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      Vol. 30 ， Issue 5 ， 2024

        Original Article

      • XU Min,LIU Hao,SU Meng-qing,Ll Lan,YU Ai-ling,CHEN Ken,HUANG Yun-ke,ZHAO Qiu-long,HUANG Wen-ya,HUANG Xi
        Vol. 30, Issue 5, Pages: 387-397(2024) DOI: 10.1007/s11655-024-3651-6
        Abstract：Objective:To develop an interference-free and rapid method to elucidate Guanxin Ⅱ (GXⅡ)'s representative vasodilator absorbed bioactive compounds (ABCs) among enormous phytochemicals.Methods:The contents of ferulic acid, tanshinol, and hydroxysafflor yellow A (FTA) in GXⅡ/rat serum after the oral administration of GXⅡ (30 g/kg) were detected using ultra-performance liquid chromatography-mass spectrometry. Totally 18 rats were randomly assigned to the control group (0.9% normal saline), GXⅡ (30 g/kg) and FTA (5, 28 and 77 mg/kg) by random number table method. Diastolic coronary flow velocity-time integral (VTI), i.e., coronary flow or coronary flow-mediated dilation (CFMD), and endothelium-intact vascular tension of isolated aortic rings were measured. After 12 h of exposure to blank medium or 0.5 mmol/L H2O2, endothelial cells (ECs) were treated with post-dose GXⅡ of supernatant from deproteinized serum (PGSDS, 300 μL PGSDS per 1 mL of culture medium) or FTA (237, 1539, and 1510 mg/mL) for 10 min as control, H2O2, PGSDS and FTA groups. Nitric oxide (NO), vascular endothelial growth factor (VEGF), endothelin-1 (ET-1), superoxide dismutase (SOD), malondialdehyde (MDA) and phosphorylated phosphoinositide 3 kinase (p-PI3K), phosphorylated protein kinase B (p-AKT), phosphorylated endothelial nitric oxide synthase (p-eNOS) were analyzed. PGSDS was developed as a GXⅡ proxy of ex vivo herbal crude extracts.Results:PGSDS effectively eliminates false responses caused by crude GXⅡ preparations. When doses equaled the contents in GXⅡ/its post-dose serum, FTA accounted for 98.17% of GXⅡ-added CFMD and 92.99% of PGSDS-reduced vascular tension. In ECs, FTA/PGSDS was found to have significant antioxidant (lower MDA and higher SOD, P <0.01) and endothelial function-protective (lower VEGF, ET-1,P <0.01) effects. The increases in aortic relaxation, endothelial NO levels and phosphorylated PI3K/Akt/eNOS protein induced by FTA/PGSDS were markedly abolished by NG-nitro-L-arginine methyl ester (L-NA, eNOS inhibitor) and wortmannin (PI3K/AKT inhibitor), respectively, indicating an endothelium-dependent vasodilation via the PI3K/AKT-eNOS pathway (P <0.01).Conclusion:This study provides a strategy for rapidly and precisely elucidating GXⅡ's representative in/ex vivo cardioprotective absorbed bioactive compounds (ABCs)-FTA, suggesting its potential in advancing precision ethnomedicine.  
