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      Vol. 30 ， Issue 10 ， 2024

        Original Article

      • XIONG Zhi-yi,LU Ying,HE Li-yun,ZHANG Run-shun,ZHOU Xue-zhong,LI Peng,LIU Yan-jiao,ZHU Jian-gui,YAN Shi-yan,LIU Bao-yan
        Vol. 30, Issue 10, Pages: 867-876(2024) DOI: 10.1007/s11655-024-3661-4
        Abstract：Objective:To assess efficacy of Chinese medicine (CM) on insomnia considering characteristics of treatment based on syndrome differentiation.Methods:A total of 116 participants aged 18 to 65 years with moderate and severe primary insomnia were randomized to the placebo (n=20) or the CM group (n=96) for a 4-week treatment and a 4-week follow-up. Three CM clinicians independently prescribed treatments for each patient based on syndromes differentiation. The primary outcome was change in total sleep time (TST) from baseline. Secondary endpoints included sleep onset latency (SOL), wake time after sleep onset (WASO), sleep efficiency, Pittsburgh Sleep Quality Index (PSQI) and CM symptoms.Results:The CM group had an average 0.6 h more (95% confidence interval (CI): 0.3–0.9, P<0.001) TST and 34.1% (10.3%–58.0%, P=0.005) more patients beyond 0.5 h TST increment than that of the placebo group. PSQI was changed –3.3 (–3.8 to –2.7) in the CM group, a –2.0 (–3.2 to –0.8, P<0.001) difference from the placebo group. The CM symptom score in the CM group decreased –2.0 (–3.3 to –0.7, P=0.003) more than the placebo group. SOL and WASO changes were not significantly different between groups. The analysis of prescriptions by these clinicians revealed blood deficiency and Liver stagnation as the most common syndromes. Prescriptions for these clinicians displayed relative stability, while the herbs varied. All adverse events were mild and were not related to study treatment.Conclusions:CM treatment based on syndrome differentiation can increase TST and improve sleep quality of primary insomnia. It is effective and safe for primary insomnia. In future studies, the long-term efficacy validation and the exploratory of eutherapeutic clinicians' fixed herb formulas should be addressed. (Registration No. NCT01613183)  
        Keywords：primary insomnia;Chinese medicine;syndrome differentiation;randomized controlled trial   
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        Published：2024-09-23
      • BAI Rui-na,GU Feng,CHE Qian-zi,ZHANG Xuan,CAI Ya-jie,XI Rui-xi,ZHAO Yang,GUO Ming,DONG Guo-ju,GAO Zhu-ye,FU Chang-geng,WANG Pei-li,DU Jian-peng,ZHANG Da-wu,DUAN Wen-hui,LI Li-zhi,YANG Qiao-ning,SHI Da-zhuo
        Vol. 30, Issue 10, Pages: 877-885(2024) DOI: 10.1007/s11655-024-3664-1
        Abstract：Objectives:To evaluate the effectiveness and safety of Qishen Yiqi Dripping Pill (QSYQ) in patients with acute coronary syndrome (ACS) after percutaneous coronary intervention (PCI).Methods:This multicentre prospective cohort study was conducted at 40 centers in China. Patients with ACS after PCI entered either the QSYQ or Western medicine (WM) groups naturally based on whether they had received QSYQ before enrollment. QSYQ group received QSYQ (0.52 g, 3 times a day for 12 months) in addition to WM. The primary endpoint included cardiac death, non-fatal myocardial infarction, and urgent revascularization. The secondary endpoint included rehospitalization due to ACS, heart failure, stroke, and other thrombotic events. Quality of life was assessed by the Seattle Angina Questionnaire (SAQ).Results:A total of 936 patients completed follow-up of the primary endpoint from February 2012 to December 2018. Overall, 487 patients received QSYQ and WM. During a median follow-up of 566 days (inter quartile range, IQR, 517–602), the primary endpoint occurred in 46 (9.45%) and 65 (14.48%) patients in QSYQ and WM groups respectively [adjusted hazard ratio (HR) 0.60, 95% confidence interval (CI) 0.41–0.90; P=0.013]. The secondary endpoint occurred in 61 (12.53%) and 74 (16.48%) patients in QSYQ and WM groups, respectively (adjusted HR 0.76, 95% CI 0.53–1.09; P=0.136). In sensitivity analysis, the results still demonstrated that WM combined with QSYQ reduced the risk of the primary endpoint (HR 0.67, 95% CI 0.46–0.98; P=0.039). Moreover, QSYQ improved the disease perception domain of the SAQ (P<0.05).Conclusions:In patients with ACS after PCI, QSYQ combined with WM reduced the incidence of the primary endpoint. These findings provide a promising option for managing ACS after PCI and suggest the potential treatment for reducing the risk of primary endpoint included cardiac death, non-fatal myocardial infarction, and urgent revascularization through intermittent administration of QSYQ. (Registration No. ChiCTR-OOC-14005552)  
