Shenfu Injection alleviates sepsis-associated lung injury by regulating HIF-1α / 中国中药杂志

Shenfu Injection(SFI) is praised for the high efficacy in the treatment of septic shock. However, the precise role of SFI in the treatment of sepsis-associated lung injury is not fully understood. This study investigated the protective effect of SFI on sepsis-associated lung injury by a clinical trial and an animal experiment focusing on the hypoxia-inducing factor-1α(HIF-1α)-mediated mitochondrial autophagy. For the clinical trial, 70 patients with sepsis-associated lung injury treated in the emergency intensive care unit of the First Affiliated Hospital of Zhengzhou University were included. The levels of interleukin(IL)-6 and tumor necrosis factor(TNF)-α were measured on days 1 and 5 for every patient. Real-time quantitative polymerase chain reaction(RT-qPCR) was performed to determine the mRNA level of hypoxia inducible factor-1α(HIF-1α) in the peripheral blood mononuclear cells(PBMCs). For the animal experiment, 32 SPF-grade male C57BL/6J mice(5-6 weeks old) were randomized into 4 groups: sham group(n=6), SFI+sham group(n=10), SFI+cecal ligation and puncture(CLP) group(n=10), and CLP group(n=6). The body weight, body temperature, wet/dry weight(W/D) ratio of the lung tissue, and the pathological injury score of the lung tissue were recorded for each mouse. RT-qPCR and Western blot were conducted to determine the expression of HIF-1α, mitochondrial DNA(mt-DNA), and autophagy-related proteins in the lung tissue. The results of the clinical trial revealed that the SFI group had lowered levels of inflammatory markers in the blood and alveolar lavage fluid and elevated level of HIF-1α in the PBMCs. The mice in the SFI group showed recovered body temperature and body weight. lowered TNF-α level in the serum, and decreased W/D ratio of the lung tissue. SFI reduced the inflammatory exudation and improved the alveolar integrity in the lung tissue. Moreover, SFI down-regulated the mtDNA expression and up-regulated the protein levels of mitochondrial transcription factor A(mt-TFA), cytochrome c oxidase Ⅳ(COXⅣ), HIF-1α, and autophagy-related proteins in the lung tissue of the model mice. The findings confirmed that SFI could promote mitophagy to improve mitochondrial function by regulating the expression of HIF-1α.

Shenfu Injection improves chronic heart failure by regulating pyroptosis based on NLRP3/caspase-1 pathway / 中国中药杂志

This study investigated the mechanisms and targets of Shenfu Injection in the intervention in chronic heart failure(CHF) through the NOD-like receptor thermal protein domain associated protein 3(NLRP3)/caspase-1 signaling pathway. A CHF model was induced in rats by subcutaneous injection of isoproterenol. Model rats were randomly divided into a model group, a Shenfu Injection group, and a MCC950(NLRP3 inhibitor) group, and a blank group was also set up as a control. After 15 days of treatment, echocardiography was performed to measure cardiac function parameters [left ventricular ejection fraction(LVEF) and left ventricular fractional shortening(LVFS)]. Enzyme-linked immunosorbent assay(ELISA) was used to measure serum levels of N-terminal pro-brain natriuretic peptide(NT-proBNP), interleukin(IL)-1β, and IL-18. Hematoxylin-eosin(HE) and Masson staining were used to observe morphological changes in myocardial tissues, and Western blot was used to measure the expression levels of NLRP3/caspase-1 pathway-related proteins [NLRP3, caspase-1, apoptosis-associated speck-like protein containing a CARD(ASC), gasdermin D(GSDMD), IL-1β, and IL-18]. The study found that isoproterenol-induced CHF in rats resulted in decreased cardiac function, worsened myocardial fibrosis, increased expression levels of NLRP3, ASC, caspase-1, GSDMD-N, IL-1β, and IL-18 in myocardial tissues, elevated serum inflammatory factors, and induced myocardial cell pyroptosis. Following Shenfu Injection intervention, the Shenfu Injection group showed significantly improved LVEF and LVFS, a significant decrease in NT-proBNP, a marked downregulation of NLRP3, ASC, caspase-1, GSDMD-N, IL-1β, and IL-18 protein expression levels, reduced serum inflammatory factors IL-1β and IL-18 expression in CHF rats, and a decrease in the rate of TUNEL-positive cells. Shenfu Injection can significantly improve cardiac function in CHF, inhibit myocardial fibrosis, and alleviate the progression of myocardial cell pyroptosis through the inhibition of the NLRP3/caspase-1 pathway.