        Keywords：ultra-performance liquid chromatography-mass spectrometry;endothelium-dependent vasodilation;herbal extract;Guanxin Ⅱ;absorbed bioactive compound   
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        Published：2024-04-23
      • JI Xiao-di,YANG Ding,CUI Xi-yuan,LOU Li-xia,NIE Bo,ZHAO Jiu-li,ZHAO Ming-jing,WU Ai-ming
        Vol. 30, Issue 5, Pages: 398-407(2024) DOI: 10.1007/s11655-024-3654-3
        Abstract：Objective:To investigate the pharmacological mechanism of Qili Qiangxin Capsule (QLQX) improvement of heart failure (HF) based on miR133a-endoplasmic reticulum stress (ERS) pathway.Methods:A left coronary artery ligation-induced HF after myocardial infarction model was used in this study. Rats were randomly assigned to the sham group, the model group, the QLQX group [0.32 g/(kg•d)], and the captopril group [2.25 mg/(kg•d)], 15 rats per group, followed by 4 weeks of medication. Cardiac function such as left ventricular ejection fraction (EF), fractional shortening (FS), left ventricular systolic pressure (LVSP), left ventricular end diastolic pressure (LVEDP), the maximal rate of increase of left ventricular pressure (+dp/dt max), and the maximal rate of decrease of left ventricular pressure (–dp/dt max) were monitored by echocardiography and hemodynamics. Hematoxylin and eosin (HE) and Masson stainings were used to visualize pathological changes in myocardial tissue. The mRNA expression of miR133a, glucose-regulated protein78 (GRP78), inositol-requiring enzyme 1 (IRE1), activating transcription factor 6 (ATF6), X-box binding protein1 (XBP1), C/EBP homologous protein (CHOP) and Caspase 12 were detected by RT-PCR. The protein expression of GRP78, p-IRE1/IRE1 ratio, cleaved-ATF6, XBP1-s (the spliced form of XBP1), CHOP and Caspase 12 were detected by Western blot. TdT-mediated dUTP nick-end labeling (TUNEL) staining was used to detect the rate of apoptosis.Results:QLQX significantly improved cardiac function as evidenced by increased EF, FS, LVSP, +dp/dt max, -dp/dt max, and decreased LVEDP (P <0.05, P <0.01). HE staining showed that QLQX ameliorated cardiac pathologic damage to some extent. Masson staining indicated that QLQX significantly reduced collagen volume fraction in myocardial tissue (P <0.01). Results from RT-PCR and Western blot showed that QLQX significantly increased the expression of miR133a and inhibited the mRNA expressions of GRP78, IRE1, ATF6 and XBP1, as well as decreased the protein expressions of GRP78, cleaved-ATF6 and XBP1-s and decreased p-IRE1/ IRE1 ratio (P <0.05, P<0.01). Further studies showed that QLQX significantly reduced the expression of CHOP and Caspase12, resulting in a significant reduction in apoptosis rate (P <0.05, P <0.01).Conclusion:The pharmacological mechanism of QLQX in improving HF is partly attributed to its regulatory effect on the miR133a-IRE1/XBP1 pathway.  
        Keywords：heart failure;Qili Qiangxin Capsule;miR133a;endoplasmic reticulum stress;apoptosis   
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        Published：2024-04-23
      • FENG Min-chao,LUO Fang,HUANG Liang-jiang,LI Kai,CHEN Zu-min,LI Hui,YAO Chun,QIN Bai-jun,CHEN Guo-zhong
        Vol. 30, Issue 5, Pages: 408-420(2024) DOI: 10.1007/s11655-023-3559-6
        Abstract：Objective:To identify the core targets of Rheum palmatum L. and Salvia miltiorrhiza Bge., (Dahuang-Danshen, DH-DS) and the mechanism underlying its therapeutic efficacy in acute pancreatitis (AP) using a network pharmacology approach and validate the findings in animal experiments.Methods:Network pharmacology analysis was used to elucidate the mechanisms underlying the therapeutic effects of DH-DS in AP. The reliability of the results was verified by molecular docking simulation and molecular dynamics simulation. Finally, the results of network pharmacology enrichment analysis were verified by immunohistochemistry, Western blot analysis and real-time quantitative PCR, respectively.Results:Sixty-seven common targets of DH-DS in AP were identified and mitogen-activated protein kinase 3 (MAPK3), Janus kinase 2 (JAK2), signal transducer and activator of transcription 3 (STAT3), protein c-Fos (FOS) were identified as core targets in the protein interaction (PPI) network analysis. Gene ontology analysis showed that cellular response to organic substance was the main functions of DH-DS in AP, and Kyoto Encyclopedia of Genes and Genomes analysis showed that the main pathway included Th17 cell differentiation. Molecular docking simulation confirmed that DH-DS binds with strong affinity to MAPK3, STAT3 and FOS. Molecular dynamics simulation revealed that FOS-isotanshinone Ⅱ and STAT3-dan-shexinkum d had good binding capacity. Animal experiments indicated that compared with the AP model group, DH-DS treatment effectively alleviated AP by inhibiting the expression of interleukin-1β, interleukin-6 and tumor necrosis factor-α, and blocking the activation of Th17 cell differentiation (P <0.01).Conclusion:DH-DS could inhibit the expression of inflammatory factors and protect pancreatic tissues, which would be functioned by regulating Th17 cell differentiation-related mRNA and protein expressions.  
