Establishment of a rapid method for quality assessment of cardiotonic effect of Shengfupian / 药学学报

Based on the similar structure of adrenaline shared by higenamine (HI), salsolinol (SA) and coryneine (CO), a photochemical colorimetric sensor based on the displacement reaction of o-diphenol hydroxyl group and alizarin red S-phenylboric acid system was constructed to quickly distinguish and identify the cardiac strength of Shengfupian. The results show that the optimal condition of the sensor is: the molar ratio of alizarin red S (ARS) to phenylboric acid (PA) is 1∶3, reaction temperature is 0 ℃; The preparation method of the sample solution is optimized as follows: 2.5 g of Shengfupian powder was taken, 10 times the amount of methanol was added, and 300 W, 40 kHz ultrasound was carried out for 15 min; methodological studies showed that the method had good precision, repeatability and stability. The |△G| value (G is green, |△G| = |G after - G before|) of each sample was obtained by response values determination of 14 batches of Shengfupian. LC-MS/MS was used to determine the contents of three cardiac components in Shengfupian. It was found that the order of the total contents of cardiotonic components was basically consistent with |△G|. Then the correlation was analyzed, and the correlation coefficient R2 was as high as 0.87, which proved the scientificity and accuracy of this method. This study fills the methodological gap of rapid evaluation of the quality of Shengfupian, and provides the key technical support for the high quality and good price of Shengfupian in the market circulation and clinical application.

Construction of a high-throughput screening model for mitochondrial function of Aconiti Lateralis Radix Praeparata by machine learning algorithm and mechanism analysis / 中国中药杂志

A high-throughput screening machine learning model for mitochondrial function was constructed, and compounds of Aco-niti Lateralis Radix Praeparata were predicted. Deoxyaconitine with the highest score and benzoylmesaconine with the lowest score among the compounds screened by the model were selected for mitochondrial mechanism analysis. Mitochondrial function data were collected from PubChem and Tox21 databases. Random forest and gradient boosted decision tree algorithms were separately used for mo-deling, and ECFP4(extended connectivity fingerprint, up to four bonds) and Mordred descriptors were employed for training, respectively. Cross-validation test was carried out, and balanced accuracy(BA) and overall accuracy were determined to evaluate the performance of different combinations of models and obtain the optimal algorithm and hyperparameters for modeling. The data of Aconiti Lateralis Radix Praeparata compounds in TCMSP database were collected, and after prediction and screening by the constructed high-throughput screening machine learning model, deoxyaconitine and benzoylmesaconine were selected to measure mitochondrial membrane potential, reactive oxygen species(ROS) level and protein expression of B-cell lymphoma 2(Bcl-2), Bcl-2-associated X protein(Bax) and peroxisome proliferator-activated receptor-γ-coactivator 1α(PGC-1α). The results showed that the model constructed using gradient boosted decision tree+Mordred algorithm performed better, with a cross-validation BA of 0.825 and a test set accuracy of 0.811. Deoxyaconitine and benzoylmesaconine changed the ROS level(P<0.001), mitochondrial membrane potential(P<0.001), and protein expression of Bcl-2(P<0.001, P<0.01) and Bax(P<0.001), and deoxyaconitine increased the expression of PGC-1α protein(P<0.01). The high-throughput screening model for mitochondrial function constructed by gradient boosted decision tree+Mordred algorithm was more accurate than that by random forest+ECFP4 algorithm, which could be used to build an algorithm model for subsequent research. Deoxyaconitine and benzoylmesaconine affected mitochondrial function. However, deoxyaconitine with higher score also affected mitochondrial biosynthesis by regulating PGC-1α protein.

Network Pharmacology-based Analysis on Mechanism of Aconiti Lateralis Radix Praeparata and Epimedii Folium in Treatment of Chronic Heart Failure / 中国实验方剂学杂志

