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    2025, 39(9): 0.
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  • ORIGINAL ARTICLES
  • ORIGINAL ARTICLES
    LIN Ruizhi, WANG Jianyu, WEI Yajing, ZHAO Xinran, WANG Lin, YANG Jun, WANG Yongan, YU Cuiyun
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    OBJECTIVE  To construct novel central nervous system (CNS)-targeted lipid nanoparticles for the treatment of organophosphorus-induced brain injury in mice. METHODS  (1) Preparation, screening, and characterization of lipid nanoparticles. ① Lipid nanoreactivators were prepared using the thin-film hydration method, with asoxime (HI-6) as the therapeutic drug and lipid carriers composed of 1-palmitoyl-2-oleoyl-sn-glycero-3-phospho-L-serine (POPS), 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC), and cholesterol (CHOL) (PDC) at varying molar ratios (1:6:3, 3:4:3, 5:2:3 and 7:0:3) (HI-6@PDC 1:6:3, 3:4:3, 5:2:3 and 7:0:3). ② FLU-labeled lipid nanocarriers (FLU@PDC 1:6:3, 3:4:3, 5:2:3, and 7:0:3) were prepared and physically mixed with phospholipase A2 (PLA2) solution (at the final PLA2 concentration of 10 kU·L-1) to obtain FLU@PDC+PLA2. Male KM mice were randomly divided into normal control (PBS), FLU, and FLU@PDC+PLA2 (1:6:3, 3:4:3, 5:2:3, and 7:0:3) groups (n=7 per group). After intravenous (iv) administration (FLU dose: 1 mg·kg-1, carrier dose: 80 mg·kg-1), brain tissues were collected at 1 h, homogenized, centrifuged, and analyzed via fluorescence spectrophotometry to screen the optimal CNS-targeted lipid carrier composition. ③ The morphology of HI-6@PDC 5:2:3 was characterized by transmission electron microscope (TEM). The particle size, polydispersity index (PDI), and zeta potential of HI-6@PDC 5:2:3 were measured using a Zeta potential and particle size analyzer. Encapsulation efficiency and loading efficiency of HI-6@PDC 5:2:3 were determined using an ultrafiltration centrifugation method combined with high-performance liquid chromatography (HPLC). In vitro release kinetics of HI-6@PDC 5:2:3 and HI-6@PDC+PLA2 5:2:3 were assessed using a dialysis bag diffusion method combined with fluorescence spectrophotometry. (2) Validation of CNS targeting. ① Cyanine7 (Cy7)-labeled PDC 5:2:3 (Cy7@PDC) was prepared and mixed with PLA2 solution (Cy7@PDC+PLA2 5:2:3). Mice were divided into normal control, Cy7, Cy7@PDC 5:2:3 and Cy7@PDC+PLA2 5:2:3 groups (n=3 per group). After iv injection (Cy7 dose: 1 mg·kg-1, carrier dose: 80 mg·kg-1), brain fluorescence was visualized at 3 h using  a small animal in vivo imaging (IVIS) system. ② Cyanine 3 (Cy3)-labeled PDC 5:2:3 (Cy3@PDC 5:2:3) was prepared and mixed with PLA2 solution (Cy3@PDC+PLA2 5:2:3). Mice were divided into Cy3@PDC 5:2:3 and Cy3@PDC+PLA2 5:2:3 groups (n=3 per group). After iv injection (Cy3 dose: 1 mg·kg-1, carrier dose: 80 mg·kg-1), brain tissues were collected at 2 h for fluorescent staining and Cy3 fluorescence observation. (3) Therapeutic efficacy evaluation. ① Male KM mice were randomly divided into normal control, brain injury, HI-6 treatment, and HI-6@PDC+PLA2 5:2:3 treatment groups (n=6 per group). Except for the normal control, all the mice were subcutaneously (sc) injected with soman (120 μg·kg-1), followed by immediate iv treatment (HI-6 dose: 22 mg·kg-1, carrier dose: 80 mg·kg-1). At 10 min, orbital blood and brain tissues were collected before brain weight was recorded. Acetylcholinesterase (AChE) reactivation in blood and brain was measured using the Ellman method. ② Grouping and treatment were identical to ① (n=3 per group). At 24 h, brain tissues were collected for HE staining to assess histopathological damage. ③ Mice were divided into brain injury and HI-6@PDC+PLA2 5:2:3 treatment groups (n=10 per group) and treated as in ① (soman dose: 220 μg·kg-1). Survival rates, neurotoxic symptoms (tremors, salivation), and seizure latency were recorded, and survival curves were plotted. RESULTS  (1) PDC 5:2:3 exhibited the highest brain fluorescence, indicating optimal CNS targeting. HI-6@PDC 5:2:3 appeared in regular spherical shapes, and were negatively charged, with a size of (219.4±3.1) nm, PDI of 0.4±0.02, entrapment efficiency of 72.9% and loading efficiency of 49.7%. HI-6@PDC+PLA2 5:2:3 showed a cumulative release of 43.5% at 60 min, which was lower than that of rhodamine B (RB) but sufficient for CNS therapeutic timelines. (2) In vivo fluorescence and pathological fluorescence confirmed PLA2-mediated CNS delivery. (3) HI-6@PDC+PLA2 5:2:3 significantly enhanced AChE reactivation in the blood and brain compared to HI-6. Histopathology revealed mitigated brain injury in treated mice. HI-6@PDC+PLA2 5:2:3 prolonged survival, reduced convulsions, alleviated neurotoxicity, and extended seizure latency. CONCLUSION  HI-6@PDC 5:2:3 can effectively cross the blood-brain barrier via PLA2 mediation, demonstrating strong CNS targeting. It can significantly improve AChE reactivation in peripheral and central tissues and offers potent therapeutic efficacy against organophosphate-induced brain injury.
