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      Vol. 29 ， Issue 12 ， 2023

        Original Article

      • WU Yu-jie,WU Yu-jie,DENG Bo,DENG Bo,WANG Si-bo,WANG Si-bo,QIAO Rui,QIAO Rui,ZHANG Xi-wen,ZHANG Xi-wen,LU Yuan,LU Yuan,WANG Li,WANG Li,GU Shun-zhong,GU Shun-zhong,ZHANG Yu-qing,ZHANG Yu-qing,LI Kai-qiao,LI Kai-qiao,YU Zong-liang,YU Zong-liang,WU Li-xing,WU Li-xing,ZHAO Sheng-biao,ZHAO Sheng-biao,ZHOU Shuang-lin,ZHOU Shuang-lin,YANG Yang,YANG Yang,WANG Lian-sheng
        Vol. 29, Issue 12, Pages: 1059-1065(2023) DOI: 10.1007/s11655-023-3648-6
        Abstract：Background:Ventricular remodeling after acute anterior wall ST-segment elevation myocardial infarction (AAMI) is an important factor in occurrence of heart failure which additionally results in poor prognosis. Therefore, the treatment of ventricular remodeling needs to be further optimized. Compound Danshen Dripping Pills (CDDP), a traditional Chinese medicine, exerts a protective effect on microcirculatory disturbance caused by ischemia-reperfusion injury and attenuates ventricular remodeling after myocardial infarction.Objective:This study is designed to evaluate the efficacy and safety of CDDP in improving ventricular remodeling and cardiac function after AAMI on a larger scale.Methods:This study is a multi-center, randomized, double-blind, placebo-controlled, parallel-group clinical trial. The total of 268 patients with AAMI after primary percutaneous coronary intervention (pPCI) will be randomly assigned 1:1 to the CDDP group (n=134) and control group (n=134) with a follow-up of 48 weeks. Both groups will be treated with standard therapy of ST-segment elevation myocardial infarction (STEMI), with the CDDP group administrating 20 tablets of CDDP before pPCI and 10 tablets 3 times daily after pPCI, and the control group treated with a placebo simultaneously. The primary endpoint is 48-week echocardiographic outcomes including left ventricular ejection fraction (LVEF), left ventricular end-diastolic volume index (LVEDVI), and left ventricular end-systolic volume index (LVESVI). The secondary endpoint includes the change in N terminal pro-B-type natriuretic peptide (NT-proBNP) level, arrhythmias, and cardiovascular events (death, cardiac arrest, or cardiopulmonary resuscitation, rehospitalization due to heart failure or angina pectoris, deterioration of cardiac function, and stroke). Investigators and patients are both blinded to the allocated treatment.Discussion:This prospective study will investigate the efficacy and safety of CDDP in improving ventricular remodeling and cardiac function in patients undergoing pPCI for a first AAMI. Patients in the CDDP group will be compared with those in the control group. If certified to be effective, CDDP treatment in AAMI will probably be advised on a larger scale. (Trial registration No. NCT05000411)  
        Keywords：Compound Danshen Dripping Pills;acute anterior myocardial infarction;randomized controlled trial;ventricular remodeling;cardiac function;trial design   
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        Published：2023-11-21
      • CAO Ce,CAO Ce,QI Yu-tong,QI Yu-tong,WANG Ao-ao,WANG Ao-ao,WANG Zi-yan,WANG Zi-yan,LIU Zi-xin,LIU Zi-xin,MENG Hong-xu,MENG Hong-xu,LI Lei,LI Lei,LIU Jian-xun
        Vol. 29, Issue 12, Pages: 1066-1076(2023) DOI: 10.1007/s11655-023-3640-1
        Abstract：Objective:To explore the protective effect of Huoxin Pill (HXP) on acute myocardial ischemia-reperfusion (MIRI) injury in rats.Methods:Seventy-five adult SD rats were divided into the sham-operated group, model group, positive drug group (diltiazem hydrochloride, DH), high dose group (24 mg/kg, HXP-H) and low dose group (12 mg/kg, HXP-L) of Huoxin Pill (n=15 for every group) according to the complete randomization method. After 1 week of intragastric administration, the left anterior descending coronary artery of the rat's heart was ligated for 45 min and reperfused for 3 h. Serum was separated and the levels of creatine kinase (CK), creatine kinase isoenzyme (CK-MB) and lactate dehydrogenase (LDH), superoxide dismutase (SOD), and malondialdehyde (MDA), hypersensitive C-reactive protein (hs-CRP) and interleukin-1β (IL-1β) were measured. Myocardial ischemia rate, myocardial infarction rate and myocardial no-reflow rate were determined by staining with Evans blue and 2,3, 5-triphenyltetrazolium chloride (TTC). Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform (TCMSP) and Bioinformatics Analysis Tool for Molecular mechANism of Traditional Chinese Medicine (BATMAN) databases were used to screen for possible active compounds of HXP and their potential therapeutic targets; the results of anti-inflammatory genes associated with MIRI were obtained from GeneCards, Drugbank, Online Mendelian Inheritance in Man (OMIM), and Therapeutic Target Datebase (TTD) databases was performed; Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment were used to analyze the intersected targets; molecular docking was performed using AutoDock Tools. Western blot was used to detect the protein expression of Toll-like receptor 4 (TLR4)/nuclear factor kappa-B (NFκB)/NOD-like receptor protein 3 (NLRP3).Results:Compared with the model group, all doses of HXP significantly reduced the levels of LDH, CK and CK-MB (P < 0.05, P < 0.01); HXP significantly increased serum activity of SOD (P < 0.05, P < 0.01); all doses of HXP significantly reduced the levels of hs-CRP and IL-1β (P < 0.05, P < 0.01) and the myocardial infarction rate and myocardial no-reflow rate (P < 0.01). GO enrichment analysis mainly involved positive regulation of gene expression, extracellular space and identical protein binding, KEGG pathway enrichment mainly involved PI3K-Akt signaling pathway and lipid and atherosclerosis. Molecular docking results showed that kaempferol and luteolin had a better affinity with TLR4, NFκB and NLRP3 molecules. The protein expressions of TLR4, NFκB and NLRP3 were reduced in the HXP group (P < 0.01).Conclusions:HXP has a significant protective effect on myocardial ischemia-reperfusion injury in rats, and its effect may be related to the inhibition of redox response and reduction of the inflammatory response by inhibiting the TLR4/NFκB/NLRP3 signaling pathway.  
        Keywords：Houxin Pill;myocardial ischemia-reperfusion injury;TLR4/NFκB/NLRP3 signaling pathway;network pharmacology;molecular docking   
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        Published：2023-11-21
      • LIANG Bo,LIANG Bo,ZHANG Xiao-xiao,ZHANG Xiao-xiao,GU Ning
        Vol. 29, Issue 12, Pages: 1077-1086(2023) DOI: 10.1007/s11655-023-3642-z
        Abstract：Objective:To reveal the anti-inflammatory mechanism of Guanxin Ⅴ, which is prescribed for ventricular remodeling in clinical practice.Methods:Guanxin Ⅴ-, ventricular remodeling-, and inflammation-related targets were obtained through an integrated strategy of virtual screening and systematic pharmacology, and then the shared targets were visualised with a Venn diagram. Guanxin Ⅴ network and the protein-protein interaction network were drawn, and enrichment analysis was conducted. Finally, the main results obtained from the integrated strategy were validated by molecular docking and in vivo experiments.Results:A total of 251, 11, 425, and 15, 246 Guanxin Ⅴ-, ventricular remodeling-, and inflammation-related targets were acquired, respectively. Then, 211 shared targets were considered to contribute to the mechanism of ventricular remodeling treated by Guanxin Ⅴ. Guanxin network and the protein-protein interaction network were drawn, and enrichment analysis showed some cardiovascular-related biological processes and signaling pathways. Molecular docking revealed that the Guanxin Ⅴ-derived compounds could align with key targets. Final in vivo experiments proved that Guanxin Ⅴ reverses ventricular remodeling by inhibiting inflammation.Conclusion:Guanxin Ⅴ relieves ventricular remodeling by regulating inflammation, which provides new ideas for the anti-ventricular remodeling mechanism of Guanxin Ⅴ.  