        Keywords：Qishen Yiqi Dripping Pill;acute coronary syndrome;percutaneous coronary intervention;primary and secondary endpoint   
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        Published：2024-09-23
      • CUI Xin-yu,LIU Tian-hua,BAI Ya-li,ZHANG Meng-di,LI Guo-dong,ZHANG Yu-ting,YUAN Yue-ying,ZHANG Ya-wen,YU Li-shuang,HAN Li-na,WU Yan
        Vol. 30, Issue 10, Pages: 886-895(2024) DOI: 10.1007/s11655-024-3658-z
        Abstract：Objective:To study the effect of Shexiang Tongxin Dropping Pill (STDP) on angiogenesis in diabetic cardiomyopathy mice with coronary microcirculation dysfunction (CMD).Methods:According to a random number table, 6 of 36 SPF male C57BL/6 mice were randomly selected as the control group, and the remaining 30 mice were injected with streptozotocin intraperitoneally to replicate the type 1 diabetes model. Mice successfully copied the diabetes model were randomly divided into the model group, STDP low-dose group [15 mg/(kg•d)], medium-dose group [30 mg/(kg•d)], high-dose group [60 mg/(kg•d)], and nicorandil group [15 mg/(kg•d)], 6 in each group. The drug was given by continuous gavage for 12 weeks. The cardiac function of mice in each group was detected at the end of the experiment, and coronary flow reserve (CFR) was detected by chest Doppler technique. Pathological changes of myocardium were observed by hematoxylin-eosin staining, collagen fiber deposition was detected by masson staining, the number of myocardial capillaries was detected by platelet endothelial cell adhesion molecule-1 staining, and the degree of myocardial hypertrophy was detected by wheat germ agglutinin staining. The expression of the vascular endothlial growth factor (VEGF)/endothelial nitric oxide synthase (eNOS) signaling pathway-related proteins in myocardial tissue was detected by Western blot.Results:Compared with the model group, medium- and high-dose STDP significantly increased the left ventricular ejection fraction and left ventricular fraction shortening (P<0.01), obviously repaired the disordered cardiac muscle structure, reduced myocardial fibrosis, reduced myocardial cell area, increased capillary density, and increased CFR level (all P<0.01). Western blot showed that high-dose STDP could significantly increase the expression of VEGF and promote the phosphorylation of vascular endothelial growth factor receptor 2, phosphoinositide 3-kinase, protein kinase B, and eNOS (P<0.05 or P<0.01).Conclusion:STDP has a definite therapeutic effect on diabetic CMD, and its mechanism may be related to promoting angiogenesis through the VEGF/eNOS signaling pathway.  
        Keywords：Shexiang Tongxin Dropping Pill;type 1 diabetes;diabetic cardiomyopathy;coronary microcirculation dysfunction;angiogenesis   
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        Published：2024-09-23
      • OU Xiao-min,CAI Jing,HU Xiao-yue,ZENG Qiao-huang,LAN Tao-hua,JIANG Wei
        Vol. 30, Issue 10, Pages: 896-905(2024) DOI: 10.1007/s11655-024-3663-2
        Abstract：Objective:To explore the effects of Huxin formula (HXF) in curtailing atherosclerosis and its underlying mechanism.Methods:According to random number table method, 24 specific pathogen free male ApoE-/- mice were randomly divided into model group, HXF low-dose (HXF-L) group (8.4 g/kg daily), HXF high-dose (HXF-H) group (16.8 g/kg daily), and pravastatin (8 mg/kg daily) group in Experiment Ⅰ (n=6 per group). C57BL/6J mice served as the control group (n=6). ApoE-/- mice in HXF-L, HXF-H, pravastatin groups were fed a Western diet and administered continuously by gavage for 12 weeks, while C57BL/6J mice in the control group were fed conventional lab mouse chow for 12 weeks. Further, Tregs were depleted by weekly intraperitoneal injection of purified anti-mouse CD25 antibody (PC61, 250 μg per mouse) for 4 weeks in Experiment Ⅱ (n=6 per group). Oil Red O and Masson staining were used to evaluate the plaque area and aortic root fibrosis. The CD4+CD25+Foxp3+Treg counts in the lymph nodes and spleen cells were detected using flow cytometric analysis. The transforming growth factor-β1 (TGF-β1), interleukin (IL)-10, and IL-6 serum levels were