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      Vol. 28 ， Issue 4 ， 2022

        Original Article

      • Ling QU,Xiao-chun LIANG,Guo-qing TIAN,Gai-li ZHANG,Qun-li WU,Xiu-mei HUANG,Ya-zhong CUI,Yu-ling LIU,Zhu-fang SHEN,Guo-qing MA,Hao LU,Yi LI,Hong JIANG,Xi-yan YANG,Guang-de ZHANG,Chen-hua YANG
        Vol. 28, Issue 4, Pages: 304-311(2022) DOI: 10.1007/s11655-021-2885-9
        Abstract：Objective:To assess the efficacy and safety of mulberry twig alkaloids (Sangzhi alkaloids, SZ-A) for treatment of type 2 diabetes in a randomized, double-blind, placebo-controlled multicenter clinical trial.Methods:A total of 200 patients were randomized to receive SZ-A (n=100) or placebo (n=100) for 16 weeks. The data analysis system for electronic data capture clinical trial central randomization system was used for randomization and dispensing of drugs. The primary outcome was the change in glycosylated hemoglobin (HbA1c) level. The secondary outcome included the proportions of cases with HbA1c <7.0% and HbA1c <6.5%, fasting blood glucose (FBG), postprandial blood glucose (PBG), area under curve for the PBG (AUC0-2h ), body weight, and body mass index (BMI). Adverse events (AEs), severe adverse events (SAEs), treatment-related adverse events (TAEs), gastrointestinal disorders (GDs), blood pressure, routine blood tests, and liver and kidney function were monitored.Results:Compared with baseline, the change of HbA1c at week 16 was –0.80% (95% CI: –0.98% to –0.62%) and –0.09% (95% CI: –0.27% to 0.09%) in SZ-A group and placebo group, respectively. The proportion of patients with HbA1c <7% and <6.5% was higher in the SZ-A group than in the placebo group (46.8% vs. 21.6% and 29.9% vs. 10.8%). The observed values and changes in FBG, 1 h-PBG, 2 h-PBG, and AUC0-2h differed significantly between groups (P<0.001), but differences were not significant in body weight and BMI (P>0.05). The incidence rates of AEs, TAEs, and GDs differed significantly between groups (P=0.010, P=0.005, and P=0.006, respectively), whereas the incidence rates of SAEs showed no significant differences between groups (P=1.000).Conclusion:SZ-A are effective and safe for treatment of type 2 diabetes. [The protocol was registered in http://www.chictr.org.cn/showproj. aspx?proj=60117 (ChiCTR2000038550)]  
        Keywords：type 2 diabetes mellitus;mulberry twig alkaloids tablets (Sangzhi alkaloids);efficacy;safety;placebo   
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        Published：2022-03-29
      • Hui GUAN,Guo-hua DAI,Wu-lin GAO,Tong ZHANG,Cong SUN,Li-li REN,Xiao-ming HOU,Zhang LIU
        Vol. 28, Issue 4, Pages: 312-318(2022) DOI: 10.1007/s11655-021-2875-y
        Abstract：Objective:To explore the effect of Shenmai Injection (SMI) on the long-term prognosis of patients with chronic heart failure (CHF).Methods:The Hospital Information System was used to extract data of CHF patients, and the retrospective cohort study was conducted for analysis. In non-exposed group, standardized Western medicine treatment and Chinese patent medicine or decoction were applied without combination of SMI while in the exposed group, SMI were applied for more than 7 days. Evaluation indicators are followed with New York Heart Association functional classification (NYHA classification), left ventricular ejection fraction (LVEF), N-terminal brain natriuretic peptide precursor (NT-ProBNP), cardiogenic death and heart failure (HF) readmission. Statistical analysis includes Kaplan-Meier analysis and Cox regression which are used to explore the relationship between SMI and outcome events.Results:A total of 1,211 eligible CHF patients were involved and finally 1,047 patients were followed up successfully. After treatment, the cases of NYHA classification decline in the exposed and non-exposed groups accounted for 64.30% and 43.45%, respectively; the improvement values of LVEF were 8.89% and 7.91%, respectively; the improvement values of NT-ProBNP were 909 pg/mL and 735 pg/mL, respectively. After exposure on SMI, the rates of cardiogenic death and HF readmission reduced from 15.43% to 10.18% and 38.93% to 32.37%. According to Kaplan-Meier analysis, the log-rank P value of SMI and cardiogenic death was 0.014, while the counterpart of SMI and HF readmission was 0.025. Cox regression analysis indicated that for cardiogenic death, age, cardiomyopathy, diabetes, and NYHA classification were risk factors while β-blockers, aldosterone receptor antagonists, Chinese patent medicine/ decoction and SMI were protective factors. Likewise, for HF readmission, age, cardiomyopathy, and NYHA classification were risk factors while SMI was a protective factor.Conclusion:Combination with SMI on the standardized Western medicine treatment can effectively reduce cardiogenic mortality and readmission rate in CHF patients, and thereby improve the long-term prognosis.  