Objective:To explore the mechanism of the prescription consisting Aconiti Lateralis Radix Praeparata and Epimedii Folium in the treatment of chronic heart failure （CHF） based on network pharmacology，followed by verification in H9c2 myocardial cells with hypoxia-reoxygenation injury <italic>in vitro</italic> and in zebrafish with vascular endothelial growth factor receptor （VEGFR） tyrosine kinase inhibitor Ⅱ （VRI） -induced vascular insufficiency. Method:The active ingredients in Aconiti Lateralis Radix Praeparata and Epimedii Folium were searched from the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform （TCMSP），the corresponding target genes from the Universal Protein Resource （UniProt）， and the CHF-related targets from Online Mendelian Inheritance in Man （OMIM） and GeneCards. Both the active ingredient-potential target network and the active ingredient-CHF-related target network were generated using Cytoscape 3.6.1， followed by the protein-protein interaction （PPI） network construction and Gene Ontology （GO） and Kyoto Encyclopedia of Genes and Genome （KEGG） enrichment analysis based on MetaScape. H9c2 myocardial cells exposed to hypoxia-reoxygenation were selected for determining the proliferation-promoting effect by methyl thiazolyl tetrazolium （MTT） assay. The protein expression of B-cell lymphoma-2（Bcl-2）， Bcl-2-associated X protein（Bax），cysteinyl aspartate-specific protease-3（Caspase-3）， protein kinase B（PKB/Akt），phosphorylated protein kinase B（p-Akt），phosphorylated extracellular signal-regulated kinases 1/2 （p-ERK1/2），extracellular signal-regulated kinase 1/2 （ERK1/2）， and poly adenosine diphosphate ribose polymerase（PARP）was detected by Western blotting. The efficacy of the prescription in promoting angiogenesis was verified in a zebrafish model of VRI-induced vascular injury. Result:There were 28 active ingredients for the prescription， 209 corresponding targets， 1 296 CHF-related targets， and 94 common gene targets shared by the prescription and CHF. PPI network clustering suggested that Aconiti Lateralis Radix Praeparata and Epimedii Folium alleviated CHF by interfering with cell differentiation and metabolism and angiogenesis. GO analysis revealed that CHF relief was achieved via the intervention in such biological processes as cell migration，vascular development， and angiogenesis. Pharmacodynamic experiments verified that Epimedii Folium （10 mg·L^-1） alone and the prescription （10 mg·L^-1）both enhanced the proliferation of H9c2 myocardial cells under the hypoxia-reoxygenation condition （<italic>P</italic><0.05），while the latter also increased the expression of Bcl-2，Bcl-2/Bax， and PARP （<italic>P</italic><0.05） and reduced the expression of Caspase-3， Akt， and ERK （<italic>P</italic><0.05）. The prescription at the concentrations of 0.3 and 0.1 g·L^-1 promoted angiogenesis （<italic>P</italic><0.05）. Conclusion:Aconiti Lateralis Radix Praeparata and Epimedii Folium exert the therapeutic effect against CHF via multiple ingredients，multiple targets， and multiple channels. Such combination promotes the proliferation of H9c2 myocardial cells under hypoxic condition and protects zebrafish from vascular injury by up-regulating the expression of Bcl-2 and PARP，increasing Bcl-2/Bax ratio，and down-regulating the expression of Caspase-3，Akt， and ERK.

Research progress on structure and activity of C19 diterpeneoid alkaloids from Aconiti Lateralis Radix Praeparata / 中草药

Aconiti Lateralis Radix Praeparata (Fuzi in Chinese) is a commonly used Chinese materia medica in clinic, with the effects in rescuing from collapse by restoring yang, eliminating cold to stop pain, warming yang and transforming qi. C19 diterpenoid alkaloids from Fuzi can be divided into three types: diester type, monoester type and amine alcohol type, which can lead to neurotoxicity and cardiotoxicity while exerting anti-inflammatory, analgesic, anti-tumor and other pharmacodynamic effects. In this paper, the chemical structure, pharmacology and toxicological effects of C19 diterpene alkaloids of Fuzi were systematically combed, in order to provide a theoretical basis for safer and more effective use of Fuzi in clinic.

Study on influence factors of Aconiti Lateralis Radix Praeparata by microwave processing technology / 中草药

Objective: To explore the influence factors of processing Aconiti Lateralis Radix Praeparata by microwave-drying, so as to lay a foundation for its industrial development. Methods: The drying process of Aconiti Lateralis Radix Praeparata was investigated by water ratio, drying rate and energy consumption analysis. The aconite morphology, contents of diester alkaloids, monoester alkaloids and alkanolamine alkaloids were used as indexes to study the effects of slice thickness, water content, microwave power and processing time on aconite processing. Results : The thickness, rehydration rate, microwave power and processing time had influence on the processing process and alkaloid content of aconite. When the thickness was 5 mm, the drying process had shorter drying time, faster drying rate and lower the energy consumption, but it had a higher content of diester alkaloids and lower content of the total alkaloids. When the rehydration rate of raw aconite slices was 60%, the drying time was the shortest. The order of average drying rate was 100% rehydration rate > 60% rehydration rate > 80% rehydration rate > 40% rehydration rate. The order of content of diester alkaloids was 60% rehydration rate > 100% rehydration rate > 80% rehydration rate > 40% rehydration rate. The order of total alkaloids content was 60% rehydration rate > 80% rehydration rate = 100% rehydration rate > 40% rehydration rate. The influence of rehydration rate on energy consumption was not obvious. When the processing time was the same, the drying process under the microwave power of 550 W had the shortest drying time, the fastest drying rate, the lowest content of diester aconitine and the highest content of total alkaloid. However, with the increase of processing time, the aconite was easier to be burnt under a high microwave power. Conclusion: The appropriate thickness, moisture content, microwave power and processing time in aconite processing process are helpful to reduce the toxicity of aconite and improve the quality of aconite. Therefore, the thickness of the slices should choose 3 mm, the moisture content should be 60%-80%, and the processing time should be reduced according to the increase of microwave power.