examined by MILLIPLEX® MAP technology. Quantitative real-time reverse transcription PCR (qRT-PCR) and Western blot were utilized to assess the expression of TGF-β mRNA and protein in the aorta. The expression of CD4+T lymphocytes, macrophages and smooth muscle cells in the aortic root were detected by immunofluorescence staining.Results:HXF reduced plaque area in ApoE-/- mice (P<0.01). HXF increased the Treg counts in the lymph nodes and spleen cells (P<0.05 or P<0.01). Moreover, HXF alleviated inflammatory response via elevating IL-10 and TGF-β1 serum levels (P<0.05), while decreasing the IL-6 serum levels in ApoE-/- mice (P>0.05). Also, HXF upregulated the expression of TGF-β mRNA and protein in the aorta (P<0.05). Additionally, HXF attenuated CD4+T lymphocytes, macrophages and smooth muscle cells in aortic root plaque (P<0.01). Furthermore, the depletion of Tregs with CD25 antibody (PC61) curtailed the reduction in plaque area and aortic root fibrosis by HXF (P<0.01).Conclusion:HXF relieved atherosclerosis, probably by restraining inflammatory response, reducing inflammatory cell infiltration and attenuating aortic root fibrosis by increasing Treg counts.  
        Keywords：atherosclerosis;Huxin Formula;Tregs;immune responses;inflammation   
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        Published：2024-09-23
      • WANG Ting-ting,YU Li-li,ZHENG Jun-meng,HAN Xin-yi,JIN Bo-yuan,HUA Cheng-jun,CHEN Yu-shan,SHANG Sha-sha,LIANG Ya-zhou,WANG Jian-ru
        Vol. 30, Issue 10, Pages: 906-916(2024) DOI: 10.1007/s11655-024-3666-z
        Abstract：Objective:To investigate potential mechanisms of anti-atherosclerosis by berberine (BBR) using ApoE-/- mice.Methods:Eight 8-week-old C57BL/6J mice were used as a blank control group (normal), and 56 8-week-old AopE-/- mice were fed a high-fat diet for 12 weeks, according to a completely random method, and were divided into the model group, BBR low-dose group (50 mg/kg, BBRL), BBR medium-dose group (100 mg/kg, BBRM), BBR high-dose group (150 mg/kg, BBRH), BBR+nuclear factor erythroid 2-related factor 2 (NRF2) inhibitor group (100 mg/kg BBR+30 mg/kg ML385, BBRM+ML385), NRF2 inhibitor group (30 mg/kg, ML385), and positive control group (2.5 mg/kg, atorvastatin), 8 in each group. After 4 weeks of intragastric administration, samples were collected and serum, aorta, heart and liver tissues were isolated. Biochemical kits were used to detect serum lipid content and the expression levels of malondialdehyde (MDA) and superoxide dismutase (SOD) in all experimental groups. The pathological changes of atherosclerosis (AS) were observed by aorta gross Oil Red O, aortic sinus hematoxylin-eosin (HE) and Masson staining. Liver lipopathy was observed in mice by HE staining. The morphology of mitochondria in aorta cells was observed under transmission electron microscope. Flow cytometry was used to detect reactive oxygen species (ROS) expression in aorta of mice in each group. The content of ferrous ion Fe2+ in serum of mice was detected by biochemical kit. The mRNA and protein relative expression levels of NRF2, glutathione peroxidase 4 (GPX4) and recombinant solute carrier family 7 member 11 (SLC7A11) were detected by quantitative real time polymerase chain reaction (RT-qPCR) and Western blot, respectively.Results:BBRM and BBRH groups delayed the progression of AS and reduced the plaque area(P<0.01). The characteristic morphological changes of ferroptosis were rarely observed in BBR-treated AS mice, and the content of Fe2+ in BBR group was significantly lower than that in the model group (P<0.01). BBR decreased ROS and MDA levels in mouse aorta, increased SOD activity (P<0.01), significantly up-regulated NRF2/SLC7A11/GPX4 protein and mRNA expression levels (P<0.01), and inhibited lipid peroxidation. Compared with the model group, the body weight, blood lipid level and aortic plaque area of ML385 group increased (P<0.01); the morphology of mitochondria showed significant ferroptosis characteristics; the serum Fe2+, MDA and ROS levels increased (P<0.05 or P <0.01), and the activity of SOD decreased (P <0.01). Compared with BBRM group, the iron inhibition effect of BBRM+ML385 group was significantly weakened, and the plaque area significantly increased (P<0.01).Conclusion:Through NRF2/SLC7A11/GPX4 pathway, BBR can resist oxidative stress, inhibit ferroptosis, reduce plaque area, stabilize plaque, and exert anti-AS effects.  