Protective effect of Shenfu Injection on regulation of autophagy in rats with chronic heart failure based on PI3K/Akt/mTOR pathway / 中国中药杂志

This study aimed to investigate the mechanism and target sites of Shenfu Injection in the intervention of chronic heart fai-lure based on the PI3K/Akt/mTOR autophagy signaling pathway. The chronic heart failure model was induced in rats by subcutaneous injection of isoproterenol. The model rats were randomly divided into model group, Shenfu Injection group, and 3-methyladenine autophagy inhibitor(3-MA) group. A normal group was also set up. After 15 days of administration, cardiac function indexes of the rats were detected by echocardiography. The serum N-terminal pro-B-type natriuretic peptide(NT-proBNP) levels were measured using the ELISA. HE and Masson staining was performed to observe the morphological changes in myocardial tissues, and electron microscopy was used to observe the autophagosomes in myocardial tissues. Western blot was conducted to measure the changes in autophagy-related proteins(LC3 Ⅱ/Ⅰ and p62), PI3K, Akt, mTOR, and phosphorylation levels. The results showed that compared with normal group, model group in rats led to reduced cardiac function, significant activation of cardiac autophagy, increased fibrotic lesions in myocardial tissues, structural disorder of the myocardium, increased autophagosomes, and cytoplasmic vacuolization. Compared with model group, Shenfu Injection group in rats led to cardiac function significantly improved, myocardial fibrosis decreased, and the number of autophagosomes and cytoplasmic vacuolization decreased. The phosphorylation levels of PI3K, Akt, and mTOR were significantly increased(P<0.01). In the 3-MA group, autophagy was inhibited through the activation of the PI3K/Akt/mTOR signaling pathway, resulting in improved cardiac function, reduced myocardial fibrosis, and no significant cytoplasmic vacuolization. The findings suggest that Shenfu Injection can activate the PI3K/Akt/mTOR signaling pathway and inhibit autophagy, thereby improving cardiac function.

Efficacy and safety of Shenfu injection combined with chemical medicine in the treatment of coronary heart disease combined with heart failure：a meta-analysis / 中国药房

OBJECTIVE To systematically evaluate the efficacy and safety of Shenfu injection combined with chemical medicine in the treatment of coronary heart disease combined with heart failure. METHODS Retrieved from CNKI， CBM， VIP， Wanfang， PubMed， Embase and the Cochrane Library， randomized controlled trials （RCTs） about Shenfu injection combined with chemical medicine （trial group） versus chemical medicine （control group） in the treatment of heart failure with coronary heart disease were collected during the inception to August 2022. After literature screening and data extraction， the qualities of included literature were evaluated and rated by using Cochrane manual and GRADE system. Meta-analysis and Egger’s were performed with RevMan 5.3 software， and TSA 0.9.5.10 Beta software was used for trial sequential analysis. RESULTS Seventeen studies were included， with a total sample of 1 355 patients. The quality grade evidence of GRADE was all low. Meta-analysis showed that cardiac function efficacy [RR＝1.23， 95%CI （1.16，1.30）， P＜0.000 01]， the decrease of brain natriuretic peptide [MD＝－96.06， 95%CI （－116.47， －75.64）， P＜0.000 01] and the increase of left ventricular ejection fraction [MD＝5.32， 95%CI （4.03，6.60）， P＜0.000 01] in trial group were significantly better than control group； there was no statistical significance in the incidence of ADR between 2 groups [RR＝0.52，95%CI（0.22，1.22），P＝0.13]. The results of sequential analysis showed that the sample size included in this study met the requirements of meta-analysis； the results of Egger’s test showed that the results were robust and publication bias had no significant effect on the results. CONCLUSIONS Shenfu injection combined with chemical medicine in the treatment of coronary heart disease combined with heart failure can further improve the clinical symptoms and related indicators， and no serious adverse reaction is observed.

Evaluation of age-adjusted Charlson comorbidity index on prognosis and application timing of Shenfu injection in elderly patients with septic shock / 中华急诊医学杂志

Objective:To evaluate the value of age-adjusted Charlson comorbidity index (aCCI) in the clinical prognosis of sepsis and septic shock in the elderly, and to further explore the role of aCCI in evaluating the timing of Shenfu injection in elderly patients with septic shock.Methods:Clinical data of elderly patients with sepsis and septic shock in Dongzhimen Hospital of Beijing University of Chinese Medicine from January 1, 2019 to January 1, 2022 were retrospectively analyzed. With the median aCCI score of all samples as the cutoff value, the patients were divided into the low aCCI score group and high aCCI score group. The prognosis of elderly patients with septic shock and the application timing of Shenfu injection with aCCI score and sequential organ failure assessment (SOFA) were compared.Results:A total of 61 patients were included, including 31 patients in the high aCCI score group. The proportion of septic shock in elderly sepsis patients was lower in the low aCCI score group ( P < 0.05). The aCCI score (95% CI: 1.229-2.615; P< 0.01) was more valuable than SOFA score (95% CI: 1.035-1.607; P< 0.05) in predicting septic shock in elderly patients with sepsis. The 28-day survival rate in the low aCCI score group was higher than that in the high aCCI score group ( P < 0.05). Both the SOFA score (95% CI: 1.010-1.364) and the aCCI score (95% CI: 1.072-10.501) were independent factors affecting the 28-day survival rate. The use of Shenfu injection was associated with 28-day survival outcome in elderly patients with septic shock (95% CI: 0.012-0.788; P < 0.05). Conclusions:aCCI score is more effective than SOFA score in assessing the risk of shock in elderly patients with septic shock, and has a certain predictive value for the survival and prognosis of elderly patients with sepsis. Shenfu injection may be beneficial to the survival and prognosis of elderly patients with septic shock, but it needs to be further verified by large-scale prospective studies.