        Keywords：Guanxin Ⅴ;Chinese medicine;ventricular remodeling;inflammation   
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        Published：2023-11-21
      • LIN Po-li,LIN Po-li,CAO Jun-ling,CAO Jun-ling,REN Ping,REN Ping,CHEN Jia-li,CHEN Jia-li,CAO Bo-ya,CAO Bo-ya,HE Ping,HE Ping,ZHENG Chang-hui,ZHENG Chang-hui,LI Qi-wen,LI Qi-wen,WANG Wei,WANG Wei,ZHANG Jian
        Vol. 29, Issue 12, Pages: 1087-1098(2023) DOI: 10.1007/s11655-023-3644-x
        Abstract：Objective:To explore the potential molecular mechanism of tetrahydropalmatine (THP) on acute myocardial ischemia (AMI).Methods:First, the target genes of THP and AMI were collected from SymMap Database, Traditional Chinese Medicine Database and Analysis Platform, and Swiss Target Prediction, respectively. Then, the overlapping target genes between THP and AMI were evaluated for Grene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis and protein-protein interaction network analysis. The binding affinity between the protein and THP was assessed by molecular docking. Finally, the protective effects of THP on AMI model and oxygen and glucose deprivation (OGD) model of H9C2 cardiomyocyte were explored and the expression levels of target genes were detected by RT-qPCR in vivo and in vitro.Results:MMP9, PPARG, PTGS2, SLC6A4, ESR1, JAK2, GSK3B, NOS2 and AR were recognized as hub genes. The KEGG enrichment analysis results revealed that the potential target genes of THP were involved in the regulation of PPAR and hormone pathways. THP improved the cardiac function, as well as alleviated myocardial cell damage. Furthermore, THP significantly decreased the RNA expression levels of MMP9, PTGS2, SLC6A4, GSK3B and ESR1 (P < 0.05, P < 0.01) after AMI. In vitro, THP significantly increased H9C2 cardiomyocyte viability (P < 0.05, P < 0.01) and inhibited the RNA expression levels of PPARG, ESR1 and AR (P < 0.05, P < 0.01) in OGD model.Conclusions:THP could improve cardiac function and alleviate myocardial injury in AMI. The underlying mechanism may be inhibition of inflammation, the improvement of energy metabolism and the regulation of hormones.  
        Keywords：tetrahydropalmatine;acute myocardial infarction;inflammation;energy metabolism;hormone   
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        Published：2023-11-21
      • LI Si-nai,LI Si-nai,LIU Zi-hao,LIU Zi-hao,ZHOU Ming-xue,ZHOU Ming-xue,LIU Wei-hong,LIU Wei-hong,LAI Xiao-lei,LAI Xiao-lei,LI Ping,LI Ping,ZHANG Lei,ZHANG Lei,SHANG Ju-ju,SHANG Ju-ju,QIU Sheng-lei,QIU Sheng-lei,LOU Yan,LOU Yan,TAN Yu-pei,TAN Yu-pei,XING Wen-long,XING Wen-long,LIU Hong-xu
        Vol. 29, Issue 12, Pages: 1099-1110(2023) DOI: 10.1007/s11655-023-3647-7
        Abstract：Objective:To investigate the involvement of endothelial cells (ECs)-derived exosomes in the anti-apoptotic effect of Danhong Injection (DHI) and the mechanism of DHI-induced exosomal protection against post-infarction myocardial apoptosis.Methods:A mouse permanent myocardial infarction (MI) model was established, followed by a 14-day daily treatment with DHI, DHI plus GW4869 (an exosomal inhibitor), or saline. Phosphate-buffered saline (PBS)-induced ECs-derived exosomes were isolated, analyzed by miRNA microarray and validated by droplet digital polymerase chain reaction (ddPCR). The exosomes induced by DHI (DHI-exo), PBS (PBS-exo), or DHI+GW4869 (GW-exo) were isolated and injected into the peri-infarct zone following MI. The protective effects