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      Vol. 27 ， Issue 11 ， 2021

        Original Article

      • Xiao-juan MA,Wen-hui DUAN,Ying ZHANG,Jie GAO,Bao-yi GUAN,Ke-ji CHEN,Da-zhuo SHI
        Vol. 27, Issue 11, Pages: 803-810(2021) DOI: 10.1007/s11655-021-2878-8
        Abstract：Objective:To investigate the combined anti-inflammatory effect of activating blood circulation and detoxifying Chinese medicines in unstable angina (UA) patients.Methods:This study was an open-labeled, randomized controlled trial conducted in 5 centers in Beijing. A total of 154 patients were randomized into two groups at a 1:1 ratio by random numbers. Based on the conventional treatment, patients in the activating blood circulation (ABC) group were treated with Guanxin Danshen Droping Pill (冠心丹参滴丸, 0.4 g, thrice daily), and patients in the activating blood circulation and detoxifying (ABCD) group were treated with Guanxin Danshen Droping Pill (0.4 g, thrice daily) and Andrographis tablet (0.2 g, thrice daily) for 4 weeks. The primary outcome was the serum level of high sensitive C reaction protein (hs-CRP), and the secondary outcome index included the serum levels of tumor necrosis factor α (TNF-α), interleukin 6 (IL-6), soluble CD40 ligand (sCD40L), thrombomodulin (TM), the score of angina pectoris, the score of blood stasis syndrome, and the score of Chinese medicine symptoms, observed at week 0 and week 4.Results:A total of 144 patients completed the trial (ABC group, n=70; ABCD group, n=74). There were no significant differences in the clinical baseline characteristics between the two groups. When compared with the ABC group, ABCD group showed better performance in reducing the level of inflammatory factors, especially hs-CRP (P<0.05), IL-6 (P<0.01) and TNF-α (P<0.01). In term of clinical symptoms, ABCD group played a better role in improving the scores of angina pectoris and blood stasis syndrome than ABC group (all P<0.05).Conclusions:The combination of Guanxin Danshen Dropping Pill and Andrographis tablet exert significant anti-inflammatory effect on UA patients, which is superior to single Guanxin Danshen Dropping Pill. (Registration No. ChiCTR-TRC-13004072)  
        Keywords：Chinese medicine;unstable angina;inflammation;randomized controlled trial   
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        Published：2021-11-05
      • Yu WANG,Jie-hong YANG,Hai-tong WAN,Yu HE,Bin XU,Chang-shan AI,Hui-fen ZHOU,Li YU,Hao-fang WAN,Xiao-dong BIE
        Vol. 27, Issue 11, Pages: 811-818(2021) DOI: 10.1007/s11655-021-2857-0
        Abstract：Objective:To evaluate the efficacy and safety of Yangyin Yiqi Huoxue Granule (养阴益气活血 颗粒, YYHG) in the treatment of ischemic stroke (IS) patients with qi-yin deficiency and blood stasis syndrome (QYDBSS), and to explore its effective dosage.Methods:The total of 288 patients were randomly assigned to the YYHG high-dose, YYHG low-dose, positive control (administered Xiaoshuantong Granule, XSTG, 消栓通颗粒), or placebo control (administered inert granule) groups (72 cases per group) by software-drived competitive block randomization. The trial was conducted for a 28-day period, with a 180-day follow-up period. The primary outcome was the comprehensive curative evaluation, and secondary outcomes were the National Institute of Health Stroke Scale (NIHSS) score, Barthel activities of daily living (ADL) index score, the quality of life index (QLI) score, and the Chinese medicine syndrome (CMS) score. All analyses were done on an intention-to-treat basis. The clinical safety was also assessed.Results:The total of 288 participants were recruited between June 1, 2008 and September 30, 2009, and 287 patients received intervention; the treatment groups were well balanced at baseline. The comprehensive cure rates of YYHG high-dose, low-dose, positive and placebo control groups were 63.38%, 31.94%, 36.11% and 6.14%, respectively; there was a statistical difference between the two groups (P<0.01), while the high-dose YYHG treatment group was significantly higher than the other 3 groups (P<0.01). The