        Keywords：berberine;ApoE-/-;ferroptosis;atherosclerosis;oxidative stress;NRF2/SLC7A11/GPX4 pathway   
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        Published：2024-09-23
      • OU Jin-ying,LIU Shan-hong,TANG Dong-kai,SHI Ling-zhu,YAN Li-jun,HUANG Jing-yan,ZOU Li-fang,QUAN Jing-yu,YOU Yan-ting,CHEN Yu-yao,YU Lin-zhong,LU Zi-bin
        Vol. 30, Issue 10, Pages: 917-926(2024) DOI: 10.1007/s11655-024-3656-1
        Abstract：Objective:To explore the protective effect and the underlying mechanism of silibinin (SIB), one of the active compounds from Silybum marianum (L.) Gaertn in endotoxemia.Methods:Mouse peritoneal macrophage were isolated via intraperitoneally injection of BALB/c mice with thioglycolate medium. Cell viability was assessed using the cell counting kit-8, while cytotoxicity was determined through lactate dehydrogenase cytotoxicity assay. The protein expressions of interleukin (IL)-1α, IL-1β, and IL-18 were determined by enzyme-linked immunosorbent assay. Intracellular lipopolysaccharide (LPS) levels were measured by employing both the limulus amoebocyte lysate assay and flow cytometry. Additionally, proximity ligation assay was employed for the LPS and caspase-11 interaction. Mice were divided into 4 groups: the control, LPS, high-dose-SIB (100 mg/kg), and low-dose-SIB (100 mg/kg) groups (n=8). Zebrafish were divided into 4 groups: the control, LPS, high-dose-SIB (200 μmol/L), and low-dose-SIB (100 μmol/L) groups (n=30 for survival experiment and n=10 for gene expression analysis). The expression of caspase-11, gasdermin D (GSDMD), and N-GSDMD was determined by Western blot and the expressions of caspy2, gsdmeb, and IL-1β were detected using quantitative real-time PCR. Histopathological observation was performed through hematoxylin-eosin staining, and protein levels in bronchoalveolar lavage fluid were quantified using the bicinchoninicacid protein assay.Results:SIB noticeably decreased caspase-11 and GSDMD-mediated pyroptosis and suppressed the secretion of IL-1α, IL-1β, and IL-18 induced by LPS (P<0.05). Moreover, SIB inhibited the translocation of LPS into the cytoplasm and the binding of caspase-11 and intracellular LPS (P<0.05). SIB also attenuated the expression of caspase-11 and N-terminal fragments of GSDMD, inhibited the relative cytokines, prolonged the survival time, and up-regulated the survival rate in the endotoxemia models (P<0.05).Conclusions:SIB can inhibit pyroptosis in the LPS-mediated endotoxemia model, at least in part, by inhibiting the caspase-11-mediated cleavage of GSDMD. Additionally, SIB inhibits the interaction of LPS and caspase-11 and inhibits the LPS-mediated up-regulation of caspase-11 expression, which relieves caspase-11-dependent cell pyroptosis and consequently attenuates LPS-mediated lethality.  