Detoxification mechanism of Aconiti Lateralis Radix Praeparata combined with dried Rehmanniae Radix based on metabolic enzymes in liver / 中国中药杂志

The enzymes CYP1 A2 and CYP3 A4 were measured by building a "Cocktail" probe drug and the incubation system of liver microsomes. The compatibility of Aconiti Lateralis Radix Praeparata combined with dried Rehmanniae Radix on CYP450 enzyme protein and gene expression was explored from the level of protein and molecular biology. It explored the molecular mechanism of compatibility detoxication of Aconiti Lateralis Radix Praeparata to provide scientific support for clinical safe and effective application of Aconiti Lateralis Radix Praeparata. The CYP450 enzyme activity was determined by using "Cocktail" probe drugs. The content of CYP450 enzyme was measured by CO reduction of differential spectrum method. The mRNA expression of CYP1 A2 and CYP3 A4 enzyme was detected by RT-PCR technology. Compared with the blank group, the CYP1 A2 and CYP3 A4 enzyme activity and mRNA expression were increased in the dried Rehmanniae Radix combined with Aconiti Lateralis Radix Praeparata group with significant differences(P<0.05), while the CYP3 A4 enzyme activity and mRNA expression were no influence in the Aconiti Lateralis Radix Praeparata group. The CYP3 A4 enzyme activity and mRNA expression were increased in the dried Rehmanniae Radix and the dried Rehmanniae Radix combined with Aconiti Lateralis Radix Praeparata group, and there were significant differences(P<0.05). The content of CYP450 enzyme was decreased in the Aconiti Lateralis Radix Praeparata group, contributed to extremely significant difference(P<0.01). The content of CYP450 enzyme was increased in the dried Rehmanniae Radix and the dried Rehmanniae Radix combined with Aconiti Lateralis Radix Praeparata group, and there were significant differences(P<0.05). The CYP1 A2 and CYP3 A4 enzyme activity and gene expression were enhanced after dried Rehmanniae Radix combined with Aconiti Lateralis Radix Praeparata. The metabolism of toxic ingredients of Aconiti Lateralis Radix Praeparata was accelerated to reach an effect of detoxication. The detoxication mechanism of compatibility of Aconiti Lateralis Radix Praeparata was verified from the viewpoint of liver metabolic enzymes.

Herbalogical study of Aconiti Lateralis Radix Praeparata(Fuzi) / 中国中药杂志

As a most important Chinese materia medica, Aconiti Lateralis Radix Praeparata(Fuzi) had been widely used in China for thousands of years. This herbalogical study was systematically performed based on variation characteristics of the naming, habitat, harvesting, processing and properties. The sharp toxicity of Fuzi had been well known since the spring and autumn period in the history, which was much earlier than that its medical properties was understood and applied. Sichuan province was regarded as the geo-authentic region of Fuzi all along, where the best quality goods could be provided for clinic use. The study showed the harvesting time of Fuzi was changing in different periods, and the possible effects were of climate change and artificial planting. The perishable characteris-tics of Fuzi severely limited its storage period; therefore, different kinds of storage methods were effectively used since Tang Dynasty. For thousands of years, Fuzi had been processed with various accessories to reduce toxicity, while simultaneously the study on processing mechanism was on going all the time. Fuzi was widely used in clinical practice to cure Yang depletion syndrome, which was based on its function of enhancing Yang and removing cold. Along with the further study on quality evaluation standard, Fuzi will probably get a much wider range of applications.

Molecular docking combined with network pharmacology to study molecular mechanism of Guizhi Shaoyao Zhimu Decoction in treatment of rheumatoid arthritis / 中草药

Objective: To predict the active constituents and targets of Guizhi Shaoyao Zhimu Decoction (GSZD) in the treatment of rheumatoid arthritis by using molecular docking and network pharmacology, and to analyze the effect of multi component-multi target-multi pathway combined with the theory of compatibility of TCM prescriptions. Methods: The main chemical constituents of nine kinds of Chinese herbal medicines (Cinnamomi Ramulus, Paeoniae Radix Alba, Anemarrhenae Rhizoma, Glycyrrhizae Radix et Rhizoma, Ephedrae Herba, Zingiberis Rhizoma Recens, Atractylodis Macrocephalae Rhizoma, Saposhnikoviae Radix and Aconiti Lateralis Radix Praeparata) were collected from TCMSP, TCM-Datebas@Taiwan and PubChen Compound database. The protein targets to the treatment of rheumatoid arthritis are found through DrugBank and TTD databases and uploaded to the String online database to build the network relationship of protein interaction. Appropriate crystal structures of protein targets were downloaded from PDB database, and molecular docking between compounds and targets was performed by using Discovery studio 4.5.0 software. A drug-compound-target visualization network was constructed by using Cytoscape 3.6.1 software to elucidate the main mechanism of GSZD against rheumatoid arthritis. Results: The results of molecular docking showed that there were 316 potential anti-arthritis active components in GSZD, acting on 26 targets, among which MAPK1, ZADH2, P38, AKR1C2, DHODH, CA2, MMP3, MMP9, RANKL, and other proteins were the main targets. Biological function and pathway analysis indicated that the mechanism of GSZD mainly involved in bone absorption (28%), histone kinase activity (20%), peptide tyrosine phosphorylation (20%), prostaglandin metabolism (12%), and other biological processes. The main pathway was osteoclast differentiation (94.12%). Conclusion: In this study, molecular docking combined with network pharmacology was used to study the pharmacodynamic material basis and molecular mechanism of GSZD in the treatment of rheumatoid arthritis from the perspective of multi-target and multi-approach, providing reference and basis for better clinical use.

