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Editor-in-ChiefWU Yiling
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National Administration of Traditional Chinese Medicine
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Institute of Traditional Chinese MedicineChina Academy of Chinese Medical SciencesChina Association of Chinese Medicine

CN11-3495/R

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Effect of Dingzhi Xiaowan on PI3K/Akt/mTOR/HIF-1α Pathway in Post-stroke Cognitive Impairment Model Mice

ObjectiveTo investigate the effect of Dingzhi Xiaowan (DZXW) in post-stroke cognitive impairment (PSCI) model mice.MethodsThe cerebral ischemia-reperfusion injury model of mice was established by using the middle cerebral artery occlusion method. Forty C57BL/6 male mice were randomly divided into the sham operation group, model group, low-dose DZXW group (1.43 g·kg-1), and high-dose DZXW group (2.56 g·kg-1), with 10 mice in each group. Both the sham operation group and the model group were treated with equal amounts of normal saline by gavage, and the above four groups of mice were gavaged once a day for 30 consecutive days. Morris water maze test was used to evaluate the learning memory ability of mice. Serum levels of amyloid precursor protein (APP), amyloid 42 (Aβ42), acetylcholinesterase (AChE), and superoxide dismutase (SOD) were measured by enzyme-linked immunosorbent assay (ELISA). Deoxyribonucleotide end transferase-mediated nick end labelling (TUNEL) assay was applied to detect the degree of apoptosis in the mouse's hippocampal neurons. Western blot was used to detect the protein expression of phosphoinositol-3 kinase (PI3K), protein kinase B (Akt), mammalian target of rapamycin (mTOR), hypoxia-inducible factor 1-alpha (HIF-1α), B-cell lymphoma 2 (Bcl-2) homologous structural domain protein (Beclin1), sequestosome 1 (p62), microtubule-associated protein light chain 3 (LC3), Bcl-2, and Bcl-2-associated X protein (Bax) in hippocampal tissue. Prussian blue staining was used to detect iron deposition in hippocampal tissue. Transmission electron microscopy was taken to observe the ultrastructure of the mouse's hippocampal neurons.ResultsCompared with the sham operation group, the latency, APP, Aβ42, AChE, TUNEL positivity, ferric ion deposition, HIF-1α, Beclin1, Bax, and LC3Ⅱ/Ⅰ were significantly increased in the model group (P<0.01), while the number of crossing platforms, SOD, p-PI3K, p-Akt, p-mTOR, p62, and Bcl-2 were significantly decreased (P<0.01). Compared with the model group, the latency, APP, Aβ42, AChE, TUNEL positivity rate, ferric ion deposition, HIF-1α, Beclin1, Bax, and LC3Ⅱ/Ⅰ were significantly reduced in the DZXW groups (P<0.05), while the number of crossing platforms, SOD, p-PI3K, p-Akt, p-mTOR, p62, and Bcl-2 were significantly higher (P<0.05).ConclusionDZXW can alleviate cognitive impairment induced by oxidative stress-aggravated hippocampal neuronal damage in PSCI model mice by modulating the PI3K/Akt/mTOR/HIF-1α autophagy signalling pathway.

Effect of Dingzhi Xiaowan on PI3K/Akt/mTOR/HIF-1α Pathway in Post-stroke Cognitive Impairment Model Mice
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Volume 31 期 16,2025 2025年31卷第16期
    桂枝茯苓丸通过HIF-1α/HO-1信号通路抑制子宫内膜异位症铁死亡,为临床治疗提供新理论依据。