Effect of Reduning Injection， Shenfu Injection Combined with Gefitinib on Proliferation， Stemness Characteristics and Metabolism of Non-small Cell Lung Cancer Cells / 中国实验方剂学杂志

ObjectiveTo compare and observe the effect of Reduning injection （mainly clearing heat）， Shenfu injection （mainly warming Yang） combined with gefitinib on the proliferation， apoptosis， stemness characteristics and metabolism of lung cancer cells. MethodDifferent non-small cell lung cancer （NSCLC） cell lines were selected and intervened with gefitinib （5， 10， 20 μmol·L-1）， Reduning injection （0.6%， 0.9%）， Shenfu injection （0.6%， 0.9%）， gefitinib combined with Reduning injection， and gefitinib combined with Shenfu injection. Cell proliferation in each group was detected by cell counting kit-8 （CCK-8） assay， and cell apoptosis was detected by flow cytometry. The mRNA and protein expressions of lung cancer stem cell markers sex determining region Y-box 2 （Sox2） and aldehyde dehydrogenase family 1 member A1 （ALDH1A1） were determind by real-time quantitative polymerase chain reaction （Real-time PCR） and Western blot， respectively. The redox ratio of lung cancer cells was observed by femtosecond label-free imaging （FLI） and energy metabolism instrument was used to determine the glycolysis level in cells. ResultCompared with the blank group， Reduning injection reduced the survival rate of lung cancer cells （P<0.05）， increased the apoptosis rate （P<0.05）， down-regulated the mRNA and protein expressions of Sox2 and ALDH1A1 （P<0.05）， and up-regulated the redox ratio of cells （P<0.05）， while Shenfu injection exerted no remarkable effect on the above indexes. In addition， compared with gefitinib alone， Reduning injection combined with gefitinib inhibited the survival rate of lung cancer cells （P<0.05）， promoted the cell apoptosis （P<0.05）， down-regulated the mRNA and protein expressions of Sox2 and ALDH1A1 （P<0.05）， up-regulated the redox ratio of cells （P<0.05）， and lowered the proton efflux rate of glycolysis （P<0.05）， while Shenfu injection combined with gefitinib failed to affect these indexes of lung cancer cells significantly. ConclusionReduning injection may inhibit stemness characteristics of tumor cells by regulating their metabolism to enhance the proliferation-inhibiting and pro-apoptotic effects of gefitinib on lung cancer cells， while Shenfu injection had no significant enhancing effect on gefitinib. This indicates that epidermal growth factor receptor tyrosine kinase inhibitors （EGFR-TKIs） should be used in combination with heat-clearing Chinese medicines.

Therapeutic Effects of Shenfu Injection in Shock / 中国结合医学杂志

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.

Pathogenesis of chronic heart failure in rats based on ferroptosis-mediated oxidative stress and intervention effect of Shenfu Injection / 中国中药杂志

This study aims to investigate the pathogenesis of chronic heart failure based on ferroptosis-mediated oxidative stress and predict the targets of Shenfu Injection in treating chronic heart failure. A rat model of chronic heart failure was established by the isoproterenol induction method. According to the random number table method, the modeled rats were assigned into three groups: a model group, a Shenfu Injection group, and a ferrostatin-1(ferroptosis inhibitor) group. In addition, a normal group was designed. After 15 days of intervention, the cardiac mass index and left ventricular mass index were determined. Echocardiography was employed to eva-luate the cardiac function. Hematoxylin-eosin staining and Masson staining were employed to reveal the pathological changes and fibrosis of the heart, and Prussian blue staining to detect the aggregation of iron ions in the myocardial tissue. Transmission electron microscopy was employed to observe the mitochondrion ultrastructure in the myocardial tissue. Colorimetry was adopted to measure the levels of iron metabolism, lipid peroxidation, and antioxidant indicators. Flow cytometry was employed to measure the content of lipid-reactive oxygen species(ROS) and the fluorescence intensity of ROS. Western blot and RT-qPCR were employed to determine the protein and mRNA levels, respectively, of ferroptosis-related factors in the myocardial tissue. The results showed that the rats in the model group had reduced cardiac function, elevated levels of total iron and Fe~(2+), lowered level of glutathione(GSH), increased malondialdehyde(MDA), decreased superoxide dismutase(SOD) and glutathione peroxidase(GSH-Px), and rising levels of ROS and lipid-ROS. In addition, the model group showed fibrous tissue hyperplasia with inflammatory cell infiltration and myocardial fibrosis, iron ion aggregation, and characteristic mitochondrial changes specific for iron death. Moreover, the model group showcased upregulated protein and mRNA levels of p53 and COX2 and downregulated protein and mRNA levels of GPX4, FTH1, SLC7A11, and Nrf2 in the myocardial tissue. The intervention with Shenfu Injection significantly improved the cardiac function, recovered the iron metabolism, lipid peroxidation, and antioxidant indicators, decreased iron deposition, improved mitochondrial structure and function, and alleviated inflammatory cell infiltration and fibrosis. Furthermore, Shenfu Injection downregulated the mRNA and protein levels of p53 and COX2 and upregulated the mRNA and protein levels of GPX4, FTH1, SLC7A11, and Nrf2 in the myocardial tissue. Shenfu Injection can improve the cardiac function by regulating iron metabolism, inhibiting ferroptosis, and reducing oxidative stress injury.