of DHI and DHI-exo on MI hearts were measured by echocardiography, Masson's trichrome staining, and TUNEL apoptosis assay. The Western blotting and quantitative reverse transcription PCR (qRT-PCR) were used to evaluate the expression levels of miR-125b/p53-mediated pathway components, including miR-125b, p53, Bak, Bax, and caspase-3 activities.Results:DHI significantly improved cardiac function and reduced infarct size in MI mice (P < 0.01), which was abolished by the GW4869 intervention. DHI promoted the exosomal secretion in ECs (P < 0.01). According to the results of exosomal miRNA microarray assay, 30 differentially expressed miRNAs in the DHI-exo were identified (28 up-regulated miRNAs and 2 down-regulated miRNAs). Among them, DHI significantly elevated miR-125b level in DHI-exo and DHI-treated ECs, a recognized apoptotic inhibitor impeding p53 signaling (P < 0.05). Remarkably, treatment with DHI and DHI-exo attenuated apoptosis, elevated miR-125b expression level, inhibited capsase-3 activity, and down-regulated the expression levels of proapoptotic effectors (p53, Bak, and Bax) in post-MI hearts, whereas these effects were blocked by GW4869 (P < 0.05 or P < 0.01).Conclusion:DHI and DHI-induced exosomes inhibited apoptosis, promoted the miR-125b expression level, and regulated the p53 apoptotic pathway in post-infarction myocardium.  
        Keywords：Exosome;Danhong Injection;Chinese medicine;miR-125b;myocardial infarction;apoptosis   
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        Published：2023-11-21
      • ZHOU Chun-hong,ZHOU Chun-hong,YANG Hua,YANG Hua,ZOU Li-fang,ZOU Li-fang,LIU Di-fa,LIU Di-fa,YU Lin-zhong,YU Lin-zhong,CAO Hui-hui,CAO Hui-hui,DENG Li-e,DENG Li-e,WANG Zhang-wei,WANG Zhang-wei,LU Zi-bin,LU Zi-bin,LIU Jun-shan
        Vol. 29, Issue 12, Pages: 1111-1120(2023) DOI: 10.1007/s11655-023-3643-y
        Abstract：Objective:To explore the anti-inflammatory effects of ethyl lithospermate in lipopolysaccharide (LPS)-stimulated RAW 264.7 murine-derived macrophages and zebrafish, and its underlying mechanisms.Methods:3-[4, 5-dimethylthiazol-2-yl]-2, 5-diphenyltetrazoliumbromide (MTT) assays were performed to investigate the toxicity of ethyl lithospermate at different concentrations (12.5–100 μmol/L) in RAW 264.7 cells. The cells were stimulated with LPS (100 ng/mL) for 12 h to establish an inflammation model in vitro, the production of pro-inflammatory cytokines interleukin (IL)-6 and tumor necrosis factor α (TNF-α) were assessed by enzyme linked immunosorbent assay (ELISA). Western blot was used to ascertain the protein expressions of signal transducer and activator of transcription 3 (STAT3), nuclear factor kappa B (NF-κB) p65, phospho-STAT3 (p-STAT3, Tyr705), inhibitor of NF-κB (IκB) α, and phospho-IκBα (p-IκBα, Ser32), and confocal imaging was used to identify the nuclear translocation of NF-κB p65 and p-STAT3 (Tyr705). Additionally, the yolk sacs of zebrafish (3 days post fertilization) were injected with 2 nL LPS (0.5 mg/mL) to induce an inflammation model in vivo. Survival analysis, hematoxylin-eosin (HE) staining, observation of neutrophil migration, and quantitative real-time polymerase chain reaction (qRT-PCR) were used to further study the anti-inflammatory effects of ethyl lithospermate and its probable mechanisms in vivo.Results:The non-toxic concentrations of ethyl lithospermate have been found to range from 12.5 to 100 μmol/L. Ethyl lithospermate inhibited the release