Effect of Yinfupian and Yangfupian on Brown Adipose Tissue of Yang Deficiency Mice / 中国实验方剂学杂志

Objective:To observe the expression of brown adipose tissue (BAT), cells, proteins and corresponding genes in Yang deficiency model mice induced by Rhei Radix et Rhizoma suspension, and to explore the thermogenesis of processed products of Aconiti Lateralis Radix Praeparata with Jianchang faction characteristics. Method:Twenty mice, half male and half female, were randomly selected as the normal female and male groups. And the other 80 mice were administrated with Rhei Radix et Rhizoma suspension (the content of 0.25 g·mL-1) to establish Yang deficiency model, after the model was established, they were randomly divided into the model female and male groups, female and male groups of Shengfupian, female and male groups of Yinfupian, female and male groups of Yangfupian, 10 mice in each group. Mice were intragastric administrated with corresponding medical solution for two weeks (1.54 g·kg-1·d-1) according to groups. Normal group and model group were given equal volume distilled water. After administration, BAT of scapular region of mice was collected and the changes of BAT cells were observed by hematoxylin-eosin (HE) staining. The expression of uncoupling protein 1 (UCP1) and its mRNA were detected by Western blot and real-time fluorescence quantitative polymerase chain reaction (Real-time PCR). Result:Compared with the normal group of the same sex, the proportion of BAT in the model group decreased significantly (P<0.01). Compared with the model group of the same sex, the proportion of BAT in female mice from Shengfupian and Yinfupian groups increased significantly (P<0.01), while there was no significant difference between each administration group and model group in the male mice. Compared with normal mice of the same sex, there were many scattered vacuoles in BAT cells of the model group, and fewer cells could be observed due to larger vacuoles. Compared with the model group of the same sex, BAT cells in mice from the Shengfupian group showed fewer vacuoles, smaller cells and tight arrangement, the density of BAT cells in mice from the Yangfupian group also increased significantly, while the vacuoles in BAT cells of mice from the Yinfupian group decreased relatively and the cells did not increase significantly. Compared with the same sex mice, the expression level of UCP1 in the model group and the normal group was statistically significant (P<0.05, P<0.01). In the female mice, the expression level of UCP1 in Yangfupian group was significantly higher than that in the model group (P<0.05), each administration group of male mice was significantly different from that of the model group of the same sex (P<0.05), of which Yangfupian was the most significant. The relative expression of UCP1 mRNA in the model group was significantly lower than that in the normal group of the same sex (P<0.05, P<0.01). In the female mice, compared with the model group, the relative expression levels of UCP1 mRNA in Yangfupian group, Shengfupian group and Yinfupian group increased significantly (P<0.05, P<0.01), compared with Yangfupian group, the relative expression levels of UCP1 mRNA in Shengfupian and Yinfupian were also significantly different (P<0.05). In the male mice, compared with the model group, the relative expression of UCP1 mRNA in Yangfupian group was significantly increased (P<0.01), but there was no significant difference in Shengfupian group and Yinfupian group, in addition, compared with Yangfupian group, the relative expression of UCP1 mRNA in Shengfupian group and Yinfupian group had significant difference (P<0.05). Conclusion:Shengfupian, Yinfupian and Yangfupian all have obvious improvement on Yang deficiency syndrome induced by Rhei Radix et Rhizoma suspension. The mechanism may be to promote the expression of UCP1 protein and its mRNA and enhance the activity of BAT. And the effect of Yangfupian is the best.