improvement of NIHSS, ADL, QLI and CMS scores of the YYHG high-dose and low-dose groups was significantly better than that of the positive control group and the placebo control group (P<0.05). In terms of improving the classification of the NIHSS scale and the assessment of the ADL scale, the YYHG high-dose group was significantly better than the other three groups (P<0.05), and the YYHG low-dose group was better than the placebo control group (P<0.01). At the same time, except for the QLI score, the high-dose group was better than the low-dose group (P<0.05). In terms of safety, adverse reactions after YYHG treatment were generally mild (3.78%), and no serious adverse reactions have been reported.Conclusion:YYHG is safe and effective in the treatment of IS patients with QYDBSS.  
        Keywords：stroke;qi-yin deficiency and blood stasis syndrome;Chinese medicine;randomized controlled trial   
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        Published：2021-11-05
      • Ming-ming WANG,Mei XUE,Zhong-hai XIN,Yan-hui WANG,Rui-jie LI,Hong-yan JIANG,Da-zhuo SHI
        Vol. 27, Issue 11, Pages: 819-824(2021) DOI: 10.1007/s11655-021-2854-3
        Abstract：Objective:To elucidate the underlying mechanism of Panax notoginseng saponin (PNS) on gastric epithelial cell injury and barrier dysfunction induced by dual antiplatelet (DA).Methods:Human gastric mucosal epithelial cell (GES-1) was cultured and divided into 4 groups: a control, a DA, a PNS+DA and a LY294002+PNS+DA group. GES-1 apoptosis was detected by flow cytometry, cell permeability were detected using Transwell, level of prostaglandins E2 (PGE2), 6-keto-prostaglandin F1α (6-keto-PGF1α) and vascular endothelial growth factor (VEGF) in supernatant were measured by enzyme linked immunosorbent assay (ELISA), expression of phosphatidylinositide 3-kinase (PI3K), phosphorylated-PI3K (p-PI3K), Akt, phosphorylated-Akt (p-Akt), cyclooxygenase-1 (COX-1), cyclooxygenase-2 (COX-2), glycogen synthase kinase-3β (GSK-3β) and Ras homolog gene family member A (RhoA) were measured by Western-blot.Results:DA induced apoptosis and hyper-permeability in GES-1, reduced supernatant level of PGE2, 6-keto-PGF1α and VEGF (P<0.05). Addition of PNS reduced the apoptosis of GES-1 caused by DA, restored the concentration of PGE2, 6-keto-PGF1α and VEGF (P<0.05). In addition, PNS attenuated the alteration of COX-1 and COX-2 expression induced by DA, up-regulated p-PI3K/p-Akt, down-regulated RhoA and GSK-3β. LY294002 mitigated the effects of PNS on cell apoptosis, cell permeability, VEGF concentration, and expression of RhoA and GSK-3β significantly.Conclusions:PNS attenuates the suppression on COX/PG pathway from DA, alleviates DA-induced GES-1 apoptosis and barrier dysfunction through PI3K/Akt/ VEGF-GSK-3β-RhoA network pathway.  
        Keywords：Panax notoginseng saponins;dual antiplatelet;permeability;cyclooxygenase;PI3K   
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        Published：2021-11-05
      • Xin HUANG,Min-zhou ZHANG,Bo LIU,Shi-yu MA,Xin YIN,Li-heng GUO
        Vol. 27, Issue 11, Pages: 825-831(2021) DOI: 10.1007/s11655-021-2869-9
        Abstract：Objective:To evaluate the protective effects of Astragaloside Ⅳ (AST) in a rat model of myocardial injury induced by cecal ligation and puncture (CLP).Methods:The model of sepsis-induced cardiac dysfunction was induced by CLP. Using a random number table, 50 specific pathogen free grade of Sprague Dawley rats were randomized into 5 groups: the sham group (sham), the model group (CLP, 18 h/72 h) and AST group (18 h/72 h). Except the sham group, the rats in other groups received CLP surgery to induce sepsis. CLP groups received intragastric administration with normal saline after CLP. AST groups received intragastric administration with AST solution (40 mg/kg) once a day. The levels of inflammatory mediators and oxidative stress markers in the serum of the septic rats were determined via enzyme-linked immunosorbent assay (ELISA) at different time point, such as interleukin 6 (IL-6), IL-10, high mobility group box-1 protein