    TANG Li, ZHANG Yi, WU Lulu, LIANG Yingying, GONG Wenying, TAN Quanning

    Vol. 31, Issue 16, Pages: 1-11(2025) DOI: 10.13422/j.cnki.syfjx.20250802
    摘要:ObjectiveThis study aims to investigate the molecular mechanism by which Guizhi Fulingwan (GFW) inhibits ferroptosis in endometriosis (EMT) through the regulation of the hypoxia inducible factor-1α/heme oxygenase 1 (HIF-1α/HO-1) signaling pathway.MethodsMachine learning was employed to identify ferroptosis-related biomarkers associated with EMT. Network pharmacology was utilized to identify the active components of GFW and its potential therapeutic targets against EMT, including core targets. Functional enrichment analysis was conducted to explore the biological processes, molecular functions, cellular components, and signaling pathways associated with the potential targets. An EMT rat model was established via autologous transplantation. Thirty female Sprague-Dawley (SD) rats were randomly divided into five groups: sham-operated, model, positive control (dienogest at 0.2 mg·kg-1), low-dose GFW (2.5 g·kg-1), and high-dose GFW (5 g·kg-1). After modeling, the rats received their respective treatment by oral gavage for 28 consecutive days, while the sham and model groups received equal volumes of distilled water. Serum and ectopic endometrial tissues were collected. Hematoxylin and eosin (HE) staining was employed to evaluate morphological alterations in ectopic lesions. Quantitative real-time polymerase chain reaction (Real-time PCR) and Western blot were conducted to assess mRNA and protein expression of HIF-1α, HO-1, glutathione peroxidase 4 (GPX4), spermidine/spermine N1-acetyltransferase (SAT1), and prostaglandin-endoperoxide synthase 2 (PTGS2). Tissue levels of malondialdehyde (MDA), glutathione (GSH), and ferrous iron (Fe²⁺) were quantified using commercial assay kits. Serum levels of interleukin-6 (IL-6) and transforming growth factor-β1 (TGF-β1) were measured via enzyme-linked immunosorbent assay (ELISA).ResultsFive ferroptosis-related biomarkers in EMT were identified: ALOX12, CHAC1, SAT1, AST1, and HO-1. Network pharmacology analysis revealed 42 active components of GFW and 192 potential therapeutic target genes related to EMT treatment, with FOS, JUN, HO-1 identified as core targets. Functional enrichment analysis indicated that the potential targets were primarily involved in oxidative stress response and reactive oxygen species metabolism and were enriched in the HIF-1 signaling pathway. Compared to the sham-operated group, the model group exhibited significant increases in both mRNA and protein expression of HIF-1α, HO-1, and PTGS2, as well as elevated tissue levels of Fe²⁺ and MDA. Conversely, GSH levels and the expression of GPX4 and SAT1 were markedly reduced, and serum levels of IL-6 and TGF-β1 levels were significantly higher (P<0.01). Compared with the model group, all GFW-treated groups showed significant downregulation of HIF-1α and HO-1, reduced Fe²⁺ levels, and downregulated expression of MDA, PTGS2, IL-6, and TGF-β1. Meanwhile, GSH, GPX4, and SAT1 expression levels were significantly increased (P<0.05, P<0.01), effectively ameliorating iron overload and oxidative stress, thereby demonstrating therapeutic efficacy in EMT, with the high-dose GFW demonstrating the most pronounced therapeutic effects.ConclusionGFW exerts therapeutic effects on endometriosis by regulating the HIF-1α/HO-1 signaling pathway to rectify iron metabolism disorders and attenuate free iron-induced oxidative damage. It upregulates the antioxidative defense system to inhibit lipid peroxidation cascades and modulates inflammatory cytokine networks. These effects collectively disrupt the pathological interaction between ferroptosis and chronic inflammation, providing a novel theoretical foundation for the clinical application of GFW in EMT treatment.  
    关键词:Guizhi Fulingwan;endometriosis;ferroptosis;hypoxia inducible factor-1α/heme oxygenase 1 (HIF-1α/HO-1) signaling pathway;network pharmacology   
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    最新研究发现,黄芪桂枝五物汤通过调控细胞自噬改善骨骼肌稳态,治疗类风湿关节炎肌少症,为临床应用提供参考依据。

    WAN Yakun, LIU Yuan, QU Yuan, GUO Jingyu, LIU Ting, BAI Zhihui, ZHANG Di, JIANG Ping