Analysis of 16 618 Prescriptions of Chinese Patent Medicine Containing Aconiti Lateralis Radix Praeparata Based on Three Data Mining Models / 中国实验方剂学杂志

Objective::Through data mining analysis of Chinese patent medicine prescription containing Aconiti Lateralis Radix Praeparata (CPMCA) in a hospital, the characteristic rules of clinical medication of this kind of Chinese patent medicine were analyzed from the perspective of traditional Chinese medicine (TCM) syndrome differentiation and treatment, and the application prospect of data mining in TCM prescription analysis was explored. Method::CPMCA in the hospital outpatient clinics from November 2017 to October 2018 was conducted. The clinical application of this kind of Chinese patent medicine was retrospectively analyzed from the aspects of basic situation of patients, TCM diseases, TCM syndromes and so on. The clinical application of CPMCA was reviewed and analyzed. Three kinds of data mining algorithms in Microsoft SQL Server Analysis Services 2012 were used to analyze the characteristics of prescription medication. Result::A total of 8 kinds of Chinese patent medicines containing Aconiti Lateralis Radix Praeparata were used in a hospital, and most of them were used by patients under 14 years old, among them, the dosage of Xiaoer Feike granules was the largest. The TCM diseases were mostly cough, cold and asthma, while the TCM syndromes were mostly cold-heat complicated syndrome, wind-phlegm syndrome and external contraction of wind evil. The CPMCA for nourishing and warming kidney-Yang included Jingui Shenqiwan, Longlu capsules, Wangbi capsules and Guifu Dihuang pills. The TCM diseases were mostly arthralgia syndrome, vertigo, and consumptive disease, meanwhile, the syndromes were mainly deficiency of liver and kidney, kidney deficiency and blood stasis, and deficiency of spleen and kidney. Decision tree analysis showed that the CPMCA had the characteristics of age distribution, among which TCM diseases and syndromes were the main decision points. According to the age, sex, diagnosis of Chinese and western medicine, and TCM syndromes of this type of prescription, the CPMCA were divided into 10 categories by cluster analysis. Correlation analysis showed that the combination of Xiaoer Feike granules was the most common, but the correlation was not high. And Jingui Shenqiwan, Qili Qiangxin capsules, Longlu capsules and Wangbi capsules had their own strong associated medication. Conclusion::The application of data mining algorithm in multi-factor analysis of clinical prescription is close to the clinical dialectical treatment thinking of TCM. Combined with the basic statistics, it can be seen that the CPMCA in a hospital is consistent with the characteristics of TCM syndrome differentiation and treatment.

Screening of Antitumor Active Components and Key Targets of Aconiti Lateralis Radix Praeparata-Pinelliae Rhizoma Based on PI3K/Akt Pathway / 中国实验方剂学杂志

Objective:Screen out the antitumor constituents of Aconiti Lateralis Radix Praeparata-Pinelliae Rhizoma base on system pharmacology with chemical constituents of Aconiti Lateralis Radix Praeparata-Pinelliae Rhizoma as study objects, in order to provide the theoretical basis for the development of antitumor and nontoxic activities of Aconiti Lateralis Radix Praeparata-Pinelliae Rhizoma. Method:The small molecule ligand library of Aconiti Lateralis Radix Praeparata-Pinelliae Rhizoma was built based on Traditional Chinese Medicine Systems Pharmacology(TCMSP), energy of Aconiti Lateralis Radix Praeparata-Pinelliae Rhizoma was matched with the key protein targets of phosphatidylinositol 3-kinase/protein kinase B (PI3K/Akt) signal pathway by molecular docking (SYBYL2.1, Tripos), the Aconiti Lateralis Radix Praeparata-Pinelliae Rhizoma-targets network model was established based on Cytoscape 3.5.1, and the physicochemical properties of the antitumor activity in Aconiti Lateralis Radix Praeparata-Pinelliae Rhizoma were predicted by using SwissADME and admetSAR. Result:There were 25 small molecule constituents of Aconiti Lateralis Radix Praeparata-Pinelliae Rhizoma. Through the energy match, key antitumor constituents of Pinelliae Rhizoma were gondoic acid, 10,13-eicosadienoic, baicalin, 12,13-epoxy-9-hydroxynonadeca-7,10-dienoic acid. Key antitumor constituents of Aconiti Lateralis Radix Praeparata were deltoin, sitosterol, neokadsuranic acid B, 11,14-eicosadienoic acid. Phosphatidylinositol 3-kinase (PI3Kα), phosphatase and tensin homolog deleted on chromosome ten (PTEN), phosphoinositide dependent protein kinase 1 (PDK1) were key antitumor targets of Aconiti Lateralis Radix Praeparata-Pinelliae Rhizoma. There were 8 key antitumor constituents of Aconiti Lateralis Radix Praeparata-Pinelliae Rhizoma, which had a low CYP450 inhibition and basically followed the Lipinski rule. Conclusion:Antitumor nontoxic constituents of Aconiti Lateralis Radix Praeparata-Pinelliae Rhizoma and key targets are screened out from the molecular level, which provides the new ideas for the effective use of nontoxic traditional Chinese medicine(TCM) and breaks the restrictions in using nontoxic TCM.

