Volume 14,Issue 4,2022 Table of Contents

1 Network pharmacology in quality control of traditional Chinese medicines

Ziyi Wang , Shao Li

2022, 14(4):477-478. DOI: https://doi.org/10.1016/j.chmed.2022.09.001

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Traditional Chinese medicine (TCM) has been widely used to treat and prevent diseases for thousands of years in China and is generally recognized for its unique holistic view and remarkable therapeutic effect on complex diseases. The worldwide interest to TCM has been increasing in recent years, especially since TCM has shown inspiring efficacy in the treatment of COVID-19. These attentions include both recognition of the important role of TCM and doubts about its efficacy and safety. At present, the internationalization and modernization of TCM are facing many challenges, such as unclear biological mechanism of herbs and formulae, and the difficulty of ensuring the quality and safety of TCM. Given the multi-component and multi-target characteristics of TCM, how to systematically describe the interaction between TCM and complex diseases, evaluate the efficacy and toxicity of TCM and carry out quality control has become the focus and difficulty of research. Network pharmacology, as a systematic and holistic medical research paradigm, can help to systematically reveal the biological basis of TCM, and has been widely used in the research of TCM bioactive ingredients, syndromes, formulae, and other topics. The concept of "network target" based on TCM research (Li et al., 2011) has been used to explore new methods and applications since its inception, leading to a new discipline of TCM network pharmacology (Li and Zhang, 2013). On the one hand, TCM network pharmacology research shows the tendency of combining computational, experimental and clinical approaches (Wang et al., 2021), and the research paradigm is improving continuously. On the other hand, the application of network pharmacology is expanding to a variety of aspects in TCM research. It has been applied in fields such as exploring the biological basic of disease and syndrome, uncovering the mechanism of TCM formulae, identifying toxic components and quality markers (Q-Marker) of traditional Chinese medicine and so on. The concept of Q-Marker which was proposed by Prof. Liu to standardize the quality research of TCM has established an effective research framework for the quality control of traditional Chinese medicine (Liu et al., 2017). Since it was proposed, Q-Marker has been utilized by researchers to analyze many TCM herbs and formulae, making an important contribution to the TCM quality control system. A previous research strategy of predicting and determining Q-Marker based on network pharmacology method (Wang et al, 2019) shows the potential of network pharmacology combined with Q-Marker in the application of quality control of TCM. The effectiveness and safety of TCM are taken into consideration when determining Q-Marker. There have been many successful application cases of network pharmacology in studying the effective ingredients and mechanism of TCM, and network pharmacology is also being used more and more frequently in the study of TCM toxicity. This issue will publish a research paper titled “Integrating systematic pharmacology-based strategy and experimental validation to explore mechanism of Tripterygium glycoside on cholangiocyte-related liver injury” on the use of network pharmacology to explore the toxic components of TCM and their underlying mechanisms. Tripterygium glycoside (TG) extracted from Tripterygium wilfordii have been used in clinical treatment of rheumatoid arthritis and other diseases, and there are several new indications under study. However, hepatotoxicity, the main adverse effect of TG in clinical practice, is an urgent problem to be solved. By combining network pharmacological analysis with in vivo and in vitro experimental verification, the authors discovered that triptolide, the primary toxic component of TG, could inhibit proliferation and promoted apoptosis of cholangiocytes by inhibiting the phosphorylation of ERK1/2 and AKT and activating Bax and cleaved-Caspase 3 signaling. This study is a typical example of using network pharmacology to predict the toxic components and mechanisms of TCM. At the same time, it also shows that network pharmacology can be combined with Q-Marker strategy to identify the toxicity Q-Marker of TCM, and aids in the quality control and standardization of traditional Chinese medicine. As a discipline that has been developed for a short period of time, there are still many challenges in the theory, methodology and application of network pharmacology. The quality control research of TCM using network pharmacology also needs more investigation and exploration. The publication of Network Pharmacology Evaluation Method Guidance in 2021 has positive implications for the standardization of network pharmacology research and promotes the healthy development of the discipline (Li, 2021). However, as the fields of network pharmacology research continues to expand, the guidance cannot cover all kinds of research and need to be updated and revised in time. With the combination with new technologies such as artificial intelligence high-throughput technologies, network pharmacology will undoubtedly develop at a high speed. We look forward to a wider application of network pharmacology in TCM research, which will provide new scientific evidence for deciphering the mysteries of TCM and thus promote the inheritance, innovation and development of TCM.