Mechanism of action of Shen-Fu decoction on cardiogenic shock based on network pharmacology and experimental validation / 中国药理学通报

Aim To investigate the mechanism of action of Shen-Fu decoction in the prevention and treatment of cardiogenic shock based on network pharmacology and animal experiments. Methods The relevant targets and signaling pathways of cardiogenic shock of Shen-Fu decoction were predicted by network pharmacology, and a cardiogenic shock rat model was created by coronary artery ligation. Before modeling, rats were given the appropriate dose of Shen-Fu decoction or saline by gavage for 14 days according to the group, and real-time mean arterial pressure (MAP) changes were recorded after successful modeling. HE method was used to detect the myocardial histopathological changes of cardiogenic shock. TUNEL method was employed to detect rat myocardial cell apoptosis, and Western blotting was applied to determine the expression levels of rat myocardial Bax, Bcl-2, caspase-3, cleaved caspase-3 proteins. Results A total of 51 potential active ingredients of Shen-Fu decoction were screened out by network pharmacology, 80 targets of co-action with cardiogenic shock, and 43 core targets of close relationship between proteins, and GO enrichment analysis revealed that the core proteins were involved in the biology process (BP), mainly involving positive regulation of apoptotic process. KEGG enrichment analysis showed signaling pathways involving atherosclerosis-related, apoptosis and other signaling pathways. The results of animal model validation showed that Shen-Fu decoction could increase the shock blood pressure of rats with cardiogenic shock and alleviate the pathological changes of myocardial tissue, reduce the degree of apoptosis of rat cardiomyocytes, reduce the expression level of caspase-3, cleaved caspase-3 and Bax protein in rat myocardial tissue, and improve the expression level of Bcl-2 protein in myocardial tissue of rats. Conclusions The potential active ingredient of Shen-Fu decoction may play a role in the prevention and control of cardiogenic shock rats by acting on the target Bax, Bcl-2 to regulate the apoptosis signaling pathway of cardiomyocytes.

Mechanism of Shenfu injection in regulating stress response based on network pharmacology and molecular docking / 中华麻醉学杂志

Objective:To investigate the potential mechanism of Shenfu injection in regulating stress response via the neuro-endocrine-immune system by network pharmacology and molecular docking. Methods:The main active ingredients and related targets of Shenfu injection were screened using the Traditional Chinese Medicine System Pharmacology Database and Analysis Platform.PharmMapper, Swiss Target Prediction platform and Uniprot database were used to predict the target and unify the gene names.GeneCards, OMIM, TTD, CTD, Drugbank, Disgenet and Pharmgkb databases were searched to screen the related targets regulated by stress responses.Venny 2.1 tool was used to obtain the potential effect targets of the intersection between Shenfu injection and stress response regulation, and the STRING database was imported to construct the interaction PPI network and screen the key targets.Potential effect targets were uploaded to Metascape database online analysis for study on the mechanism through GO and KEGG enrichment analysis.Autoduck and Pymol were used for molecular docking and visualization.Results:Forty-three main active ingredients and 257 related targets for Shenfu injection were obtained by component screening and target prediction.A total of 4 811 targets related to stress response regulation were retrieved from the database, 188 potential effect targets were obtained by intersection with Shenfu injection component-related targets, and 14 key targets were obtained by PPI network screening.Eighteen samples were screened by GO enrichment analysis, which mainly involved the circulatory system and humoral regulation, responses to external stimuli and trauma, MAPK cascade reaction, postsynaptic membrane, receptor complex and ion channel complex and neurotransmitter receptor activity, etc.KEGG enrichment analysis showed 20 highly correlated pathways, mainly covering neuroactive ligand-receptor interaction, calcium signaling pathway, adrenergic signaling, steroid hormone biosynthesis, IL-17, TNF, MAPK, cGMP-PKG, PI3K-Akt, NF-κB, Toll-like receptor signaling pathway and cell apoptosis, etc.The results of molecular docking indicated that the main active components had good binding force with the key target.Conclusions:The components of Shenfu injection such as kaempferol, β-sitosterol, Demethyldelavaine, Stigmasterol, ginsenoside, Carnosifloside, hypaconitine may act on targets such as AKT1, TNF, IL1B, PTGS2, HSP90AA1, MAPK1, NFKBIA, NR3C1 and ADRB2 and regulate the stress response through the mechanisms such as regulation of the functional state of the neuro-endocrino-immune system, inhibition of inflammatory responses, anti-oxidative stress and reduction of cell apoptosis.