Effect of Aconiti Lateralis Radix Praeparata Polysaccharide on Expressions of MMP-2,MMP-14 in Gastric Cancer Xenografts in Nude Mice / 中国实验方剂学杂志

Objective: To observe the growth inhibition effect of Aconiti Lateralis Radix Praeparata polysaccharide on the gastric cancer xenografts in nude mice and the expressions of matrix metalloproteinase-2 (MMP-2) and matrix metalloproteinase-14 (MMP-14) in tumor tissues. Method: The nude mice xenograft model was established and randomly divided into model group, 5-fluorouracil group (5-FU, 0.01 g · kg-1), high and low-dose Aconiti Lateralis Radix Praeparata polysaccharide groups (0.2, 0.1 g · kg-1). Each group was given drug by gavage for 15 days. The effect of Aconiti Lateralis Radix Praeparata polysaccharide on the weight of gastric cancer in nude mice was observed. Morphological changes of tumor cells were observed under light microscope. The content of transforming growth factor-β1 (TGF-β1) in serum was determined by enzyme-linked immunosorbent assay (ELISA). The protein and mRNA expressions of MMP-2, MMP-14 in tumor tissues were detected by immunohistochemistry, Western blot and Real-time PCR. Result: The tumor inhibition rates of high and low-dose Aconiti Lateralis Radix Praeparata polysaccharides were 52.83%,40.57%, respectively. Compared with model group, the tumor weight of high and low-dose Aconiti Lateralis Radix Praeparata polysaccharide was significantly lower (Pβ1 content in nude mice (PPPPPPPConclusion: Aconiti Lateralis Radix Praeparata polysaccharide can inhibit the growth of gastric cancer xenografts in nude mice and the expression of TGF-β1.The anti-tumor mechanism may be related to the down-regulation of MMP-2, MMP-14 protein and mRNA expressions.

Comparative study on six alkaloids in Aconiti Lateralis Radix Praeparata and Aconiti Radix in Jiangyou of Sichuan Province based on multivariate statistical analysis / 中草药

Objective: To establish a UPLC method for the simultaneous determination of benzoylmesaconitine, benzoylaconitine, benzoylhypaconitine, mesaconitine, hypaconitine and aconitinein Aconiti Lateralis Radix Praeparata (ALRP) and Aconiti Radix (AR), and to compare the content difference of six alkaloids in the samples with multivariate statistical analysis. Methods Alkaloids in ALRP and AR were extracted with 0.05 mol/mL hydrochloric acid solution by ultrasonic extraction. The UPLC method was performed on a BEH C18 (100 mm × 2.1 mm, 1.7 μm) through a gradient elution of acetonitrile and water at a flow rate of 0.1 mL/min with column temperature at 35 ℃. The injection volume was set at 4.0 μL, and the detection wavelength was set at 235 nm. Difference significance analysis, activity ratio analysis, toxic constituents index analysis, correlation analysis, hierarchical cluster heatmap analysis, principal component analysis, and TOPSIS analysis were used for data processing to comprehensively evaluate the quality of ALRP and AR. Results The method was in accordance with the regulations. Compared with the content of six alkaloids in ALRP and AR, significant difference existed in mesaconitine, benzoylhypaconitine, aconitine, and monoester diterpenoid alkaloids (MDAs); Significant difference existed in benzoylmesaconitine and benzoylaconitine; There were no significant difference in hypaconitine and diester-diterpenoid alkaloids (DDAs). Taking the six alkaloids as indexes, the sample No. 15 of ALRP was the best in quality and the samples No. 7 of AR was the best in quality. Conclusion The established method is simple, accurate and reliable with good precision, repeatability and stability, which can be used for the simultaneous determination of six alkaloids in ALRP and AR. It is much more accurate and convenient to conduct the quality evaluation by using activity ratio, toxic constituents index and multivariate statistical analysis. The study could provide a reference for improving analysis and determination of ester-type alkaloids in ALRP and AR in ChP, and providing a reference for quality control and evaluation of ALRP and AR.

Development situation and countermeasures of genuine Aconiti Lateralis Radix Praeparata industry by SWOT model / 中草药

To clarify the present situation and the limiting factors of the development of the genuine Aconiti Lateralis Radix Praeparata industry, which is important to fully explore the development potential of the genuine Aconiti Lateralis Radix Praeparata industry and promote the adjustment and optimization of its industrial structure. Through SWOT model, the advantages, disadvantages, opportunities and challenges in the development process of genuine Aconiti Lateralis Radix Praeparata industry were analyzed, and some suggestions on how to speed up the development of genuine Aconiti Lateralis Radix Praeparata industry were put forward.