2 Analysis on internal mechanism of zedoary turmeric in treatment of liver cancer based on pharmacodynamic substances and pharmacodynamic groups

Zeyu Li a , b , c , Erwei Hao a , b , c , Rui Cao a , b , c , Si Lin a , b , c , Linghui Zou a , b , c , Tianyan Huang a , b , c , Zhengcai Du a , b , c , Xiaotao Hou a , b , c , Jiagang Deng a , b , c

2022, 14(4):479-493. DOI: https://doi.org/10.1016/j.chmed.2022.06.007

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Zedoary tumeric (Curcumae Rhizoma, Ezhu in Chinese) has a long history of application and has great potential in the treatment of liver cancer. The anti liver cancer effect of zedoary tumeric depends on the combined action of multiple pharmacodynamic substances. In order to clarify the specific mechanism of zedoary tumeric against liver cancer, this paper first analyzes the mechanism of its single pharmacodynamic substance against liver cancer, and then verifies the joint anti liver cancer mechanism of its "pharmacodynamic group". By searching the research on the anti hepatoma effect of active components of zedoary tumeric in recent years, we found that pharmacodynamic substances, including curcumol, zedoarondiol, curcumenol, curzerenone, curdione, curcumin, germacrone, β-elemene, can act on multi-target and multi-channel to play an anti hepatoma role. For example, curcumin can regulate miR, GLO1, CD133, VEGF, YAP, LIN28B, GPR81, HCAR-1, P53 and PI3K/Akt/mTOR, HSP70/TLR4 and NF-κB. Wnt/TGF/EMT, Nrf2/Keap1, JAK/STAT and other pathways play an anti hepatoma role. Network pharmacological analysis showed that the core targets of the "pharmacodynamic group" for anti-life cancer are AKT1, EGFR, MAPK8, etc, and the core pathways are neuroactive live receiver interaction, nitrogen metabolism, HIF-1 signaling pathway, etc. At the same time, by comparing and analyzing the relationship between the specific mechanisms of pharmacodynamic substance and "pharmacodynamic group", it is found that they have great reference significance in target, pathway, biological function, determination of core pharmacodynamic components, formation of core target protein interaction, in-depth research of single pharmacodynamic substance, increasing curative effect and so on. By analyzing the internal mechanism of zedoary tumeric pharmacodynamic substance and "pharmacodynamic group" in the treatment of liver cancer, this paper intends to provide some ideas and references for the deeper pharmacological research of zedoary tumeric and the relationship between pharmacodynamic substance and "pharmacodynamic group".

3 Post-infectious cough of different syndromes treated by traditional Chinese medicines: A review

Wanru Jianga , Jiaxin Qia , Xu Lib , Gang Chena , Di Zhoua , b , Wei Xiaoa , b , c , Ning Lia

2022, 14(4):494-510. DOI: https://doi.org/10.1016/j.chmed.2022.09.002

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The application of traditional Chinese medicines (TCMs) has a history of more than 2000 years, which have the characteristics of multi-component, multi-target, and high safety. Post-infectious cough (PIC) is a respiratory disease with high incidence. It belongs to subacute cough and accounts for as much as 40%?50%. Cough is the main clinical manifestation of PIC. PIC seriously affects people's life quality because of complex etiology, long-term course of disease, treatment difficulties and other characteristics. Western medicines are based on the principle of symptomatic treatment, so they are often difficult to control PIC fundamentally. These factors could due to that PIC is prolonged and unable to heal repeatedly. TCMs have obvious advantages in treating PIC, with accurate curative effects, less side effects and adverse reactions and are effective in improving PIC-related symptoms and indicators, enhancing patients' life quality and reducing pain. TCMs, guided by holistic concept and syndrome differentiation, advocate determine treatment on the basis of pattern types, and have remarkable clinical treatment effects. As for TCMs etiology, pathogenesis and syndrome types of PIC, TCM scholars have not yet reached a unified standard. However, most of them think that wind pathogen can cause PIC alone, or it can be combined with other evils, which might be the main mechanism of PIC. This paper discusses the advantages and limitations of TCMs in PIC treatment from etiology, pathogenesis, distribution of syndrome types and treatment of TCMs. This article focuses on the treatment methods and pharmacodynamic material basis of wind pathogen, providing ideas in treating PIC of TCMs clinically and innovative drug development.

4 Pharmacological and analytical aspects of alkannin/shikonin and their derivatives: An update from 2008 to 2022

Kirandeep Kaura , Rashi Sharmaa , Atamjit Singha , Shivani Attrib , Saroj Arorab , Sarabjit Kaura , Neena Bedia

2022, 14(4):511-527. DOI: https://doi.org/10.1016/j.chmed.2022.08.001

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Alkannin/shikonin (A/S) and their derivatives are naturally occurring naphthoquinones majorly found in Boraginaceae family plants. They are integral constituents of traditional Chinese medicine Zicao (roots of Lithospermum erythrorhizon). In last two decades significant increase in pharmacological investigations on alkannin/shikonin and their derivatives has been reported that resulted in discovery of their novel mechanisms in various diseases and disorders. This review throws light on recently conducted pharmacological investigations on alkannin/shikonin and their derivatives and their outputs. Various analytical aspects are also discussed and brief summary of patent applications on inventions containing alkannin/shikonin and its derivatives is also provided.