B1 (HMGB-1), superoxide dismutase (SOD), and malondialdehyde (MDA). Cardiac function was determined by echocardiography. Moreover, changes in myocardial pathology were evaluated using hematoxylin and eosin staining. The levels of lactate dehydrogenase (LDH) and creatine kinase-MB (CK-MB) were analysed to determine the status of CLP-induced myocardium. In addition, the apotosis of myocardial cells was analysed by terminal-deoxynucleoitidyl transferase mediated nick end labeling (TUNEL). The protein levels of B-cell lymphoma-2 (Bcl-2), Bcl-2-associated X (Bax), IκB kinase α (IKKα), nuclear factor kappa B p65 (NF-κB p65) were detected by Western blot analysis. Moreover, survival rate was investigated.Results:AST improved the survival rate of CLP-induced rats by up to 33.3% (P<0.05). The cardioprotective effect of AST was observed by increased ejection fraction, fractional shortening and left ventricular internal diameter in diastole respectively (P<0.01 or P<0.05). Subsequently, AST attenuated CLP-induced myocardial apoptosis and the ratio of Bcl-2/Bax in the myocardium, as well as the histological alterations of myocardium (P<0.01 or P<0.05); the generation of inflammatory cytokines (IL-6, IL-10, HMGB-1) and oxidative stress markers (SOD, MDA) in the serum was significantly alleviated (P<0.01 or P<0.05). On the other hand, AST markedly suppressed CLP-induced accumulation of IKK-α and NF-κB p65 subunit phosphorylation (P<0.01 or P<0.05).Conclusions:AST plays a significant protective role in sepsis-induced cardiac dysfunction and survival outcome. The possible mechanism of cardioprotection is dependent on the activation of the IKK/NF-κB pathway in cardiomyocytes.  
        Keywords：Astragaloside Ⅳ;cecal ligation and puncture;myocardial dysfunction   
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        Published：2021-11-05
      • Fei-lin GE,Ming NIU,Zi-xin HAN,Jun-ling CAO,Jia-bo WANG,Zhao-fang BAI,Hai-bo SONG,Yu-ming GUO,Xiao-he XIAO
        Vol. 27, Issue 11, Pages: 832-837(2021) DOI: 10.1007/s11655-021-3442-2
        Abstract：Objective:To analyze clinical feature and information of medication to explore the risk signals of preparations containing Psoraleae Fructus (BGZP) related with hepatobiliary adverse drug reactions (ADR), in order to reinforce pharmacovigilance.Methods:A retrospective study was conducted based on hepatobiliary ADR related with BGZP from the China Adverse Drug Reaction Monitoring System in years from January 2012 to December 2016. Serious and general ADRs were analyzed and assessed.Results:There were 355 cases of hepatobiliary ADR related to BGZP. Both the amount of cases and the proportion of serious ADR showed an increasing growth by years (P<0.05). It was found that 10.43% of 355 cases may be involved with irrational drug use, including overdose, repeated medication, and combination of multiple drugs. There were 190 cases which used BGZP (non-combination), and they were mainly for common in diseases caused by abnormal immune activation (accounting for 40.53% of the total cases). Especially at the age group with the most cases with age of 41–50 years, the cases associated with immunological diseases of female were obviously more than that of male (P<0.05). The latency of hepatobiliary ADR related to BGZP ranged from 1 to 386 days, and the median latency was 27.5 days, along with the range of cumulative dose (0.45–520.02 g) as well as the daily dose (0.09–2.64 g/d) after the conversion.Conclusions:Cases of hepatobiliary ADR related to BGZP showed significant individual differences, and there was no correlation between drug usage duration and dosage and the occurrence of hepatobiliary ADR. It may be similar with idiosyncratic drug-induced liver injury, and recommended that BGZP should be used with more caution under monitoring liver function, especially in female patients with immunological diseases.  
        Keywords：drug safety;hepatobiliary adverse drug reaction;Psoraleae Fructus;pharmacovigilance   
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        Published：2021-11-05

