essential for organisms. Sleep disorders, such as insomnia, sleep fragmentation, and sleep deprivation, deeply impact the physical activity and mental health of humans. The significant role of sleep in brain function has been well accepted in recent years. This article aims to summarize the research related to sleep disorders, sleep-wake control, the relationships between sleep and  attention, and the potential underlying mechanisms. Current interventions are also outlined in the hope of providing insights into sleep and cognitive function.
  • REVIEWS
    Research advances in major structural proteins of monkeypox virus and its monoclonal antibody
    ZHANG Qing, ZHANG Mengmeng, YU Jijun, FENG Jiannan, WEI Yinxiang, WANG Jing
    2025, 39(8): 619. https://doi.org/10.3867/j.issn.1000-3002.2025.08441
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    Monkeypox, caused by the monkeypox virus (MPXV), is a zoonotic infectious disease characterized clinically by fever, rash, and lymphadenopathy. In September 2024, the outbreak of a novel MPXV Clade Ib variant in the Democratic Republic of the Congo was designated by the World Health Organization as a public health emergency of international concern, highlighting deficiencies in current prevention and control systems. Although modified attenuated smallpox vaccines exhibit cross-protective efficacy against MPXV infection, their adverse effects still limit clinical applications. Furthermore, the therapeutic efficacy of tecovirimat — the FDA emergency-authorized antiviral drug for Smallpox — is limited. Recent studies have shown that tecovirimat does not significantly improve lesion healing time or reduce overall mortality in patients infected with MPXV CladeⅠ. Monoclonal antibodies, which neutralize viral activity by targeting critical membrane proteins, have emerged as a pivotal strategy to overcome current therapeutic bottlenecks by integrating therapeutic, diagnostic and prophylactic functions. This article reviews the epidemiological and virological characteristics of MPXV, along with functional characteristics of MPXV major membrane proteins, including A29L, A35R, B6R, E8L, M1R and H3L, focusing on the research progress in monoclonal antibodies against these key targets. Their protective effects in vitro/in vivo are explored while such as strategies monoclonal antibody combination therapy are recommended to enhance efficacy and overcome drug resistance. 
  • REVIEWS
    Research progress in in vitro testing methods of developmental neurotoxicity
    LUO Huan, TAO Gonghua, XIAO Ping
    2025, 39(8): 631. https://doi.org/10.3867/j.issn.1000-3002.2025.08377
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    Developmental neurotoxicity (DNT) has been recognized as an important aspect of risk assessment. However, traditional in vivo tests are limited by an increasing need to assess the risk of numerous industrial chemicals. The DNT in-vitro testing battery (DNT IVB) has emerged that can reduce animal use with potential cost-efficiencies. In this article, the progress and targets of DNT IVB are explored in general and the DNT in vitro testing methods and alternative in vitro models in particular. The applicability of DNT in vitro testing data based on integrated approach to testing and assessment (IATA) is evaluated. In conclusion, with the development of high-throughput screening and human-derived cell models, DNT IVB can better align with priority testing requirements in modern DNT risk assessment frameworks and deliver validated in vitro alternatives for regulatory compliance.