        Keywords：Rheum palmatum L.;Salvia miltiorrhiza Bge.;molecular docking simulation;network pharmacology;acute pancreatitis;Th17 cell differentiation   
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        Published：2024-04-23
      • YUE Tong-tong,CAO Ying-jie,CAO Ya-xuan,LI Wei-xia,WANG Xiao-yan,SI Chun-ying,XIA Han,ZHU Ming-jun,TANG Jin-fa,WANG He
        Vol. 30, Issue 5, Pages: 421-432(2024) DOI: 10.1007/s11655-023-3650-z
        Abstract：Objective:To investigate the main components and potential mechanism of Shuxuening Injection (SXNI) in the treatment of myocardial ischemia-reperfusion injury (MIRI) through network pharmacology and in vivo research.Methods:The Traditional Chinese Medicine Systems Pharmacology (TCMSP) and PharmMapper databases were used to extract and evaluate the effective components of Ginkgo biloba leaves, the main component of SXNI. The Online Mendelian Inheritance in Man (OMIM) and GeneCards databases were searched for disease targets and obtain the drug target and disease target intersections. The active ingredient-target network was built using Cytoscape 3.9.1 software. The STRING database, Metascape online platform, and R language were used to obtain the key targets and signaling pathways of the anti-MIRI effects of SXNI. In order to verify the therapeutic effect of different concentrations of SXNI on MIRI in rats, 60 rats were first divided into 5 groups according to random number table method: the sham operation group, the model group, SXNI low-dose (3.68 mg/kg), medium-dose (7.35 mg/kg), and high-dose (14.7 mg/kg) groups, with 12 rats in each group. Then, another 60 rats were randomly divided into 5 groups: the sham operation group, the model group, SXNI group (14.7 mg/kg), SXNI+LY294002 group, and LY294002 group, with 12 rats in each group. The drug was then administered intraperitoneally at body weight for 14 days. The main biological processes were validated using in vivo testing. Evans blue/triphenyltetrazolium chloride (TTC) double staining, hematoxylin-eosin (HE) staining, terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay, enzyme-linked immunosorbent assay (ELISA), and Western blot analysis were used to investigate the efficacy and mechanism of SXNI in MIRI rats.Results:Eleven core targets and 30 Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways were selected. Among these, the phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) pathway was closely related to SXNI treatment of MIRI. In vivo experiments showed that SXNI reduced the myocardial infarction area in the model group, improved rat heart pathological damage, and reduced the cardiomyocyte apoptosis rate (allP <0.01). After SXNI treatment, the p-PI3K/PI3K and p-AKT/AKT ratios as well as B-cell lymphoma-2 (Bcl-2) protein expression in cardiomyocytes were increased, while the Bax and cleaved caspase 3 protein expression levels were decreased (all P <0.05). LY294002 partially reversed the protective effect of SXNI on MIRI.Conclusion:SXNI protects against MIRI by activating the PI3K/AKT signaling pathway.  
        Keywords：myocardial ischemia reperfusion injury;PI3K/AKT signaling pathway;Shuxuening Injection;apoptosis;Ginkgo biloba leaves   
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        Published：2024-04-23
      • CHEN Pu,ZHOU Jun,RUAN An-min,MA Yu-feng,WANG Qing-fu
        Vol. 30, Issue 5, Pages: 433-442(2024) DOI: 10.1007/s11655-023-3653-9
        Abstract：Objective:To explore the mechanism of paeoniflorin (PF) on osteoarthritis (OA) synovial inflammation from network pharmacology to experimental pharmacology.Methods:Targets of OA were constructed by detecting the database of network database platforms (Therapeutic Target database, DrugBank and GeneCards), and the targets of PF were constructed by PubChem and Herbal Ingredients' Targets database. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis of these co-targeted genes were conducted via Database for Annotation, Visualization, and Integrated Discovery (DAVID) database, and protein-protein interaction (PPI) networks were conducted via the search tool for the retrieval of interacting genes (STRING) database. Cell counting kit-8 (CCK-8) assay was performed to assess the potential toxicity of PF on human OA fibroblast-like synoviocytes (FLS), quantitative real-time polymerase chain reaction (qPCR), enzyme-linked immunosorbent assay (ELISA) and Western blot were used to verify the potential mechanism of PF in synovial inflammation.Results:Twenty-six co-targeted genes were identified. GO enrichment results showed that these co-targeted genes were most likely localized in the cytoplasm, and the biological processes mainly involved 'cellular response to hypoxia' 'lipopolysaccharide (LPS)-mediated signaling pathway' and 'positive regulation of gene expression'. KEGG pathway analysis indicated that these co-targeted genes may function through pathways associated with 'hypoxia-inducible factor-1 (HIF-1) signaling pathway' and 'tumor-necrosis factor (TNF) signaling pathway'. The PPI network showed that the top 3 hub genes were TP53, TNF, and CASP3. Molecular docking results showed that PF was well docking with TNF. CCK-8 showed no potential toxicity of 10, 20 and 50 μmol/L PF on human OA FLS. And PF significantly decreased the expression levels of interleukin-1β, interleukin-6, TNF-α matrix metalloproteinase 13 (MMP13), and a disintegrin and metalloproteinase with thrombospondin motifs 5 (ADAMTS5) and TNF-α in LPS-induced OA FLS.Conclusion:PF exhibited potent anti-inflammatory effect in OA synovial inflammation.  