        Acupuncture Research

      • De-hua LI,Jin XIE,Yu-lan REN,Hui ZHENG,Jun-ling LYU,Jun-yan LENG,Ling-lin ZHANG,Jie ZHANG,Hai-long FAN,Fan-rong LIANG
        Vol. 27, Issue 11, Pages: 838-845(2021) DOI: 10.1007/s11655-021-2870-3
        Abstract：Objective:To assess the clinical effectiveness of acupoint application (AP) of Guan Xin Su He Pill (冠心苏合丸, GXSHP) for patients with chronic stable angina pectoris (CSAP).Methods:This study was carried out in 3 local hospitals in Chengdu, China. After baseline evaluation, eligible patients were randomly assigned to the placebo application for acupoints (PAA) group or the herbal application for acupoints (HAA) group. Patients in the HAA group underwent AP with herbal powder, which was mainly GXSHP, and patients in the PAA group underwent AP with sham drugs. For each treatment session, unilateral acupoints including Neiguan (PC 6), Danzhong (RN 17), Xinshu (BL 15) and Jueyinshu (BL 14), were stimulated for both groups. AP was performed 3 times a week with a 2-day interval for 4 weeks. The primary outcome was the frequency of angina pectoris attacks per week, while the secondary outcomes included angina pain intensity measured by the Visual Analogue Scale (VAS), dose of rescue oral drugs (nitroglycerin), scores on the Seattle Angina Questionnaire (SAQ), Self-Rating Anxiety Scale scores (SAS) and Self-Rating Depression Scale scores (SDS). Clinical outcomes were measured at week 0, 4 and 8. The safety of AP of GXSHP treatment for CSAP were assessed.Results:A total of 121 patients were enrolled. Baseline characteristics were comparable across the 2 groups. After treatment, the angina attack numbers in the HAA group were significantly reduced from 11.00 to 4.81 (P<0.05). While, for PAA group, the angina frequency was not significantly improved (baseline 10.55; post-treatment 11.05). The HAA group had significantly fewer angina attacks than the PAA group (P<0.05). Pain intensity measured by VAS in HAA group was significantly reduced from 4.06 to 3.02 (P<0.05). While, for PAA group, the VAS was significantly increased (baseline 3.62; post-treatment 3.96; P<0.05). Clinical outcomes showed better improvement after treatment in the HAA group than in the PAA group in terms of oral administration of rescue drugs, SAS, SDS and SAQ scores (P<0.05). The adverse events were also reported.Conclusion:AP of GXSHP is a safe and effective treatment for CSAP patients (Registration No. NCT02029118).  
        Keywords：acupoint application;chronic stable angina pectoris;clinical efficacy randomized controlled trial   
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        Published：2021-11-05

        Clinical Experience

      • Wen-long XING,Yong-jian WU,Hong-xu LIU,Qing-rong LIU,Qi ZHOU,Ai-yong LI,Zhu-hua ZHANG,Xuan LI
        Vol. 27, Issue 11, Pages: 846-853(2021) DOI: 10.1007/s11655-021-2872-1
        Abstract：Objective:To evaluate the effect of Danhong Injection (丹红注射液, DH) on the index of microcirculatory resistance (IMR) and myocardial injury in patients with unstable angina undergoing elective percutaneous coronary intervention (PCI).Methods:Seventy-eight patients with unstable angina were randomly divided into DH group (39 cases) and the control group (39 cases) during elective PCI. Randomization was performed using a random-number table. The DH group received DH at a dosage of 40 mL (mixed with 250 mL saline, covered by a light-proof bag, intravenous drip) during PCI and daily for 7 consecutive days, while the control group only received the same dosage of saline. Both groups received standardized treatment. The IMR and fractional flow reserve (FFR) were measured at maximal hyperemia before and after PCI. Myocardial markers, including myoglobin, creatine kinase (CK), creatine kinase MB (CK-MB), and coronary troponin T (cTnT) values were measured at baseline and 24 h after PCI.Results:Among the 78 patients enrolled, the baseline and procedural characteristics were similar between the two groups. There was no significant difference in pre-PCI myocardial markers and coronary physiological indexes between the two groups. However, post-PCI CK and CK-MB levels in the DH group were significantly lower than those in the control group (111.97±80.97 vs. 165.47±102.99, P=0.013; 13.08±6.90 vs. 19.75±15.49, P=0.016). Post-PCI myoglobin and cTNT-positive tend to be lower in the DH group than in the control group but did not reach statistical significance (88.07±52.36 vs. 108.13±90.94, P=0.52; 2.56% vs.7.69%, P=0.065). Compared with the control group, the post-IMR levels of the DH group tended to decrease, but there was no statistical difference (20.73±13.15 vs. 26.37±12.31, P=0.05). There were no statistical differences in post-FFR in both groups. The peri-procedural myocardial injury of the DH group was significantly lower than that of the control group (2.56% vs. 15.38%, P=0.025). During the 30-d follow-up period, no major adverse cardiovascular events occurred in either group.Conclusion:This study demonstrated benefit of DH in reducing myocardial injury and potential preserving microvascular function in patients with unstable angina undergoing elective PCI.  
        Keywords：peri-procedural myocardial injury;percutaneous coronary intervention;microcirculatory resistance;microvascular dysfunction   
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        Published：2021-11-05