  • ORIGINAL ARTICLES
    SU Guixin, HUANG Yulong, LI Changwei, YANG Yu, ZHANG Yang, XUE Rui, LI Shuo, ZHANG Youzhi
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    OBJECTIVE  To investigate the mechanism through which Chaixian Huashen decoction (CXHSD) ameliorates lipopolysaccharide (LPS)-induced acute lung injury (ALI) in mice. METHODS Component analysis: the components of CXHSD extract were analyzed via ultra-high performance liquid chromatography-high resolution mass spectrometry (UPLC-Q-Exactive HFX). Network pharmacology analysis was conducted to predict the potential active components and underlying therapeutic targets of CXHSD for ALI treatment. ① Animal experiment: mice were randomly divided into the normal control group, model (LPS) group, model+dexamethasone (DEX) 4 mg·kg-1 group, model+CXHSD 10 g·kg-1 group, and model+CXHSD 20 g·kg-1 group. Except for the normal control group, ALI was induced in all the mice by intratracheal instillation of LPS. Model+CXHSD groups received daily intragastric administration of corresponding treatments for 7 consecutive days. The model+DEX group was administered saline intragastrically for the initial 5 d, followed by DEX for the next 2 d. ALI was induced by intratracheal instillation of LPS 5 mg·kg-1 1 h after the 6th administration of CXHSD/DEX. 24 h after modeling, the severity of pulmonary edema was assessed using the wet to dry weight (W/D) ratio, and hematoxylin-eosin (HE) staining was used to evaluate histopathological damage. The levels of myeloperoxidase (MPO), tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), IL-1β in lung tissue homogenates and serum were measured by enzyme-linked immunosorbent assay (ELISA). The total protein concentration in bronchoalveolar lavage fluid (BALF) was measured by bicinchoninic acid (BCA) assay. Immunohistochemistry and Western blotting were used to assess the expression levels of toll-like receptor 4 (TLR4), myeloid differentiation primary response 88 (MyD88), zonula occludens-1 (ZO-1) and occludin, as well as the phosphorylation level of nuclear factor-kappa B p65 (NF-κB p65). ② Cell experiment: RAW264.7 cells were divided into the cell control group, LPS 1 mg·L-1 group, LPS 1 mg·L-1+DEX 1 mg·L-1 group, and LPS 1 mg·L-1+CXHSD 50, 100 and 200 mg·L-1 groups. After 24 h of culture, the nitric oxide (NO) content was measured with the nitrate reductase method, the levels of TNF-α, IL-1β and IL-6 in the cell supernatants of each group were detected by ELISA. RESULTS  Network pharmacology analysis indicated that CXHSD might alleviate ALI through the NF-κB pathway. ① Compared with the normal control group, the W/D ratio was elevated, pathological injuries aggravated (such as alveolar wall thickening, inflammatory infiltration, and alveolar congestion), histopathological damage pronounced, MPO activity increased, and total protein concentrations in BALF raised in the model group, in which levels of TNF-α, IL-6 and IL-1β in both lung tissue and serum became higher. Concurrently, LPS increased the expressions of p-NF-κB p65, TLR4 and MyD88, but reduced the expressions of ZO-1 and occludin. Compared with the model group, model+CXHSD groups had their pulmonary edema and lung pathological injury ameliorated as evidenced by alleviated alveolar wall thickening, inflammatory infiltration and alveolar congestion. The levels of MPO, TNF-α, IL-1β and IL-6 in both lung tissue and serum, and the total protein concentrations in BALF were significantly decreased in the model+CXHSD groups. Additionally, the expressions of TLR4, MyD88, and p-NF-κB p65 were significantly downregulated, while those of ZO-1 and occludin were prominently upregulated. ② Compared with the cell control, the levels of TNF-α, IL-1β, IL-6 and NO in the supernatant of RAW264.7 cells were significantly increased in the LPS group. Compared with the LPS group, in the supernatant of RAW264.7 cells treated with LPS+CXHSD at 100 mg·L-1, there was no significant difference in TNF-α levels. However, in the other groups treated with LPS+CXHSD, the levels of TNF-α, IL-1β, IL-6, and the content of NO were significantly reduced. CONCLUSION  CXHSD can alleviate LPS-induced ALI by inhibiting the TLR4/NF-κB pathway, attenuating inflammation, and preserving pulmonary barrier integrity.