of IL-6 and TNF-α (P < 0.05 or P< 0.01), decreased IκBα degradation and phosphorylation (P < 0.05) as well as the nuclear translocation of NF-κB p65 and p-STAT3 (Tyr705) in LPS-induced RAW 264.7 cells (P < 0.01). Ethyl lithospermate also decreased inflammatory cells infiltration and neutrophil migration while increasing the survival rate of LPS-stimulated zebrafish (P < 0.05 or P < 0.01). In addition, ethyl lithospermate also inhibited the mRNA expression levels of of IL-6, TNF-α, IκBα, STAT3, and NF-κB in LPS-stimulated zebrafish (P < 0.01).Conclusion:Ethyl lithospermate exerts anti-Inflammatory effected by inhibiting the NF-κB and STAT3 signal pathways in RAW 264.7 macrophages and zebrafish.  
        Keywords：ethyl lithospermate;anti-inflammation;nuclear factor kappa B;signal transducer and activator of transcription 3;lipopolysaccharide;zebrafish   
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        Published：2023-11-21
      • LIU Li-qun,LIU Li-qun,ZHANG Peng,ZHANG Peng,QI Ying-zi,QI Ying-zi,LI Hui,LI Hui,JIANG Yue-hua,JIANG Yue-hua,YANG Chuan-hua
        Vol. 29, Issue 12, Pages: 1121-1132(2023) DOI: 10.1007/s11655-023-3645-9
        Abstract：Objective:To interpret the pharmacology of quercetin in treatment of atherosclerosis (AS).Methods:Fourteen apolipoprotein E-deficient (ApoE-/-) mice were divided into 2 groups by a random number table: an AS model (ApoE-/-) group and a quercetin treatment group (7 in each). Seven age-matched C57 mice were used as controls (n = 7). Quercetin [20 mg/(kg•d)] was administered to the quercetin group intragastrically for 8 weeks for pharmacodynamic evaluation. Besides morphological observation, the distribution of CD11b, F4/80, sirtuin 1 (Sirt1) and P21 was assayed by immunohistochemistry and immunofluorescence to evaluate macrophage infiltration and tissue senescence. Ultra-performance liquid chromatography/tandem mass spectrometry (UPLC-MSC/MS) was performed to study the pharmacology of quercetin against AS. Then, simultaneous administration of an apelin receptor antagonist (ML221) with quercetin was conducted to verify the possible targets of quercetin. Key proteins in apelin signaling pathway, such as angiotensin domain type 1 receptor-associated proteins (APJ), AMP-activated protein kinase (AMPK), peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α), tissue plasminogen activator (TPA), uncoupling protein 1 (UCP1) and angiotensin Ⅱ receptor 1 (AT1R), were assayed by Western blot.Results:Quercetin administration decreased lipid deposition in arterial lumen and improved the morphology of ApoE-/- aortas in vivo. Quercetin decreased the densities of CD11b, F4/80 and P21 in the aorta and increased the level of serum apelin and the densities of APJ and Sirt1 in the aorta in ApoE-/- mice (all P < 0.05). Plasma metabolite profiling identified 118 differential metabolites and showed that quercetin affected mainly glycerophospholipids and fatty acyls. Bioinformatics analysis suggested that the apelin signaling pathway was one of the main pathways. Quercetin treatment increased the protein expressions of APJ, AMPK, PGC-1α, TPA and UCP1, while decreased the AT1R level (all P < 0.05). After the apelin pathway was blocked by ML221, the effect of quercetin was abated significantly, confirming that quercetin attenuated AS by modulating the apelin signaling pathway (all P < 0.05).Conclusion:Quercetin alleviated AS lesions by up-regulation the apelin signaling pathway.  