        Evidence-Based Integrative Medicine

      • Qi-qi XIN,Xun CHEN,Rong YUAN,Ya-hui YUAN,Jia-qi HUI,Yu MIAO,Wei-hong CONG,Ke-ji CHEN
        Vol. 27, Issue 11, Pages: 858-866(2021) DOI: 10.1007/s11655-021-2871-2
        Abstract：Objective:To investigate the correlation of platelet and coagulation function with blood stasis syndrome (BSS) in coronary heart disease (CHD).Methods:The protocol for this meta-analysis was registered on PROSPERO (CRD42019129452). PubMed, Excerpta Medica Database (Embase), the Cochrane Library, and China National Knowledge Infrastructure (CNKI) were searched from inception to 1st June, 2020. Trials were considered eligible if they enrolled BSS and non-BSS (NBSS) patients with CHD and provided information on platelet and coagulation function. The platelet function, coagulation function, and fibrinolytic activity were compared between the BSS and NBSS groups. Forest plots were generated to show the SMDs or ESs with corresponding 95% CIs for each study. Subgroup analysis and sensitivity analysis were performed to explore potential sources of heterogeneity.Results:The systematic search identified 1, 583 articles. Thirty trials involving 10, 323 patients were included in the meta-analysis. The results showed that mean platelet volume, platelet distribution width, platelet aggregation rate, platelet P selectin, fibrinogen, plasminogen activator inhibitor-1 (PAI-1), thromboxane B2 (TXB2), 6-keto-prostaglandin F1alpha (6-keto-PGF1α), and TXB2/6-keto-PGF1α were higher in the BSS group than in the NBSS group (P<0.05 or P<0.01). Activated partial thromboplastin time was lower in the BSS group than in the NBSS group in the acute phase of CHD (P<0.01). The R and K values in thromboelastography and tissue plasminogen activator (t-PA) and t-PA/PAI-1 were lower in the BSS group than in the NBSS group (all P<0.01). No difference was found in the results of platelet count, plateletcrit, maximum amplitude, von Willebrand factor, prothrombin time, thrombin time, international normalized ratio, etc. between groups.Conclusions:Increased platelet function, hypercoagulability, and decreased fibrinolytic activity were found among CHD patients with BSS.  
        Keywords：coronary heart disease;blood stasis syndrome;platelet;coagulation   
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        Published：2021-11-05

        Review

      • Zhao-ying LIANG,Cai-wen QIAN,Tao-hua LAN,Qiao-huang ZENG,Wei-hui LU,Wei JIANG
        Vol. 27, Issue 11, Pages: 867-873(2021) DOI: 10.1007/s11655-021-2877-9
        Abstract：Inflammation and immune disorders are integral to the occurrence and progression of atherosclerosis (AS). With the role of regulatory T cells (Tregs) in immune regulation attracting attention, it has been widely accepted that Treg decrease and dysfunction are involved in AS pathogenesis. Chinese medicine (CM) has the advantages of being dual-directional, multi-targeted, and having minimal side effects in immune regulation. The anti-atherosclerosis effects of CM via Treg modulation have been revealed in clinical and animal studies. Therefore, this article reviews existing research on Tregs, the relationship between Tregs and AS, and the progress of CM for treating and prevention of atherosclerotic cardio-cerebrovascular diseases by regulating Tregs. Although the underlying mechanisms remain to be elucidated, CM treatment targeting Treg cells might provide a promising and novel future approach for prevention and treatment of AS.  
        Keywords：Chinese medicine;atherosclerosis;regulatory T cells;immunization;inflammation   
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        Published：2021-11-05
      • Guang-tao HU,Yong WANG
        Vol. 27, Issue 11, Pages: 874-880(2021) DOI: 10.1007/s11655-021-2864-1
        Abstract："Timely, near, and expectation" is the main principle of battlefield rescue for military combat stress reaction (CSR). Post-traumatic stress disorder (PTSD) is the most common form of CSR and a long-term persistent mental disorder that is caused by unusual threatening or catastrophic psychological trauma. Chinese medicine (CM) has abundant resources, is simple, easy to master, with few side effects. This article summarizes the cellular and animal experimental mechanisms of CM treatment on PTSD, suggesting that traditional Chinese herbs and acupuncture can protect brain functional areas, and adjust hypothalamus-pituitary-adrenal axis. Traditional Chinese herbs and acupuncture have shown good anti-stress efficacy and fewer side effects in clinical application, which may improve the CSR in the battlefield.  
        Keywords：combat stress reaction;post-traumatic stress disorder;Chinese medicine;acupuncture treatment   
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