  • ORIGINAL ARTICLES
    LI Wenqian, JIAO Yuanyuan, YANG Wen, WANG Mingyu, XING Yaling, WANG Shengqi
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    OBJECTIVE  To investigate the activity and mechanism of tetrandrine (TET) against influenza A virus in vitro and in vivo. METHODS  (1) Cell experiments. ① Human non-small cell lung cancer cells (A549) were divided into TET 0 (cell control), 1.25, 2.5, 5, 10, 20 and 25 μmol·L-1 groups, and H1N1+TET 0, 1.25, 2.5, 5, 10, 20 and 25 μmol·L-1 groups. The TET groups were treated with the corresponding concentrations of TET while the H1N1+TET groups were infected with H1N1 for 1 h before the corresponding concentrations of TET were added. After 48 h, cell viability was detected using the CCK-8 method. ② The cells were divided into cell control, H1N1+TET 0, 2.5, 5, and 10 μmol·L-1 groups and treated as in ①. After 24 h of incubation, the mRNA expressions of matrix protein 1(M1), hemagglutinin (HA), interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), interferon-β (IFN-β) were tested by the real-time quantitative PCR (RT-qPCR). The expression levels of M1, HA, neuraminidase (NA), nucleoprotein (NP), and phosphorylation of  signal transducer and activator of transcription 3 (STAT3) protein were detected by Western blotting. (2) Animal experiments. ① Male BALB/c mice were randomly divided into the solvent control group, H1N1 group, H1N1+oseltamivir phosphate (Ose) 20 mg·kg-1 group, and H1N1+TET 25, 50 and 100 mg·kg-1 groups. The solvent control group and the H1N1 group were ig administered with 0.5% carboxymethyl cellulose sodium (CMC-Na), while the H1N1+Ose group and the H1N1+TET 25, 50 and 100 mg·kg-1 groups were ig given suspensions of the respective concentrations of drugs in 0.5% CMC-Na. After three consecutive days of pretreatment, all these groups except the solvent control group were intranasally inoculated with H1N1 to establish an influenza-infected mouse model. The survival rate and body mass of mice were monitored and recorded for 15 consecutive days post-H1N1 infection.  ② The grouping and treatment were the same as ①. After infection, mice were sacrificed on day 3 and 5. The expression levels of M1, HA, TNF-α, IL-1β and IL-6 in lung tissues were detected by RT-qPCR, and those of M1, HA, NA, NP, and phosphorylation of STAT3 protein in mice lung tissues by Western blotting. Hematoxylin-Eosin (HE) staining was performed to observe the pathological changes of lung tissues in mice. The levels of IL-6, TNF-α and IFN-β in bronchoalveolar lavage fluid (BALF) were determined by enzyme-linked immunosorbent assays (ELISA). RESULTS  (1)① The half maximal inhibitory concentration study showed a value of 18.06 μmol·L-1 for A549 effected by TET. Compared with the H1N1 group, TET 2.5, 5 and 10 μmol·L-1 significantly increased cell viability. ② The expression levels of M1, HA mRNA and M1, HA, NA protein in the TET 2.5, 5 and 10 μmol·L-1 groups were significantly lowered compared with the H1N1 group. TET 5 μmol·L-1 significantly decreased H1N1-induced IL-6, TNF-α and IFN-β mRNA expression levels in A549 cells. TET 5 and 10 μmol·L-1 could significantly mitigate the phosphorylation of STAT3. (2) ① Compared with the H1N1 group, TET 50 mg·kg-1 significantly improved the survival rate of H1N1-infected mice while TET 25 mg·kg-1 significantly elevated the body-weight of H1N1-infected mice. In the TET 50 mg·kg-1 group, expressions of HA and M1 mRNA, and HA, M1, NA and NP protein in the lung tissues of H1N1-infected mice were significantly reduced compared with the H1N1 group. Compared with the H1N1 group, TET 50 mg·kg-1 significantly decreased the lung index, improved inflammatory lesions in lung tissues, inhibited the mRNA expressions of TNF-α, IL-6 and IFN-β in lung tissues, and down regulated the expressions of TNF-α, IL-6 and IFN-β proinflammatory cytokines in the BALF of the H1N1-infected mice. In addition, TET 50 mg·kg-1 also significantly inhibited STAT3 phosphorylation in lung tissues of mice infected with H1N1. CONCLUSION  TET can inhibit H1N1 infection both in vivo and in vitro. The potential mechanism may be related to the inhibition of the IL-6/STAT3 pathway, which subsequently suppresses the inflammatory response induced by H1N1.