Identification of chemical constituents in Shenfu injection and study on anti-inflammatory activities of its poly- acetylene compounds / 中国药房

OBJECTIVE To study the chemical constituents in S henfu injection and the anti-inflammatory activities of its polyacetylene compounds. METHODS Shenfu injection was separated and purified by macroporous adsorption resin ，medium pressure liquid chromatography ，preparative thin layer chromatography and reversed-phase semi-preparative high-performance liquid chromatography，and the compound structure was identified according to the physicochemical properties and spectral data. RAW 264.7 cell inflammation model was used to evaluate the anti-inflammatory activities of polyacetylene compounds . The effects of active polyacetylene compounds on the expressions of cyclooxygenase- 2（COX-2）protein were evaluated by Western blot assay. RESULTS Twelves compounds were isolated and identified from Shenfu injection ，including 8 ginsenoside compounds ，i.e. ginsenoside Rg 1（1），ginsenoside Re （2），ginsenoside Rb 1（3），ginsenoside Rk 1（4），20（R）-ginsenoside Rh 1（5），20（S）-ginsenoside Rg3 （6），notoginsenoside R 1（7），panaxatriol（8）；4 polyacetylene compounds ，i.e.（3R，9R，10R）-panaxytriol（9），panaxydol（10）， heptadeca-1，8-dien-4，6-diyne-3，10-diol（11）and panaxynol （12）. Among 4 polyacetylene compounds ，only compound 10 had anti-inflammatory activity. Compound 10 was not toxic to normal RAW 264.7 cells；when the concentration of compound 10 ranged 12.5-50.0 μmol/L，it could significantly reverse the lipopolysaccharide-induced NO content increase in cell supernatant （P＜0.05 or P＜0.01）；when the concentration of co mpound 10 was 50.0 μmol/L，it could significantly reverse the lipopolysaccharide-induced protein expression increase of COX- 2 in cells （P＜0.05）. CONCLUSIONS Compounds 4，7，10-12 are identified and reported in Shenfu injection for the first time ，and panaxydol possesses a certain anti-inflammatory effect.

Effects of Shenfu yixin granule on mitochondrial autophagy of cardiomyocytes in rats with heart failure after acute yocardial infarction / 中国药房

OBJECTIVE To study the effects of Shenfu yixin granule on mitochondrial autophagy of cardiomyocytes in rats with heart failure after acute myocardial infarction. METHODS The model of heart failure after acute myocardial infarction was established by ligaturing the anterior descending branch of the left coronary artery in rats. The model rats were divided into model group，Shenfu yixin granule low-dose and high-dose groups （1.76，8.8 g/kg），Fosinopril sodium tablets group （positive control ，4 mg/kg），sham operation group was set up （only threading without ligation at the same position ），with 8 rats in each group. After 4 weeks of drug intervention ，the hemodynamic indexes of rats in each group were measured by physiological recorder. The pathological changes of myocardial tissue were observed in each group. The level of oxidative stress in cardiomyocytes ， mitochondrial membrane potential ，protein expression of PTEN-induced putative kinase 1（PINK1），E3 ubiquitin ligase Parkin and ubiquitin binding protein P 62 in myocardial tissue of rats in each group were detected. RESULTS Compared with sham operation group ，the pathological injuries such as myocardial fiber morphology disorder and inflammatory cell infiltration were serious. The left ventricular end systolic pressure （LVESP），maximum rate of rise of left ventricular internal pressure （+dp/dtmax）， maximun rate of decrease of left ventricular internal pressure （－dp/dtmax），total antioxidant capacity ，mitochondrial membrane potential，PINK1，Parkin and P 62 protein expression were significantly decreased in model group （P＜0.01）. The left ventricular end diastolic pressure （LVEDP），the level of reactive oxygen species and the activity of reduced nicotinamide adenine dinucleotide phosphate in left ventricular ischemic cardiomyocytes were significantly increased （P＜0.01）. Compared with model group ，the pathological injuries of myocardial tissue in intervention groups were alleviated ，and above indexes were improved in varying degrees（P＜0.01 or P＜0.05）. CONCLUSIONS Shenfu y ixin granule can reduce the level of oxidative stress and alleviate heart failure after acute myocardial infarction ，which may be related to the activation of Parkin-dependent pathway to strengthen mitochondrial autophagy and reduce mitochondrial dysfunction.