5 Molecular mechanisms of anti-cancer bioactivities of seaweed polysaccharides

Tingting Liu a , Qing Lib , c , Xu xu b , c , Guoxia Li a , Chengwang Tian b , c , d , Tiejun Zhang b , c , d

2022, 14(4):528-534. DOI: https://doi.org/10.1016/j.chmed.2022.02.003

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Seaweed is a traditional Chinese medicine homologous to food, in which polysaccharides are responsible for anti-cancer by enhancing immunity, inducing cancer cell apoptosis, inhibiting cancer cell invasion and metastasis or directly scavenging oxidative free radicals that induce cancer cell changes. Among them, regulating immunity and promoting cancer cell apoptosis are intensively studied due to the important role in preventing cancer. Here we reviewed seaweed in the apoptosis-inducing signaling pathways including PI3K/AKT, ROS and JNK and discussed challenges in studying seaweed.

6 Comparative authentication of Semiliquidambar cathayensis and its substituted species via macroscopic and microscopic features

Dan Zhua , Xincheng Qub , Xuemei Suna , Shihuan Yana , Hongwei Guoa , Yaoli Lic

2022, 14(4):535-542. DOI: https://doi.org/10.1016/j.chmed.2021.12.006

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Objective: Ban Fenghe recorded in the Quality Standard of Yao Medicine of Guangxi Zhuang Autonomous Region (Volume 1) is derived from the dried stems and leaves of Semiliquidambar cathayensis. It is usually confused with medicinal herbs from Pterospermum heterophyllum and Dendropanax dentiger. However they are very different in chemical composition, and should not be used as the same drug. To ensure their safety and efficacy, a method based on macroscopic and microscopic characteristics was developed to distinguish them. Methods: A total of 14 batches of Ban Fenghe samples from three species were collected from different producing areas in China. The macroscopic characteristics were examined by observing external traits. The tissue structures of transverse sections of stems and leaves, the leaf epidermis, and the powder were observed microscopically. Results: The branchlets and leaf surfaces of S. cathayensis and P. heterophyllum were hairy, especially the lower leaf surfaces of P. heterophyllum were densely covered with hairs, but those of D. dentiger were hairless. The pericyclic fibers of S. cathayensis stems were intermittently distributed in a circular shape and accompanied by stone cells, whereas those of P. heterophyllum and D. dentiger were bundled without stone cells. So stone cells and hairs were present in S. cathayensis powder, stone cells were not found in P. heterophyllum and D. dentiger powder, and hairs were not present in D. dentiger powder. The distribution sites, sizes and types of secretory tissues of these three species were also different in transverse sections of stems and leaves. Stomata on the lower epidermis of S. cathayensis leaves were paracytic, whereas those of P. heterophyllum and D. dentiger were anomocytic. Conclusion: Ban Fenghe drugs derived from S. cathayensis could readily be distinguished from those of P. heterophyllum and D. dentiger by macroscopic and microscopic features.

7 Specification and grade of Saposhnikoviae Radix (Saposhnikovia divaricata)

Lijuan Lva , Xing Lib , c , Erhuan Zangc , Yumei Yanc , Min Yangc , Wenle Wangb , Chunhong Zhangc , d

2022, 14(4):543-553. DOI: https://doi.org/10.1016/j.chmed.2021.11.005

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Objective Saposhnikoviae Radix (Fangfeng in Chinese), the roots of Saposhnikovia divaricata, lacks commodity specification and grade standardization in the current market. This study investigated the existing specifications and grades of Saposhnikoviae Radix to provide a standardized scientific reference for its market use. Methods Based on a textual research of Chinese herbal medicine from the Han Dynasty to the present, medicinal materials of different specifications and grades obtained from Saposhnikoviae Radix in the main producing areas of China were collected and the markets for these materials were investigated. Field investigations were performed in the major producing areas such as Northeast China, Hebei Province, and Inner Mongolia. Four major Chinese herbal medicine markets in China were investigated. Sensory indices were used to categorize the two specifications (wild and cultivated) according to the shape, color, texture, and cross-section. High-performance liquid chromatography was performed to determine the active components. Vernier calipers and measuring tape were used to measure the diameter and length, respectively, of 41 samples. Using Excel and the R Language software, cluster analysis and descriptive statistical analysis were performed to assist in the application of new specifications and grades based on physical characteristics, pharmacological activity, and chemical composition. Results The two specifications (wild and cultivated) of Saposhnikoviae Radix were divided into three grades each based on the length and diameter. Prim-O-glucosylcimifugin, 5-O-methylvisamminoside, and the length of Saposhnikoviae Radix can be used as a basis for classifying the commodity specifications and grades. The specifications and grade standards of Saposhnikoviae Radix were established based on the following eight aspects: shape, surface characteristics, texture, cross section, taste, prim-O-glucosylcimifugin content, 5-O-methylvisamminoside content and length. Conclusion The formulation of this standard stipulates the commodity specification level of Saposhnikoviae Radix. It is also suitable for the evaluation of commodity specifications in the process of production, circulation and use of Saposhnikoviae Radix.