        Keywords：Shenmai Injection;chronic heart failure;cohort study;outcome events;long-term prognosis   
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        Published：2022-03-29
      • Yan LU,Mei-ling YANG,A-ling SHEN,Shan LIN,Mei-zhong PENG,Tian-yi WANG,Zhu-qing LU,Yi-lian WANG,Jun PENG,Jian-feng CHU
        Vol. 28, Issue 4, Pages: 319-329(2022) DOI: 10.1007/s11655-021-2882-z
        Abstract：Objective:To explore the effect of Kuanxiong Aerosol (KXA) on isoproterenol (ISO)-induced myocardial injury in rat models.Methods:Totally 24 rats were radomly divided into control, ISO, KXA low-dose and high-dose groups according to the randomized block design method, and were administered by intragastric administration for 10 consecutive days, and on the 9th and 10th days, rats were injected with ISO for 2 consecutive days to construct an acute myocardial ischemia model to evaluate the improvement of myocardial ischemia by KXA. In addition, the diastolic effect of KXA on rat thoracic aorta and its regulation of ion channels were tested by in vitro vascular tension test. The influence of KXA on the expression of calcium-CaM-dependent protein kinase Ⅱ (CaMKⅡ)/extracellular regulated protein kinases (ERK) signaling pathway has also been tested.Results:KXA significantly reduced the ISO-induced increase in ST-segment, interventricular septal thickness, cardiac mass index and cardiac tissue pathological changes in rats. Moreover, the relaxation of isolated thoracic arterial rings that had been precontracted using norepinephrine (NE) or potassium chloride (KCl) was increased after KXA treatment in an endothelium-independent manner, and was attenuated by preincubation with verapamil, but not with tetraethylammonium chloride, 4-aminopyridine, glibenclamide, or barium chloride. KXA pretreatment attenuated vasoconstriction induced by CaCl2 in Ca2+ -free solutions containing K+ or NE. In addition, KXA pretreatment inhibited accumulation of Ca2+ in A7r5 cells mediated by KCl and NE and significantly decreased p-CaMKⅡ and p-ERK levels.Conclusion:KXA may inhibit influx and release of calcium and activate the CaMKⅡ/ERK signaling pathway to produce vasodilatory effects, thereby improving myocardial injury.  
        Keywords：Kuanxiong Aerosol;myocardial ischemia;vasodilation;Ca2+;CaMKⅡ/ERK pathway   
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        Published：2022-03-29
      • Yu TAN,Yu-long BIE,Li CHEN,Yi-han ZHAO,Lei SONG,Li-na MIAO,Yan-qiao YU,Hua CHAI,Xiao-juan MA,Da-zhuo SHI
        Vol. 28, Issue 4, Pages: 330-338(2022) DOI: 10.1007/s11655-021-2881-0
        Abstract：Objective:To investigate whether Lingbao Huxin Pill (LBHX) protects against acute myocardial infarction (AMI) at the infarct border zone (IBZ) of myocardial tissue by regulating apoptosis and inflammation through the sirtuin 1 (SIRT1)-mediated forkhead box protein O1 (FOXO1) and nuclear factor-κB (NF-κB) signaling pathways.Methods:Six-week-old Wistar rats with normal diet were randomized into the sham, the model, Betaloc (0.9 mg/kg daily), LBHX-L (0.45 mg/kg daily), LBHX-M (0.9 mg/kg daily), LBHX-H (1.8 mg/kg daily), and LBHX+EX527 (0.9 mg/kg daily) groups according to the method of random number table, 13 in each group. In this study, left anterior descending coronary artery (LADCA) ligation was performed to induce an AMI model in rats. The myocardial infarction area was examined using a 2,3,5-triphenyltetrazolium chloride solution staining assay. A TdT-mediated dUTP nick-end labeling (TUNEL) assay was conducted to assess cardiomyocyte apoptosis in the IBZ. The histopathology of myocardial tissue at the IBZ was assessed with Heidenhain, Masson and hematoxylin- eosin (HE) staining assays. The expression levels of tumor necrosis factor α (TNF-α), interleukin (IL)-6, IL-1β, and intercellular adhesion molecule-1 were measured using enzyme-linked immunosorbent assays (ELISAs). The mRNA expressions of SIRT1 and FOXO1 were detected by real-time qPCR (RT-qPCR). The protein expressions of SIRT1, FOXO1, SOD2, BAX and NF-κB p65 were detected by Western blot analysis.Results:The ligation of the LADCA successfully induced an AMI model. The LBHX pretreatment reduced the infarct size in the AMI rats (P<0.01). The TUNEL assay revealed that LBHX inhibited cardiomyocyte apoptosis at the IBZ. Further, the histological examination