Network meta-analysis of efficacy of Chinese medicine injection in treatment of heart failure after acute myocardial infarction / 中国医师杂志

Objective:This study aimed to systematically evaluate the efficacy of Chinese medicine injection (CMI) in the treatment of heart failure (HF) after acute myocardial infarction (AMI).Methods:China National Knowledge Infrastructure (CNKI), WanFang Data, VIP, The Cochrane Library, PubMed, and EMbase databases were electronically searched from inception to October 2021 to identify randomized controlled trials (RCTs) on CMI for treating HF after AMI. Two reviewers independently screened literature, extracted data, and evaluated the bias risk of included studies. Network meta-analysis was then performed by ADDIS1.16.6 software and Stata 16.0 software.Results:A total of 55 studies were included involving 4 760 patients with HF after AMI and 3 types of CMIs, including Shenmai, Shenfu, Xinmailong injections. The results of network meta-analysis showed that Xinmailong injection was superior to Shenmai injection and Shenfu injection in improving the total effective rate and reducing left ventricular end diastolic diameter (LVEDD); Shenmai injection was superior to Xinmailong injection and Shenfu injection in reducing B-type natriuretic peptide (BNP); Shenfu injection was superior to Shenmai injection and Xinmailong injection in increasing left ventricular ejection fraction (LVEF) and reducing heart rate (HR).Conclusions:The combined 3 types of CMIs for treating HF after AMI can improve the clinical efficacy when compared with conventional Western medicine treatment. Among them, Xinmailong injection is better in improving the total effective rate and reducing LVEDD, Shenmai injection is more advantageous in reducing BNP, and Shenfu injection has the best efficacy in improving LVEF and reducing HR.

Serum metabolomic study of Shenfu decoction on adriamycin-induced cardiomyopathy in mice / 药学实践杂志

Objective To study the reversal effect of Shenfu decoction（SFD）on adriamycin-induced cardiomyopathy and explore its mechanism by using serum metabolomic technology. Methods The BALB/c mouse model of cardiomyopathy induced by adriamycin was established. The corresponding intervention was given. The serum lactate dehydrogenase（LDH）and creatine phosphatase isoenzyme MB（CK-MB）were measured. The ejection fraction (EF) and shortening fraction (FS) were measured by echocardiography. Mouse serum was collected for gas chromatography-mass spectrometry (GC-MS) analysis. The data obtained was analyzed by multivariate and univariate statistical analysis to compare the changes of endogenous metabolites in the serum of mice in the normal group, model group and Shenfu decoction treatment group, to find the potential biomarkers of Shenfu decoction to reverse the adriamycin-induced cardiomyopathy. Metabolic pathway analysis was used to explore the targeted metabolic pathway of Shenfu decoction. Results The levels of serum LDH and CK-MB in the model group were increased significantly, and the values of EF and FS decreased significantly, indicating that the model was successfully established. The above indicators were significantly improved after treatment with Shenfu decoction. 13 potential biomarkers of adriamycin-induced cardiomyopathy were identified by metabonomic analysis, and Shenfu decoction had significant reversal effect on 11 metabolites. Metabolic pathway analysis showed that the synthesis of phenylalanine, tyrosine and tryptophan, arachidonic acid metabolism, phenylalanine metabolism, tricarboxylic acid cycle and dicarboxylic acid metabolism were the main targeted metabolic pathways of Shenfu decoction. Conclusion Shenfu decoction can reverse adriamycin-induced cardiomyopathy by regulating the unbalanced synthesis of phenylalanine, tyrosine and tryptophan, as well as the metabolism of arachidonic acid, phenylalanine, dicarboxylic acid and tricarboxylic acid cycle.

Efficacy and Safety of Shenfu Qiangxin Pills Combined with Chemical Medicine Conventional Therapy in the Treatment of Chronic Heart Failure ：A Meta-analysis / 中国药房

OBJECTIVE：To systematically evaluate the effectiveness and safety of Shenfu qiangxin pills combined with chemical medicine conventional therapy in the treatment of chronic heart failure ，and to provide evidence-based reference for clinical drug use. METHODS ：Retrieved from CNKI ，Wanfang database ，VIP，Google Scholar ，PubMed，the Cochrane Library and Embase database ，RCTs about Shengfu qiangxin pills combined with chemical medicine conventional therapy （trial group ） versus chemical medicine conventional treatment （control group ）were collected during the inception to May 12th，2020. After literature screening and data extraction ，the quality of the literatures was evaluated with risk bias assessment tool recommended by Cochrane 5.1.0 system evaluator manual. Meta-analysis and sensitivity analysis were performed by using Stata 14.0 software. RESULTS：A total of 7 RCTs were included ，involving 596 patients. Meta-analysis results showed that the total response rate of trial group was significantly higher than that of control group [OR ＝4.14，95％CI（2.15，7.97），P＜0.000 01]；the results of sub-group analysis according to the different criteria for determining the efficacy showed that the total response rates of trial group determined by Lee integral method and cardiac function grading method were sig nificantly higher than that of the control group （P＜0.05）. After treatment ，N-terminal pro-B-type natriuretic peptide （NT-proBNP） level of trial group was significantly lower than that of control group [OR ＝－1.33，95％CI（－1.55， qq.com －1.11），P＜0.000 01]. Results of sub-group analysis accor- ding to cardiac failure type showed that NT-proBNP level of patients with chronic heart failure in trial group was lower than control group （P＜0.001）. The level of left ventricular ejection fraction （LVEF）in trial group after treatment [WMD ＝5.76，95％CI （5.05，6.47），P＜0.000 01] was significantly higher than control group ；after treatment ，the level of B-type natriuretic peptide [SMD＝－1.61，95％CI（－2.58，－0.54），P＜0.000 01]，left ventricular end-diastolic diameter （LVEDD）level [WMD ＝ －6.06，95％CI（－6.84，－5.27），P＜0.000 01]，left ventricular end-systolic diameter level [WMD ＝－0.52，95％CI（－5.70，－4.33）， P＜0.000 01] were significantly lower than control group. There was no statistically significant difference in the incidence of ADR between 2 groups（P＞0.05）. Results of sensitivity analysis showed that when NT-proBNP ，LVEF level ，LVEDD level after treatment were used as indicators ，there was no significant difference in the analysis results after eliminating heterogeneity source ， compared with before elimination. CONCLUSIONS ：Shenfu qiangxin pills combined with chemical medicine conventional treatment has good efficacy and safety.