  • ORIGINAL ARTICLES
    BAI Rui, XIE Wenmeng, MA Chunling, LOU Qi, WEN Di
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    OBJECTIVE To screen endogenous differential metabolites in mice that die from chlorpromazine (CPZ) poisoning and investigate the detoxification mechanism of triheptanoin (TriHep) against CPZ-induced lethality. METHODS Mice were randomly divided into the following groups (half male and half female): normal control, CPZ 2.5LD50, CPZ LD50 intoxication (CPZI), CPZ LD50 death (CPZD), TriHep-control, and TriHep-intervention (TriHep+CPZ LD50). The CPZ 2.5LD50, CPZI and CPZD groups were intragastrically given a corresponding dose of CPZ, respectively. The TriHep-control group and the TriHep-intervention group were intragastrically given saline and CPZ LD50 respectively before being intragastrically given TriHep (3 μL·g-1) 10 min later. Plasma samples from the CPZ 2.5LD50 group and normal control group were analyzed using liquid chromatography-tandem mass spectrometry (LC-MS/MS) for metabolite identification and quantification. MetaboAnalyst 5.0 was employed to perform principal component analysis (PCA), orthogonal partial least squares-discriminant analysis (OPLS-DA), and metabolic pathway analysis to screen and identify differential metabolites. More comparisons were made of the levels of differential metabolites in plasma between the normal control, CPZI, CPZD, TriHep-intervention, and TriHep-control groups. RESULTS In the PCA score plot, metabolomic samples from the CPZ 2.5LD50 group and normal control group showed clear separation, indicating distinct clustering patterns. Primary screening under three conditions, including P<0.05, variable importance in projection (VIP) score≥1 and fold change (FC)≥1.5 or ≤0.67 for a comparison of CPZ 2.5LD50 group with normal control group 28 metabolites were identified. Following quantitative enrichment and structural identification, three significantly differential metabolites were confirmed: acetylcarnitine, propionylcarnitine, and succinic acid. Compared with the normal control group, both CPZI and CPZD groups showed significantly decreased plasma levels of acetylcarnitine and propionylcarnitine, while the succinic acid content was markedly increased in the CPZD group. In the TriHep control group, levels of acetylcarnitine and succinic acid were significantly elevated, with no significant change in propionylcarnitine levels. Compared with the CPZI group, the CPZD group showed a significant increase in plasma succinic acid levels, but no significant change was observed in the acetylcarnitine content. The TriHep-intervention group demonstrated metabolite profiles (all the three differential metabolites) similar to those in the CPZI group, with significantly reduced propionylcarnitine and succinic acid concentrations compared to the CPZD group. CONCLUSION  In the early stage of CPZ intoxication, TriHep can alleviate CPZ poisoning  via acetylcarnitine, which can stabilize the level of succinic acid in plasma via indirect succinic acid replenishment.