showed that the LBHX pretreatment decreased the ischemic area of myocardial tissue (P<0.05), myocardial interstitial collagen deposition (P<0.05) and inflammation at the IBZ. The ELISA results indicated that LBHX decreased the serum levels of inflammatory cytokines in the AMI rats (P<0.05 or P<0.01). Furthermore, Western blot analysis revealed that the LBHX pretreatment upregulated the protein levels of SIRT1, FOXO1 and SOD2 (P<0.05) and downregulated NF-κB p65 and BAX expressions (P<0.05). The RT-qPCR results showed that LBHX increased the SIRT1 mRNA and FOXO1 mRNA levels (P<0.05). These protective effects, including inhibiting apoptosis and alleviating inflammation in the IBZ, were partially abolished by EX527, an inhibitor of SIRT1.Conclusion:LBHX could protect against AMI by suppressing apoptosis and inflammation in AMI rats and the SIRT1- mediated FOXO1 and NF-κB signaling pathways were involved in the cardioprotection effect of LBHX.  
        Keywords：Lingbao Huxin Pill;Chinese medicine;infarct border zone;acute myocardial infarction;SIRT1   
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        Published：2022-03-29
      • Dan-chen SUN,Ran-ran WANG,Hao XU,Xue-hui ZHU,Yan SUN,Shi-qing QIAO,Wei QIAO
        Vol. 28, Issue 4, Pages: 339-348(2022) DOI: 10.1007/s11655-022-2879-2
        Abstract：Objective:To investigate the pharmacodynamic material basis, mechanism of actions and targeted diseases of Salicornia europaea L. (SE) based on the network pharmacology method, and to verify the antidepressant-like effect of the SE extract by pharmacological experiments.Methods:Retrieval tools including Chinese medicine (CM), PubMed, PharmMapper, MAS 3.0 and Cytoscape were used to search the components of SE, predict its targets and related therapeutic diseases, and construct the "Component-Target- Pathway" network of SE for central nervous system (CNS) diseases. Further, protein-protein interaction (PPI) network, Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO) function annotation of depression-related targets were analyzed to predict the antidepressant mechanism of SE. Chronic unpredictable mild stress (CUMS) model was used to construct a mouse model with depression-like symptoms. And the animals were randomly divided into 6 groups (n=10) including the normal group (nonstressed mice administered with distilled water), the CUMS group (CUMS mice administered with distilled water), the venlafaxine group (CUMS mice administered with venlafaxine 9.38 mg/kg), SE high-, medium-, and low-dose groups (CUMS mice administered with SE 1.8, 1.35 and 0.9 g/kg, respectively). Then some relevant indicators were determined for experimental verification by the forced swim test (FST), the tail suspension test (TST) and open-field test (OFT). Dopamine (DA) concentration in hippocampus and cerebral cortex, IL-2 and corticosterone (CORT) levels in blood, and nuclear factor E2 related factor 2 (Nrf2), kelch-like epichlorohydrin related protein 1 (Keap1), NAD(P) H dehydrogenase [quinone] 1 (NQO1) and heme oxygenase-1 (HO-1) levels in mice were measured by enzyme linked immunosorbent assay (ELISA) and Western blot respectively to explore the possible mechanisms.Results:The "target-disease" network diagram predicted by network pharmacology, showed that the potential target of SE involves a variety of CNS diseases, among which depression accounts for the majority. The experimental results showed that SE (1.8, 1.35 g/kg) significantly decreased the immobility period, compared with the CUMS group in FST and TST in mice after 3-week treatment, while SE exhibited no significant effect on exploratory behavior in OFT in mice. Compared with CUMS group, the SE group (0.9 g/kg) showed significant differences (P<0.05) in DA levels in the hippocampus and cerebral cortex. In addition, compared with CUMS control group, SE (1.8 g/kg) group showed a significant effect on decreasing the activities of CORT (P<0.05), and serum IL-2 level with no statistical significance. Finally, Western blot results showed that compared with the model group, Nrf2, Keap1, NQO1 and HO-1 protein expressions in SE group (1.8 g/kg) were up-regulated (all P<0.01).Conclusion:The SE extract may have an antidepressant effect, which appeared to regulate Nrf2-ARE pathway and increased levels of DA and CORT in the hippocampus and cortex.  