Effects of Shenfu Injection () on Inflammatory Response during Post-Resuscitation Myocardial Dysfunction after Cardiac Arrest in Swine / 中国结合医学杂志

OBJECTIVE@#To investigate whether Shenfu Injection (SFI, ) can alleviate post-resuscitation myocardial dysfunction by inhibiting the inflammatory response.@*METHODS@#After 8 min of ventricular fibrillation and 2 min of basic life support, 24 pigs were randomly divided into 3 groups (n=8), which were given intravenous bolus injections of SFI (1.0 mL/kg), epinephrine (EP, 0.02 mg/kg) and normal saline (SA), respectively. The animals were sacrificed at 24 h after restoration of spontaneous circulation (ROSC), and serum interleuking-6 (IL-6) and tumor necrosis factor-α (TNF-α) levels were measured by enzyme-linked immunosorbent assay (ELISA); expressions of Toll-like receptor 4 (TLR4)/nuclear factor kappa B (NF-κB) mRNAs and proteins were determined by RT-PCR and Western blot, respectively.@*RESULTS@#Compared with the EP and the SA groups, the ultrastructure of myocardial cells were slightly damaged and the systolic function of the left ventricle was markedly improved in the SFI group at 24 h after ROSC (P<0.05). In addition, compared with the EP and SA groups, the SFI group also showed significantly reduced levels of serum IL-6 and TNF-α, protein and mRNA levels of myocardial NF- κB and TLR4 (P<0.05).@*CONCLUSIONS@#Activation of TLR4/NF-κB signaling pathway may be involved in the pathological mechanisms of post-resuscitation myocardial dysfunction. SFI may block NF-κB-mediated inflammatory response by reducing the activity of NF- κB and the level of TNF-α, thus playing a protective role in post-resuscitation myocardial dysfunction.

Effect of shenfu injection on isolated empty beating hearts from miniature pigs

Abstract Objective: To investigate the effect of Shenfu (SF) injection on donor heart preservation. Methods: Twelve pigs were randomly divided into SF group (n=6) and control group (n=6). After eight hours of perfusion, the differences in hemoglobin, the expression of Bcl-2 and BAX, and changes in the myocardial ultrastructure were compared to illustrate the effects of SF injection in heart preservation. Results: The differences in free hemoglobin between the SF group and the control group were statistically significant (P=0.001), and there was significant interaction of groups with times (P=0.019), but the perfusion time may not be associated with the hemoglobin concentration (P=0.616). According to Western blotting analysis, the expression of Bcl-2 was higher in the SF group than in the control group, while the expression of BAX was not different between the two groups. As to ultrastructural changes, both groups exhibited mitochondrial swelling and myofilament lysis, but the degree of damage in the SF group was smaller. Conclusion: Our study suggests that the application of SF injection for heart preservation may protect against cardiomyocytes and erythrocytes apoptosis, and Bcl-2 protein may play a role in these physiological processes.

Effects of Shenfu Yixin Decoction on the Utilization of Fatty Acid in Primary Hypoxic Cardiomyocytes / 中国药房