    Vol. 31, Issue 16, Pages: 12-23(2025) DOI: 10.13422/j.cnki.syfjx.20250713
    摘要:ObjectiveThis study aims to explore the mechanism of action of Huangqi Guizhi Wuwutang in treating rheumatoid arthritis (RA)-associated sarcopenia by regulating autophagy and improving skeletal muscle homeostasis based on network pharmacology,bioinformatics,machine learning,and animal experiments.MethodsActive ingredients and targets of Huangqi Guizhi Wuwutang were screened using the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform (TCMSP),PubChem,and SwissTargetPrediction databases. RA-related datasets were retrieved from the GEO database,and differential genes were screened. Sarcopenia-related targets were searched through GeneCards and the Comparative Toxicology Database (CTD),and autophagy-related gene sets were downloaded from the Human Autophagy Database (HADb). Their intersection was analyzed to identify autophagy-related therapeutic targets,followed by enrichment analysis. A protein-protein interaction (PPI) network was constructed using the STRING database,and key targets were selected using multiple methods. Machine learning was applied to predict models based on the expression profiles of intersecting targets,and nomogram models were constructed based on key targets. Molecular docking of the top four active ingredients with key targets was performed using AutoDockVina. A collagen-induced arthritis (CIA) rat model was established using bovine type Ⅱ collagen,with SD rats divided into groups including a blank group,a model group,and low-,medium-,and high-dose groups of Huangqi Guizhi Wuwutang (2.44,4.88,and 9.76 g·kg-1) and administered for five consecutive weeks. Joint scores and gastrocnemius muscle mass were recorded and analyzed after modeling. Hematoxylin and eosin (HE) staining and Masson's staining were used to observe pathological changes in muscle tissue. Immunofluorescence staining was applied to observe the protein expression levels of myosin heavy chain (MYHC) and insulin-like growth factor-1 (IGF-1) in skeletal muscle. Western blot was used to detect the protein expression levels of autophagy-related proteins ATG5,Beclin1,LC3B,muscle-specific proteins (MuRF1),MaFbx,and MYHC. Real-time quantitative reverse transcription PCR (Real-time PCR) was performed to measure the mRNA expression levels of ATG5,Beclin1,LC3B,MuRF1,MaFbx,and MYHC in muscle tissue.ResultsNetwork pharmacology revealed that Huangqi Guizhi Wuwutang shared 25 common targets with autophagy genes related to RA-associated sarcopenia. The PPI network and machine learning identified six key targets,which were primarily involved in autophagy and inflammatory pathways. Animal experiments showed that compared to the blank group,the model group had significantly higher joint scores (P<0.01) and lower gastrocnemius muscle index (P<0.01). HE staining indicated a significant reduction in the cross-sectional area of gastrocnemius muscle fibers,with notable inflammatory cell infiltration and muscle atrophy in the model group. Masson's staining revealed obvious collagen fiber proliferation and deposition,with significant muscle fibrosis in the model group. The protein and mRNA expression levels of ATG5,Beclin1,LC3B,MuRF1,and MaFbx were significantly increased (P<0.01),while the protein expression of MYHC and IGF1 was significantly downregulated (P<0.01). Compared with the model group,the high-dose group of Huangqi Guizhi Wuwutang showed significantly reduced protein and mRNA expression levels of ATG5,Beclin1,LC3B,MuRF1,and MaFbx (P<0.01) and increased protein expression levels of MYHC and IGF1 (P<0.01). The cross-sectional area of muscle fibers increased,and the muscle cell morphology approached normal. Moreover,pathological abnormalities in the gastrocnemius muscle were significantly improved,with reduced collagen fiber proliferation (P<0.01).ConclusionHuangqi Guizhi Wuwutang can mediate autophagy by regulating the expression of ATG5,Beclin1,LC3B,and IGF1,thereby reducing skeletal muscle catabolism and improving skeletal muscle homeostasis,which contributes to the treatment of RA-associated sarcopenia. The findings provide insight into the mechanisms underlying the effects of Huangqi Guizhi Wuwutang in the treatment of RA-related sarcopenia and offer a reference for its enhanced clinical application.  
    关键词:Huangqi Guizhi Wuwutang;autophagy;rheumatoid arthritis;sarcopenia;skeletal muscle homeostasis;machine learning   
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    更新时间:2025-07-10
    最新研究发现,补中益气汤能有效保护妊娠期亚临床甲减后代脑发育,其机制涉及线粒体DNA甲基化异常及氧化应激调控。