        Keywords：Salicornia europaea L.;network pharmacology;tail suspension test;forced swim test;depression   
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        Published：2022-03-29
      • Lei XUAN,Jing-hai HU,Ran BI,Si-qi LIU,Chun-xi WANG
        Vol. 28, Issue 4, Pages: 349-356(2022) DOI: 10.1007/s11655-022-3464-4
        Abstract：Objective:To explore the influences of andrographolide (Andro) on bladder cancer cell lines and a tumor xenograft mouse model bearing 5637 cells.Methods:For in vitro experiments, T24 cells were stimulated with Andro (0–40 μmol/L) and 5637 cells were stimulated with Andro (0 to 80 μmol/L). Cell growth, migration, and infiltration were assessed using cell counting kit-8, colony formation, wound healing, and transwell assays. Apoptosis rate was examined using flow cytometry. In in vivo study, the antitumor effect of Andro (10 mg/kg) was evaluated by 5637 tumor-bearing mice, and levels of nuclear factor κB (NF-κB) and phosphoinositide 3-kinase/AKT related-proteins were determined by immunoblotting.Results:Andro suppressed growth, migration, and infiltraion of bladder cancer cells (P ≤0.05 or P≤ 0.01). Additionally, Andro induced intrinsic mitochondria-dependent apoptosis in bladder cancer cell lines. Furthermore, Andro inhibited bladder cancer growth in mice (P≤0.01). The expression of p65, p-AKT were suppressed by Andro treatment in vitro and in vivo (P≤ 0.05 or P≤ 0.01).Conclusions:Andrographolide inhibits proliferation and promotes apoptosis in bladder cancer cells by interfering with NF-κB and PI3K/AKT signaling in vitro and in vivo.  
        Keywords：andrographolide;Chinese medicine;bladder cancer;nuclear factor κB;PI3K-AKT   
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        Published：2022-03-29

        Acupuncture Research

      • Xin-yu CHEN,Lu-ping YANG,Ya-ling ZHENG,Yu-xi LI,Dong-ling ZHONG,Rong-jiang JIN,Juan LI
        Vol. 28, Issue 4, Pages: 357-365(2022) DOI: 10.1007/s11655-021-2883-y
        Abstract：Objective:To investigate whether the antihypertensive mechanism of electroacupuncture (EA) is associated with attenuating phenotype transformation of vascular smooth muscle cells (VSMCs) via phosphoinositide3-kinase (PI3K)/protein kinase B (Akt) and mitogen-activated protein kinase (MAPK) signaling pathways.Methods:Eight Wistar-ktoyo (WKY) rats were set as normal blood pressure group (normal group). A total of 32 spontaneous hypertensive rats (SHRs) were randomly divided into 4 groups using random number tables: a model group, an EA group, an EA+PI3K antagonist group (EA+P group), and an EA+p38 MAPK agonist+extracellular signal-regulated kinase (ERK) agonist group (EA+M group) (n=8/group). SHRs in EA group, EA+P group and EA+M group received EA treatment 5 sessions per week for continuous 4 weeks, while rats in the normal and model groups were bundled in same condition. The systolic blood pressure (SBP), diastolic blood pressure (DBP), and mean arterial pressure (MAP) of each rat was measured at 0 week and the 4th week. After 4-week intervention, thoracic aorta was collected for hematoxylin-eosin (HE) staining, immunohistochemistry [the contractile markers α-smooth muscle actin (α-SMA) and calponin and the synthetic marker osteopontin (OPN)] and Western blot [α-SMA, calponin, OPN, PI3K, phosphorylated-Akt (p-Akt), Akt, p-p42/44 ERK, total p42/44 ERK, p-p38 MAPK and total p38 MAPK].Results:EA significantly reduced SBP, DBP and MAP (P<0.01). HE staining showed that the wall thickness of thoracic aorta in EA group was significantly decreased (P<0.01). From results of immunohistochemistry and Western blot, EA increased the expression of α-SMA and calponin, and decreased the expression of OPN (P<0.01). In addition, the expression of PI3K and p-Akt increased (P<0.01), while the expression of p-p42/44 ERK and p-p38 MAPK decreased in EA group (P<0.01). However, these effects were reversed by PI3K antagonist, p38 MAPK agonist and ERK agonist.Conclusions:EA was an effective treatment for BP management. The antihypertensive effect of EA may be related with inhibition of phenotypic transformation of VSMCs, in which the activation of PI3K/Akt and the repression of MAPK pathway were involved.  