Quality evaluation of different processed products of Aconiti Lateralis Radix Praeparata combining bioassay and toxicity detection / 药学学报

There are many kinds of processed products of Aconiti Lateralis Radix Praeparata (ALRP), but their differences in toxicity and efficacy have not been identified. The minimum premature ventricular contraction (PVC) method was used to evaluate the biological toxicity of eight processed products. The results showed that the minimal toxic dose (MTD) of an ethanol extract of Shengfupian (SFP) was 0.16 g·kg-1, which was much lower than that of Heishunpian (HSP), Baifupian (BFP), Baofupian (BAP), Paofuzi (PFZ) or Zhengfupian (ZFP), with MTDs ranging from 2.64 to 5.75 g·kg-1. No cardiotoxicity was detected with Chaofupian (CFP) and Paotianxiong (PTX). A novel +dp/dtmax assay for acute heart failure in rats was developed to evaluate the cardiac activity. It was found that all eight processed products had cardiac effects, with Shengfupian showing the strongest cardiotonic effect and the ability to restore damaged cardiac function to normal within 15 minutes of injection. Heishunpian, Baifupian and the three other products displayed moderate activity, while Paofuzi and Paotianxiong were the weakest. An LC-MS/MS method was utilized to determine the content of 13 alkaloids in water extracts. The results demonstrated that hypertoxic aconitine, mesaconitine, and hypaconitine could not be detected, higenamine was only present in Shengfupian, and salsolinol was about 4-56 times higher in Shengfupian than in other products. A correlation analysis showed that salsolinol had the best correlation with the cardiotonic index, with a correlation coefficient as high as 0.817, while the three monoester alkaloids failed to correlate with the cardiotonic effect. Higenamine and salsolinol were cardiotonic, while the 11 other components had no cardiotonic activity. This study establishes methods for precise evaluation of cardiotoxicity and cardiac activity, reveals the toxicity and efficacy of common processed products, and identifies the key quality markers for cardiac activity, providing scientific support for the quality evaluation and clinical application of processed products of aconite.

Adverse reactions analysis of Aconiti Lateralis Radix Praeparata and mechanism prediction of cardiac toxicity by network pharmacology / 中国中药杂志

The aim of this paper was to provide reference for the clinical safety use of aconite through the retrieval of literature about adverse reactions,predict its mechanism of cardiac toxicity by using network pharmacology,and provide ideas for the studies on toxicity mechanism of toxic Chinese medicines. The papers on adverse reactions of aconite were searched to established a database and summarize the adverse reactions of aconite. The results of literature review showed that the main causes for adverse reactions in clinical use of aconite included overdose use,short cooking time,consumption of medicinal liquor/medicinal diet,external use and misuse and so on. Therefore,the dosage of aconite should be strictly followed in clinical application,and the decoction method should be notified to the patients in detail to avoid taking the medicinal liquor and diet containing aconite,so as to prevent the occurrence of adverse reactions as much as possible,and make the best use of aconite in clinical application in avoid its toxicity. At the same time,based on the results of literature review,the network construction and visual analysis of cardio toxicity produced by aconite were carried out by using the network pharmacology technologies. RESULTS: showed that aconite can be applied to eight biological processes such as action potential of cardiac myocytes,cardiac conduction-related cell signal transduction,cardiac myocytes contraction,action potential involved in cardiac myocytes contraction,and signal transduction from atrial myocardial cells to atrioventricular node cells,and three target genes(SCN5 A,GJA1,GJA5). It was predicted that Aconiti Lateralis Radix Praeparata may influence cardiomyocyte depolarization,intercellular information transmission and material exchange by acting on three target genes(SCN5 A,GJA1,GJA5) and regulating the sodium channel protein and the expression of gap junction protein,thus affecting the heart rhythm as well as its structure and function and causing cardiac toxicity.

Research advancement in mechanisms of processing and compatibility for detoxication of Aconitums / 中国中药杂志

Aconitums,represented by Aconite Radix,Aconiti Lateralis Radix Praeparata and Aconiti Kusnezoffh Folium,is a kind of traditional Chinese medicine with a long medicinal history in China. They possess the significant toxicity and therapeutic effects simultaneously. Their potent effects of rescuing from dying,curing rheumatism,anti-inflammation,and analgesia make Aconitums highly regarded by physicians and pharmacists of various dynasties. However,countless poisoning cases caused by an irrational use of Aconitums were reported. In case of improper application and exceeding the therapeutic window,the acute cardiotoxicity and neurotoxicity would be caused,seriously threatening health and even life of the users. Therefore,the clinical application of Aconitums is limited to some extent. To avoid its toxicity and ensure the safety of medicinal use,Aconitums is usually used in a form of its processed products instead of the crude herbs,or combined with some other traditional Chinese medicines in a normal prescription. A proper processing and compatibility method can detoxicate its severe toxicity,reduce the adverse reactions,and also significantly broaden the indications and application range of Aconitums. This provides a guarantee for the secondary exploitation and utilization of Aconitums. In this paper,the traditional processing methods of Aconitums,along with the modern advancement were reviewed,and the mechanisms of detoxification by processing and compatibility were also illuminated. The physical detoxification mode and chemical detoxification mode were found as two main detoxification ways for Aconitums. In particular,the detoxification by hydrolysis,ion-pair,and saponification were three main means. The mechanisms illustrated in this paper can be a reference to the development of modern processing method and a guidance for appropriate use of Aconitums in clinical application.