    MA Yan, LYU Xiaojiao, HUANG Yangling, MA Xiande, GAO Tianshu, CONG Peiwei, CHEN Wei

    Vol. 31, Issue 16, Pages: 24-34(2025) DOI: 10.13422/j.cnki.syfjx.20251137
    摘要:ObjectiveTo evaluate the pharmacological effect of Buzhong Yiqitang on brain development in offspring of rats with subclinical hypothyroidism (SCH) during pregnancy and explore its potential mechanism.MethodsForty-eight SPF female SD rats were divided into sham operation group (n=8) and model group (n=40). The rat model of subclinical hypothyroidism (SCH) was constructed by total thyroidectomy combined with postoperative subcutaneous injection of levothyroxine (L-T4). The modeled rats were randomly allocated into model, low-, medium-, and high-dose (5.58, 11.16, 22.32 g∙kg-1, respectively) Buzhong Yiqitang, and euthyrox (4.5×10-6 g∙kg-1) groups, with 8 rats in each group. These rats were co-housed with normal male rats for mating. Drug administration started 2 weeks before pregnancy and continued until delivery. Hematoxylin-eosin staining and Golgi-cox staining were used to observe pathological changes in the hippocampal tissue of offspring rats. Western blot was employed to detect the effects of Buzhong Yiqitang on the protein levels of cytochrome C oxidase subunitⅠ (COX)Ⅰ and COXⅣ in the hippocampal tissue of offspring rats. A colorimetric method was used to measure the mitochondrial adenosine triphosphate (ATP) content in the hippocampal tissue of offspring rats. For in vitro experiments, a hydrogen peroxide (H2O2)-induced oxidative damage model was established with rat pheochromocytoma cells (PC12). Interventions included the DNA methyltransferase inhibitor (SGI-1027), Buzhong Yiqitang-medicated serum, and euthyrox-medicated serum. The cell counting kit-8 (CCK-8) assay was used to examine the effect of Buzhong Yiqitang on cell proliferation. Immunofluorescence staining was performed to evaluate the effect on tubulin beta 3 class Ⅲ (TUBB3) in PC12 cells. Western blot was employed to assess the effects on the protein levels of DNA methyltransferases (TETs and DNMTs) in PC12 cells. The fluorescent probe 2′,7′-dichlorodihydrofluorescein diacetate (DCFH-DA), luciferase assay, and JC-1 staining were employed to assess the effects of Buzhong Yiqitang on the levels of reactive oxygen species (ROS) and ATP and the mitochondrial membrane potential in PC12 cells.ResultsCompared with the sham group, the model group showed a reduction in the number of hippocampal neurons, incomplete pyramidal cell bodies, loose arrangement, shortened average dendrite length, decreased dendritic complexity and dendritic spine density, and reduced expression levels of COXⅠ and COXⅣ and content of ATP in the brain tissue (P<0.05, P<0.01). Compared with the model group, after administration of Buzhong Yiqitang and euthyrox, hippocampal neurons exhibited regular arrangement, complete morphology, extended dendrite, increased dendritic complexity and dendritic spine density, and restored expression levels of COXⅠ and COXⅣ and content of ATP (P<0.05, P<0.01), with the medium-dose Buzhong Yiqitang group showing the best therapeutic effect. In the PC12 cell model of oxidative damage, Buzhong Yiqitang increased the cell viability (P<0.01), enhanced neuronal differentiation, down-regulated the expression levels of DNMTs (P<0.05), up-regulated the expression levels of TETs (P<0.05), decreased the ROS content (P<0.01), and restored the ATP content and mitochondrial membrane potential (P<0.01).ConclusionBuzhong Yiqitang protects brain development in offspring of pregnant rats with SCH. It mainly acts on the oxidative stress and mitochondrial dysfunction resulted from abnormal mtDNA methylation, with DNMTs and TETs as the key proteins for its effects.  
    关键词:subclinical hypothyroidism during pregnancy;offspring brain development;Buzhong Yiqitang;mitochondrial oxidative stress;methyltransferases   
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