        Keywords：silibinin;caspase-11;endotoxemia;pyroptosis;inflammation   
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        Published：2024-09-23

        Evidence-Based Integrative Medicine

      • Vito A. Damay,Ignatius Ivan
        Vol. 30, Issue 10, Pages: 927-937(2024) DOI: 10.1007/s11655-024-3665-0
        Abstract：Background:Resveratrol is a non-flavonoid polyphenol that shows promise in reducing pro-inflammatory factors and maintaining endothelial function, which hints at its potential role in slowing atherosclerosis and preventing acute coronary events.Objective:To study the cardioprotective effects of resveratrol on inflammatory mediators and endothelial function in patients with coronary artery disease (CAD).Methods:A thorough search was conducted in databases (Cochrane Library, ProQuest, PubMed, LILACS, ScienceDirect, Springer, Taylor&Francis, CNKI, Wanfang, and Weipu) until September 24, 2023. The vasopro-inflammatory mediators, endothelial function and outcomes related to cardiovascular events were observed. Titles and abstracts were assessed, and bias was evaluated with Cochrane RoB 2.0. Heterogeneity of results was explored by meta-regression, certainty of evidence was assessed by the GRADE system, and conclusive evidence was enhanced by trial sequence analysis.Results:Ten randomized controlled trials and 3 animal studies investigated resveratrol's impact on inflammatory mediators and endothelial function. In primary prevention studies, meta-analysis showed a significant reduction (95% CI: –0.73 to –0.20; P=0.0005) in tumor necrosis factor-α (TNF-α) expression with resveratrol, demonstrating a dose-dependent relationship. No significant difference was observed in interleukin-6 (IL-6) expression with P=0.58 for primary prevention and P=0.57 for secondary prevention. Vascular endothelial nitric oxide synthase (eNOS) expression was significantly increased after resveratrol pre-treatment following CAD events. Secondary prevention studies yielded no significant results; however, meta-regression identified associations between age, hypertension, and lower doses with the extent of TNF-α alterations. High certainty of evidence supported TNF-α reduction, while evidence for IL-6 reduction and eNOS elevation was deemed low.Conclusions:Resveratrol reduces TNF-α in individuals at risk for CAD, specifically 15 mg per day. However, its usefulness in patients with confirmed CAD is limited due to factors such as age, high blood pressure, and insufficient dosage. Due to the small sample size, the reduction of IL-6 is inconclusive. Animal studies suggest that resveratrol enhances endothelial function by increasing eNOS. (PROSPERO registration No. CRD42023465234)  
        Keywords：anti-inflammation;coronary artery disease;nitric oxide;resveratrol;systematic review   
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        Published：2024-09-23

        Review

      • LU Yan,XIE Xue-na,XIN Qi-qi,YUAN Rong,MIAO Yu,CONG Wei-hong,CHEN Ke-ji
        Vol. 30, Issue 10, Pages: 938-948(2024) DOI: 10.1007/s11655-024-3662-3
        Abstract：Hypertensive renal damage (HRD) is a major cause of end-stage renal disease. Among the causes of end-stage renal disease, HRD accounts for nearly 34% of the total number of cases. Antihypertensive treatment is primarily drug-based, but therapeutic efficacy is less effective and can have serious side effects. Chinese medicine (CM) has significant advantages in the treatment of HRD. CM is rich in various active ingredients and has the property of targeting multiple targets and channels. Therefore, the regulatory network of CM on disease is complex. A large number of CM have been employed to treat HRD, either as single applications or as part of compound formulations. The key possible mechanisms of CM for HRD include regulation of the renin-angiotensin-aldosterone system, antioxidation, anti-inflammation, rescue of endothelial function, regulation of vasoactive substance secretion and obesity-related factors, etc. This review summarized and discussed the recent advance in the basic research mechanisms of CM interventions for HRD and pointed out the challenges and future prospects.  
        Keywords：Chinese medicine;hypertensive renal damage;molecular mechanisms;research progress   
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        Published：2024-09-23
      • LIU Chang-xing,GUO Xin-yi,ZHOU Ya-bin,WANG He
        Vol. 30, Issue 10, Pages: 949-960(2024) DOI: 10.1007/s11655-024-3657-0
        Abstract：Acute myocardial infarction (AMI), characterized by high incidence and mortality rates, poses a significant public health threat. Reperfusion therapy, though the preferred treatment for AMI, often exacerbates cardiac damage, leading to myocardial ischemia/reperfusion injury (MI/RI). Consequently, the development of strategies to reduce MI/RI is an urgent priority in cardiovascular therapy. Chinese medicine, recognized for its multi-component, multi-pathway, and multi-target capabilities, provides a novel approach for alleviating MI/RI. A key area of interest is the nuclear factor E2-related factor 2 (Nrf2)/heme oxygenase-1 (HO-1) pathway. This pathway is instrumental in regulating inflammatory responses, oxidative stress, apoptosis, endoplasmic reticulum stress, and ferroptosis in MI/RI. This paper presents a comprehensive overview of the Nrf2/HO-1 signaling pathway's structure and its influence on MI/RI. Additionally, it reviews the latest research on leveraging Chinese medicine to modulate the Nrf2/HO-1 pathway in MI/RI treatment.  
        Keywords：nuclear factor E2-related factor 2/heme oxygenase-1 signaling pathway;myocardial ischemia/reperfusion injury;Chinese medicine;mechanisms   
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        Published：2024-09-23
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