  • ORIGINAL ARTICLES
    LIU Huan, LI Kangxing, WENG Wenjie, SHI Yujun, LIU Chunhong, NONG Zhenyi
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    OBJECTIVE  To evaluate the effects of phthalic acid esters (PAEs) on the expression of heme oxygenase-1 (HO-1) in HepG2 cells, and to construct an HO-1-based three-dimensional quantitative structure-activity relationship (3D-QSAR) model. METHODS  ① HepG2 cells were treated with seven types of PAEs: di-(2-ethylhexyl) phthalate (DEHP), di-n-octyl phthalate (DnOP), dimethyl phthalate (DMP), diethyl phthalate (DEP), dihexyl phthalate (DHXP), dimethylglycol phthalate (DMEP), and dibutyl phthalate (DBP), at final concentrations of 0 (DMSO, solvent control), 0.062 5, 0.125, 0.25, 0.5 and 1 mmol·L-1 (n=6) for 48 h at 37 ℃. The expression level of HO-1 was measured by Western blotting. ② A 3D-QSAR model was constructed using comparative molecular similarity indices analysis (CoMSIA) based on the measured HO-1 levels. The applicability domain (AD) of the model was evaluated using the leverage method. Model fitting quality and predictive ability were evaluated via the KNIME Enalos+node to verify model stability. Additionally, molecular docking was performed to validate the binding interactions between PAEs and HO-1. RESULTS  ① Compared with the solvent control group, 48 h of exposure to 0.062 5 mmol·L-1 PAEs (DMP, DMEP, DEHP, DnOP and DEP) significantly increased HO-1 protein expressions, while 1 mmol·L-1 PAEs (DMP, DBP, DnOP, DEP and DHXP) significantly suppressed HO-1 expressions. ② The 3D-QSAR model showed a non-cross-validated coefficient (R2) of 0.996 and a cross-validated coefficient (Q2) of 0.548. All the seven PAEs in the 3D-QSAR model were within the applicability domain (AD) and passed external validation. Molecular docking results indicated that DBP, DnOP, DEHP and DHXP exhibited stronger binding affinities to HO-1. CONCLUSION  Forty-eight hours of exposure of HepG2 cells to 1 mmol·L-1 PAEs can significantly suppress HO-1 expressions. The 3D-QSAR model established in this study provides a potential tool for predicting the HO-1-related toxic effects of novel PAEs.
  • REVIEWS
  • REVIEWS
    XU Lin, HUANG Qiuyu, YAN Dongmei
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    Toxic Chinese herbal medicines (TCHMs) both represent a unique class of therapeutic agents that exhibit both potent efficacy ("using toxins to combat pathogens and often curing critical conditions") and pose safety concerns ("potentially causing severe harm"). Balancing clinical effectiveness with safe applications remains a priority of research for these substances. This review summarizes the hepatotoxic mechanisms, research progress, detoxification strategies and clinical challenges associated with TCHMs documented in the 2025 Pharmacopoeia of the People′s Republic of China (VolumeⅠ) in the hope of providing evidence-based insights into the safe and rational clinical use of these hepatotoxic herbs.
  • REVIEWS
    LIU Yiming, WEI Jiale, LIU Liu, LI Changyu
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    Chronic kidney disease (CKD), a major threat to global public health, exhibits disease progression closely linked to renal cellular senescence. This review outlines the key molecular mechanisms underpinning cellular senescence in CKD, including mitochondrial dysfunction, DNA damage response, senescence-associated secretory phenotype, and the central role of epigenetic regulation. Furthermore, the advances in traditional Chinese medicine (TCM) for mitigating renal senescence through multi-target strategies such as oxidative stress inhibition, anti-inflammatory modulation, and interventions in cell cycle arrest are summarized. There is evidence that active TCM compounds and formulas exert anti-senescence potential by modulating pathways including sirtuin 1/PTEN induced kinase 1 and Wnt/β-catenin signaling. However, clinical translation remains constrained by a poor knowledge of the mechanisms, challenges to dose standardization, and a lack of clinical validation. Future studies should integrate kidney-specific transgenic models with single-cell omics to resolve the cell heterogeneity of senescence while developing novel delivery systems to enhance the targeting efficiency of TCM components so as to facilitate precision interventions in CKD.
  • REVIEWS
    XU Shansen, MA Xianglei, YUE Tingting, CHEN Yanan
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    Drug-induced liver injury (DILI), induced by drugs and/or their reactive metabolites, is a common and challenging clinical issue. Bile acid profiles reflect both the species and contents of biological bile acids, and the perturbation of bile acid homeostasis is considered one of the early pathogenesis events in DILI. This review summarizes the synthesis, transport and regulation of bile acids, the roles of bile acids in early warning, the relationships between different bile acids, clinical prognosis of DILI, and the potential therapeutic targets for DILI in the bile acid metabolic pathway, such as the pathways based on the farnesoid X receptor (FXR) and G-protein coupled bile acid receptor 1(GPBAR1), as well as the balance of the gut microbiota. This study is expected to provide data for the application of bile acid metabolism in the early diagnosis, prediction, and clinical treatment of DILI.