        Keywords：paeoniflorin;osteoarthritis;synovial inflammation;tumor necrosis factor-α;network pharmacology;Paeonia lactiflora   
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        Published：2024-04-23

        Clinical Experience

      • WU Shi-hao,SHI Wei-qi,LI Yu-hang,LIU Ru-hui,HU Da-yi,ZHENG Li-qiang,MA Wen-lin
        Vol. 30, Issue 5, Pages: 443-448(2024) DOI: 10.1007/s11655-023-3628-x
        Abstract：Objective:To evaluate the efficacy of Guanxin Danshen Dripping Pill (GXDSDP) in treating anxiety and depression in patients with coronary heart disease (CHD).Methods:A total of 1,428 patients diagnosed with CHD screened for anxiety, depression, and quality of life (QOL) at baseline received 0.4 g of GXDSDP treatment 3 times per day and returned for monthly reassessment. Patients were recruited after stable treatment for CHD and received assessment of General Anxiety Disorder-7 (GAD-7), Patient Health Questionnaire-9 (PHQ-9), and Seattle Angina Questionnaire (SAQ) for evaluating anxiety, depression, and QOL. Patients were followed up 3 times, once every 4 weeks, during outpatient visits for 12 weeks.Results:At the third follow-up (F3), the anxiety symptom of 63.79% (673/1,055) of the patients improved to sub-clinical level, and the GAD-7 score improved significantly (8.11 vs. 3.87, P<0.01); 57.52% (585/1,017) patients' depressive symptoms improved to sub-clinical level, with a significant improvement in PHQ-9 score (8.69 vs. 4.41,P <0.01) at F3. All aspects of QOL significantly improved at the end of treatment compared to those at baseline (all P <0.01) as assessed by SAQ: physical limitation (31.17 vs. 34.14), anginal stability (2.74 vs. 4.14), anginal frequency (8.16 vs. 9.10), treatment satisfaction (13.43 vs. 16.29), and disease perception (8.69 vs. 11.02).Conclusions:A fixed dosage of GXDSDP may be a potential treatment option for CHD patients comorbid with anxiety or depression. (Registration No. ChiCTR2100051523)  
        Keywords：Guanxin Danshen Dripping Pill;coronary heart disease;depression;anxiety;quality of life;Chinese medicine   
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        Published：2024-04-23

        Evidence-Based Integrative Medicine

      • XIE Shuang-ran,MA Liang,XU Xin-yu,ZHOU Shu,XIE Hui-miao,XIE Chang-sheng
        Vol. 30, Issue 5, Pages: 449-457(2024) DOI: 10.1007/s11655-024-3659-y
        Abstract：Backgroup:Currently, aromatherapy is being increasingly utilized in clinical practice, particularly in managing the side effects associated with radiotherapy and chemoradiotherapy. However, it remains to be established whether aromatherapy can effectively alleviate these symptoms.Objective:To investigate the effects of aromatherapy on the physical and mental health of patients with cancer undergoing radiotherapy and chemotherapy.Methods:Seven databases were researched from inception until September 29, 2023, including PubMed, Scopus, and Web of Science, Chinese National Knowledge Infrastructure, Wanfang database, China Biology Medicine disc and VIP Chinese Medical Journal Database. Review Manager version 5.3 was utilized for data analysis. The Cochrane Risk of Bias tool RoB2 was employed to evaluate the quality of the literature included in the study. Evidence quality rating was assessed using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach through the GRADEpro GDT online tool.Results:Nineteen studies involving 1,541 patients were included. Aromatherapy can alleviate nausea [relative risk (RR)=0.64, 95% confidence interval (CI): 0.53 to 0.78, P <0.05, I2=46%; standardized mean difference (SMD)=–0.86, 95% CI: –1.21 to –0.51, P <0.05,I2=64%] and vomiting (RR=0.54, 95% CI: 0.42 to 0.69, P <0.05, I2=35%; SMD=–1.28, 95% CI: –1.52 to –1.03, P <0.05,I2=92%), improve sleep disorders [mean difference (MD)=–3.39, 95% CI: –3.95 to –2.84, P<0.05,I2=0%], relieve pain (SMD=–1.58, 95% CI: –1.96 to –1.21, P<0.05, I2=0%), mitigate