Transcriptomics study on mechanism of Aconiti Lateralis Radix Praeparata in treatment of rats with acute heart failure / 中国中药杂志

In this study,transcriptomics technique was used to investigate the mechanism of action of Aconiti Lateralis Radix Praeparata on acute heart failure rats induced by propafenone hydrochloride.First,rats were randomly divided into normal group,model group and administration group(1.25,2.5,5 g·kg-1).A rat with acute heart failure was constructed by intravenous femoral administration of proparone hydrochloride.The changes of heart rate,+dp/dtmaxand-dp/dtmaxat 5,10,20,30 and 60 min were recorded.Then another group of rats were given the same drug delivery method.In another group of animals,serum TNF-α could be determined by ELISA with the same dosage method.High-throughput sequencing technology was used to detect all gene expression differences in cardiac tissue samples of rats with acute heart failure.Through functional annotation and enrichment analysis,gene expression signaling pathways of rats with acute heart failure and rats with post-administration heart failure were screened out.The results showed that heart rate and LV+dp/dtmaxand LV-dp/dtmaxwere significantly decreased in the model group(P<0.05),while heart rate and LV+dp/dtmax and LV-dp/dtmaxwere significantly increased in the drug group(P<0.05,P<0.01).Moreover,ANP,BNP and TNF-α in acute heart failure rats was significantly decreased in high-dose aconite decoction group(P<0.05).Transcriptomics analysis showed that the mechanism of action was mainly related to activation of PI3 K-AKT signaling pathway and Jak-STAT pathway.Compared with the model group,aconite decoction up-regulated the expression of phosphatidylinostol 3-kinase(PI3 K),lysophosphatidic acid(LAP3),Bcl-3 and STAT genes,and down-regulated the expression of integrin(ITGA),nuclear orphan receptor(Nur77) genes.It could be concluded that the mechanism of aconite in treating acute heart failure rats may be related to the regulation of the PI3 k-Akt/Jak-STAT pathway.

Overview on modern research of “Qin medicine” / 中草药

Shaanxi has a long history and profound cultural heritage. It has been referred to as “Qin” for a long time in history. Shaanxi is rich in medicinal plant resources, various main Chinese medicines such as Fraxini cortex, Gentianae Macrophyllae Radix, Ten “Qin medicine” (Astragali Radix in Zizhou County, Bupleuri Radix in Baoji, Corydalis Rhizoma in Yang County, Salviae Miltiorrhizae Radix et Rhizoma in Shangluo, Aconiti Lateralis Radix Praeparata in Hanzhong; Eucommiae Cortex in lueyang County; Gastrodiae Rhizoma in Ningshan County; Polyporus in Ningshan County; Scutellariae Radix in Chengcheng County; Corni Fructus in Foping County; Polygonati Rhizoma in Lueyang County) and “Taibaiqi medicine” are typically species of “Qin medicine”. In history, “Qin medicine” represents genuine medicinal materials produced from Shaanxi Province and the surrounding region. In recently, the industry of “Qin medicine” becomes one of the most valuable resources in Shaanxi, which also contributes to the integral part of Chinese medical and health services. Here, the research progress on germplasm resources, cultivation techniques, plantation base construction, variety breeding, bioactive compounds, and quality control of “Qin medicine” were integrated and reviewed, and its future development of “Qin medicine” was also prospected.

Determination and multivariate statistical analysis of four nucleosides in Aconiti Lateralis Radix praeparata and Aconiti Radix in Jiangyou of Sichuan Province / 中草药

Objective To establish a UPLC method for the simultaneous determination of uracil, adenosine, guanosine, and uridine in Aconiti Lateralis Radix Praeparata (ALRP) and Aconiti Radix (AR), and to compare the content difference of four nucleosides in the samples based on multivariate statistical analysis. Methods Nucleosides in ALRP and AR were extracted with purified water by ultrasonic extraction. The UPLC method was performed on a BEH C18 (100 mm × 2.1 mm, 1.7 μm) through a gradient elution of acetonitrile and water at a flow rate of 0.2 mL/min with column temperature at 30 ℃. The injection volume was set at 4.0 μL, and the detection wavelength was set at 260 nm. Difference significance analysis, hierarchical cluster heatmap analysis, principal component analysis, and TOPSIS analysis were used for data processing to comprehensively evaluate the quality of ALRP and AR. Results The method was in accordance with the regulations, the quantitative evaluation of uracil, adenosine, guanosine, and uridine was in good linear range (r2 > 0.999 3), and the average recovery was 99.86%, 99.14%, 99.74%, and 98.71% respectively, and the RSDs were all less than 2.0%. Taking the four nucleosides as indexes, the samples No. 18 of ALRP and the samples No. 23 of AR were the best in quality. Conclusion The established method is simple, accurate, and reliable with good precision, repeatability, and stability, which can be used for the simultaneous determination of four nucleosides in ALRP and AR, and it might provide the scientific basis for the study of water-soluble constituents in ALRP and AR.