        Keywords：electroacupuncture;hypertension;vascular smooth muscle cells;PI3K/AKT signaling pathway;MAPK signaling pathway   
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        Academic Exploration

      • Shan-shan BAI,Hua-yuan YANG
        Vol. 28, Issue 4, Pages: 366-373(2022) DOI: 10.1007/s11655-022-2886-3
        Abstract：The rapid development of terahertz technology promotes the realization of various terahertz imaging systems. Terahertz technology features terahertz waves as good non-invasive illumination sources due to their high spectral resolution, penetration and safety. The terahertz imaging technique (TIT) has gradually been extended from the biomedical field to the field of Chinese medicine (CM), and it has become a powerful tool for seeking scientific evidence for CM theories with the use of modern science and technology. This paper reviews the current application of TITs in the field of CM research, and most importantly offers novel proposals for the application of TITs in CM research from the perspective of CM syndrome objectification and acupuncture research and cites existing reports as reference to the feasibility of these new proposals.  
        Keywords：terahertz;Chinese medicine syndrome objectification;meridians;acupuncture;moxibustion;new proposals   
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        Published：2022-03-29

        Evidence-Based Integrative Medicine

      • Xiao-nan ZHANG,Yan-yang LI,Yuan-hui ZHANG,Wan-qin ZHANG,Ya-ping ZHU,Jun-ping ZHANG,Shi-chao LV,Long-tao LIU
        Vol. 28, Issue 4, Pages: 374-383(2022) DOI: 10.1007/s11655-022-2884-5
        Abstract：Objective:To systematically evaluate the efficacy of Shengmai San in patients with cardiotoxicity of anthracyclines.Methods:Randomized controlled trials (RCTs) were identified by searching China National Knowledge Infrastructure (CNKI), Wanfang Database, Chinese Biomedical Literature Database (CBM), PubMed, Cochrane Library, and Embase Databases from the inceptions until December 2020. The Cochrane Handbook was used to evaluate the risk of bias in the included studies. Data analysis was conducted using RevMan 5.3 software.Results:Totally 19 RCTs with 2,331 participants were included in this review. Results showed that in improving arrhythmia (13 RCTs, n=1,877, RR=0.37, 95% CI 0.25 to 0.52, P<0.00001), the treatment group was superior to the control group. In terms of reducing left ventricular end-diastolic diameter (LVEDD, 2 RCTs, n=128, MD=–0.79, 95% CI –0.93 to –0.65, P<0.00001) and left ventricular end systolic diameter (LVESD, 2 RCTs, n=128, MD=–0.58, 95% CI –0.82 to –0.35, P<0.00001), the treatment group was also better than the control group. In reducing myocardial enzymes such as creatine kinase (CK) [(3 RCTs, n=256, SMD=–0.80, 95% CI –1.16 to –0.44, P<0.0001), (2 RCTs, n=126, SMD=–0.62, 95% CI –0.98 to –0.26, P=0.0007)], the treatment group was superior to the control group.Conclusion:Shengmai San has a positive effect on the treatment of cardiotoxicity from anthracyclines. However, in the future, it is still necessary to conduct high-quality RCTs to verify its efficacy.  
        Keywords：Shengmai San;anthracyclines;cardiotoxicity;systematic review;meta-analysis   
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