OBJECTIVE：To investigate the effects of Shenfu yixin decoction on the utilization of fatty acid in primary hypoxic cardiomyocytes and its potential mechanism. METHODS ：The apical tissue of neonatal SD rats with 1-3 days old were collected ， and the primary cardiomyocytes were isolated ，cultured and identified. The cardiomyocytes were randomly divided into normal group，model group ，coenzyme Q 10 group（positive control ，1×10－4 mol/L），Shenfu yixin decoction low-dose and high-dose groups（0.25，0.5 mg/mL）. Except for normal group ，cells in other groups were cultured under 5％O2，5％CO2 and 90％N2 for 6 hours to induce hypoxic injury model. After 6 hours of hypoxia ，the content of ATP was detected by luciferase luminescence assay. Western blotting assay was adopted to detect the expression of FAT/CD 36，PPARα and PPARβ/δ. RESULTS：Compared with normal group ，the content of ATP and relative expression of FAT/CD 36 protein were decreased significantly in model group （P＜ 0.05）. Compared with model group ，the content of ATP was increased significantly in coenzyme Q 10 group and Shenfu yixin decoction high-dose group ，while the relative expression of FAT/CD 36 and PPARα protein in coenzyme Q10 group，the relative expression of FAT/CD 36 protein in Shenfu yixin decoction high-dose group as well as the relative expression of PPARα and PPARβ/δ protein in Shenfu yixin decoction groups were decreased significantly （P＜0.05）. CONCLUSIONS ：Shenfu yixin decoction can inhibit the utilization of fatty acid of primary hypoxic cardiomyocytes and improve their energy metabolism by inhibiting the expression of FAT/CD 36，PPARα and PPARβ/δ protein.

Intervention Effect of Shenfu Injection on the Nuclear Translocation of HMGB 1 in LPS-induced RAW 264.7 Cells / 中国药房

OBJECTIVE：To investigate the intervention effect of Shenfu i njection（SFI）on the nuclear translocation of high mobility group box 1（HMGB1） in lipopolysaccharide （LPS）-induced RAW 264.7 cells. METHODS ： Using LPS-induced RAW264.7 cells as objects ，the histone deacetylase inhibitor RGFP 966 as positive control ，CCK-8 assay was used to screen drug dosage，and the effects of low ，medium and high doses （3，6，12 μL/mL）of SFI on HMGB 1 nuclear translocation in RAW 264.7 cells were observed by immunofluorescence method ；mRNA expression of HMGB 1 in RAW 264.7 cells were detected by real time fluorescent PCR. Western blotting assay was used to determine protein expression of HMGB 1 and Toll-like receptor 4（TLR4）；the expression of HMGB 1 were compared between nucleus and cytoplasm. The levels of HMGB 1，IL-1β and TNF-α in supernatant of cells were detected by ELISA. RESULTS ：In blank control group ，HMGB1 was mainly located in the nucleus ；after LPS induction， HMGB1 migrated from nucleus to cytoplasm. Compared with blank control group ， mRNA and protein （No.81760738） expression of HMGB 1， protein expression of TLR 4 in RAW264.7 cells as well as the levels of HMGB 1，IL-1β and TNF-α in supernatant of cells were increased significantly in LPS group （P＜0.01）. The protein expression of HMGB 1 was decreased significantly in nucleus while was in creased significantly in cytoplasm （P＜0.01）. After SFI treatment ，the nuclear translocation and secretion of HMGB 1 were inhibited in different degrees ；compared with LPS group ，mRNA and protein expression of HMGB 1 in administration groups ，protein expression of TLR 4 in RAW 264.7 cells of positive control group ，SFI medium- and high-dose groups as well as the levels of HMGB 1，IL-1β and TNF-α in supernatant of cells in administration groups were decreased significantly （P＜0.01）. In positive control group ，SFI medium- and high-dose groups ，the protein expressions of HMGB1 in nucleus were increased significantly ，while protein expressions of HMGB 1 in cytoplasm were decreased significantly （P＜0.01）. CONCLUSIONS ：SFI may inhibit the nuclear translocation and secretion of HMGB 1 in RAW 264.7 cells，thus avoiding the activation of inflammatory pathways and the production of inflammatory factors ，so as to reduce the inflammatory response induced by LPS.

Revealing the synergistic mechanism of Shenfu Decoction for anti-heart failure through network pharmacology strategy / 中国天然药物

The present study was designed to investigate the targets and synergistic mechanism of Shenfu Decoction (SFD) in the treatment of heart failure. A heart failure animal models was established to evaluate the pharmacological effects of SFD for anti-heart failure, then constructed ingredient-target interaction network by developing ingredient and target databases, the Discovery sdudio software was used for molecular docking. In addition, we validated the predicted protein targets of active ingredients in SFD by using surface plasmon resonance (SPR) technology. Our results demonstrated that SFD could enhance ejection fraction, alleviate myocardial histopathological characteristics, and reduce the level of angiotensin converting enzyme (ACE), aldosterone (ALD), atrial natriuretic polypeptide (ANP) and Renin (REN) in heart failure rat model. In addition, the ingredient database including 349 constituents and target database including 236 proteins were established, and 75 proteins were screened and identified by molecular docking strategy. 22 core target proteins were identified through network pharmacology, and the component-core target network was constructed. Finally, the affinity between the compounds and targets were verified by the SPR analysis method. The present study suggested that SFD may act on ACE 2, REN, ACE, ICAM-1, EGF, HTR2B, PARP1, NPPB and other proteins through AC, BAC, ACN, Re, Rg1, Rb1 to exert synergistic effects against heart failure.