fatigue (SMD=–1.28, 95% CI: –2.44 to –0.11,P <0.05, I2=93%) and enhance quality of life (SMD=0.50, 95% CI: 0.22 to 0.79, P <0.05, I2=0%) in cancer patients after radiotherapy and chemotherapy, but it may not have a significant effect on anxiety. The risk of bias was high in the included studies using the Cochrane Risk of Bias tool RoB2, and no studies were considered to be of high grade according to the GRADE system.Conclusions:Aromatherapy is an efficacious, safe and economic adjunctive therapy for cancer patients, which can mend the physical symptoms and mental health of cancer patients. However, more high-quality studies are needed to verify it. (PROSPERO registration No. CRD42023390171)  
        Keywords：aromatherapy;cancer;chemoradiotherapy;physical;psychological   
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        Published：2024-04-23

        Review

      • HU Yu-xuan,QIU Sheng-lei,SHANG Ju-ju,WANG Zi,LAI Xiao-lei
        Vol. 30, Issue 5, Pages: 458-467(2024) DOI: 10.1007/s11655-023-3649-5
        Abstract：Although there have been significant advances in the treatment of heart failure in recent years, chronic heart failure remains a leading cause of cardiovascular disease-related death. Many studies have found that targeted cardiac metabolic remodeling has good potential for the treatment of heart failure. However, most of the drugs that increase cardiac energy are still in the theoretical or testing stage. Some research has found that botanical drugs not only increase myocardial energy metabolism through multiple targets but also have the potential to restore the balance of myocardial substrate metabolism. In this review, we summarized the mechanisms by which botanical drugs (the active ingredients/formulas/Chinese patent medicines) improve substrate utilization and promote myocardial energy metabolism by activating AMP-activated protein kinase (AMPK), peroxisome proliferator-activated receptors (PPARs) and other related targets. At the same time, some potential protective effects of botanical drugs on myocardium, such as alleviating oxidative stress and dysbiosis signaling, caused by metabolic disorders, were briefly discussed.  
        Keywords：botanical drugs;chronic heart failure;myocardial metabolism;pharmacological effects;review   
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        Published：2024-04-23
      • ZHONG Yi,LI Xin-yue,LIANG Tian-jun,DING Bao-zhu,MA Ke-xin,REN Wen-xuan,LIANG Wen-jie
        Vol. 30, Issue 5, Pages: 468-479(2024) DOI: 10.1007/s11655-024-3655-2
        Abstract：Activation of the NOD-like receptor protein 3 (NLRP3) inflammasome signaling pathway is an important mechanism underlying myocardial pyroptosis and plays an important role in inflammatory damage to myocardial tissue in patients with cardiovascular diseases (CVDs), such as diabetic cardiomyopathy, ischemia/reperfusion injury, myocardial infarction, heart failure and hypertension. Noncoding RNAs (ncRNAs) are important regulatory factors. Many Chinese medicine (CM) compounds, including their effective components, can regulate pyroptosis and exert myocardium-protecting effects. The mechanisms underlying this protection include inhibition of inflammasome protein expression, Toll-like receptor 4–NF-κB signal pathway activation, oxidative stress, endoplasmic reticulum stress (ERS), and mixed lineage kinase 3 expression and the regulation of silent information regulator 1. The NLRP3 protein is an important regulatory target for CVD prevention and treatment with CM. Exploring the effects of the interventions mediated by CM and the related mechanisms provides new ideas and perspectives for CVD prevention and treatment.  
        Keywords：pyroptosis;cardiovascular diseases;Chinese medicine;NOD-like receptor protein 3;mechanisms   
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        Published：2024-04-23
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