        Keywords：quercetin;atherosclerosis;plasma metabonomics;apelin signaling pathway   
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        Published：2023-11-21

        Acupuncture Research

      • ZHAO Nan-qi,ZHAO Nan-qi,LIU Ya-li,LIU Ya-li,DING Nan,DING Nan,YUAN Jing-yun,YUAN Jing-yun,MOU Dong-xiao,MOU Dong-xiao,DONG Guo-feng,DONG Guo-feng,WANG Xin,WANG Xin,WU Xiao-dong
        Vol. 29, Issue 12, Pages: 1133-1141(2023) DOI: 10.1007/s11655-023-3641-0
        Abstract：Objective:To analyze the differences in the needs of users and the value orientation of clinical practice guidelines (CPGs) by comparing the contents and formation methods of clinical questions in Chinese and Korean CPGs of acupuncture-moxibustion (Acup-Mox).Methods:The full text of CPGs was systematically searched from the official websites of Chinese and Korean traditional medicine societies and Acup-Mox associations, with the topic "Acup-Mox for treating diseases" and the retrieval time up to September 28, 2022. Two researchers screened the CPGs independently, and extracted the guidelines' topics, content, quantity and formation methods of clinical questions. The quantitative data were collected by counting the frequency, and the qualitative data were classified and described by thematic analysis.Results:A total of 29 guidelines were included in this study, including 20 Chinese guidelines (305 questions) and 9 Korean guidelines (223 questions). The differences lie in the aspects of content and diversity, and formation method. As for content and diversity, Chinese guidelines focused mainly on the questions related to treatment such as the operation of specific intervention (86, 28.2%), efficacy of intervention (78, 25.6%), and also involving questions in diagnosis, prevention, and prognosis. While the clinical questions in Korean guidelines were concentrated to efficacy of intervention (218, 97.8%). As for formation method, in Chinese guidelines, questions were usually collected directly from clinicians, and then determined and optimized by experts. In Korean guidelines, frequently used clinical Acup-Mox interventions would be screened first. Then the expert group would set up corresponding intervention control measures so as to form clinical questions related to treatment efficacy.Conclusions:The differences reflect the different needs of clinical practitioners, and the different aims or concepts in developing Acup-Mox guidelines between China and South Korea. Chinese guidelines emphasized promoting operation protocols and techniques of Acup-Mox for practical use, while Korean guidelines emphasized promoting the frequently used clinical intervention therapies. It is speculated that the guidelines from these two countries would play different roles in guiding clinical operation and supporting medical decision. In terms of formation methods of clinical questions, it is suggested to attach importance to optimizing process in formatting clinical questions to improve the clinical applicability of CPGs of Acup-Mox.  
        Keywords：association of acupuncture-moxibustion;clinical practice guidelines;clinical questions;optimize   
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        Published：2023-11-21

        Review

      • ZHANG Ming-qing,ZHANG Ming-qing,LI Chun-sheng
        Vol. 29, Issue 12, Pages: 1142-1146(2023) DOI: 10.1007/s11655-023-3631-2
        Abstract：Shock is the clinical manifestation of acute circulatory failure, which results in inadequate utilization of cellular oxygen. It is a common condition with high mortality rates in intensive care units. The intravenous administration of Shenfu Injection (SFI) may attenuate inflammation, regulate hemodynamics and oxygen metabolism; inhibit ischemia-reperfusion responses; and have adaptogenic and antiapoptotic effects. In this review, we have discussed the clinical applications and antishock pharmacological effects of SFI. Further in-depth and large-scale multicenter clinical studies are warranted to determine the therapeutic effects of SFI on shock.  
        Keywords：pathophysiology;shock;Chinese medicine;Shenfu Injection   
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        Published：2023-11-21
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