8 Taxifolin attenuates inflammation via suppressing MAPK signal pathway in vitro and in silico analysis

Xingyan Zhanga , Wenjing Zhaoa , b , Xin Lia , Huling Lia , Fujun Zhoua , c , Yutong Zhoua , Tao Cuia , c , Yuli Wanga , d , Changxiao Liua , c , e

2022, 14(4):554-562. DOI: https://doi.org/10.1016/j.chmed.2021.03.002

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Objective Taxifolin is a natural flavonoid compound that can be isolated from onions, grapes, oranges and grapefruit. It also acts as a medicine food homology with extraordinary antioxidant and anti-inflammatory activity. This study aims to explain the protective effects and potential mechanisms of taxifolin against inflammatory reaction. Methods Levels of interleukin (IL)-6, IL-1β and intracellular reactive oxygen species (ROS)were assessed in different time after the treatment of taxifolin in RAW264.7 cells induced by lipopolysaccharide (LPS). Subsequently, the mRNA and protein levels of inducible nitric oxide synthase (iNOS), vascular endothelial growth factor (VEGF), cyclooxygenase (COX)-2, tumor necrosis factor (TNF)-α and the phosphorylation expression levels of the MAPK signal pathway were also evaluated. A silico analysis was used to explain the binding situation for the investigation of taxifolin and MAPK signal pathway. And then MAPK inhibitors were used to reveal the expression level of iNOS, VEGF, COX-2 and TNF-α in RAW264.7 cells. Results It was demonstrated that cell inflammatory damage induced by LPS was significantly alleviated after the treatment of taxifolin. Then, the mRNA and protein levels of iNOS, VEGF, COX-2 and TNF-α were reduced and the phosphorylation expression levels of the MAPK signal pathway were down-regulated remarkably as well. In silico analysis, taxifolin could form a relatively stable combination with MAPK signal pathway. MAPK inhibitors showed increasing or decreasing effect in the mRNA levels of iNOS, VEGF, COX-2 and TNF-α, which suggesting that taxifolin down-regulated iNOS, VEGF, COX-2 and TNF-α expressions were not entirely through the MAPK pathway. Conclusion This finding demonstrated that taxifolin improved the inflammatory responses that partly involved in the phosphorylation expression level of MAPK signal pathway in RAW264.7 cells exposed to acute stress.

9 Integrating systematic pharmacology-based strategy and experimental validation to explore mechanism of Tripterygium glycoside on cholangiocyte-related liver injury

Yajing Li , Sen Lia , Xiaoyong Xuea , Ting Wangb , Xiaojiaoyang Lia

2022, 14(4):563-575. DOI: https://doi.org/10.1016/j.chmed.2022.02.006

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Objective: Tripterygium glycoside(TG) is widely used in clinical practice for its multiple bioactivities including anti-inflammatory and immunosuppressive effects. However, emerging studies have frequently reported TG-induced adverse reactions to multiple organs, especially liver. Here, this studyaimed to investigate the mechanism of liver damage induced by TG and explore representative components to reflect TG hepatotoxicity. Methods: Network pharmacology was used to determine the potential targets of bile duct injury caused by TG. Next, the hepatotoxic effects of TG, triptolide (TP) and celastrol (CEL) were investigated and compared in vivo and in vitro. Liver function was determined by measuring serum transaminase and histopathology staining. The cell proliferation and apoptosis were determined by cell viability assay, scratch assay and flow cytometry. The expression of gene of interest was determined by qPCR and Western blot. Results: Based on the network pharmacological analysis of 12 bioactive ingredients found in TG, a total of 35 targets and 15 pathways related to bile duct injury were obtained. Both TG and TP resulted in cholangiocyte damage and liver injury, as illustrated by increased levels of serum transaminase and oxidative stress, stimulated portal edema and lymphocytic infiltration and decreased expression of cholangiocyte marker, cytoskeletal 19. In addition, TG and TP inhibited cell proliferation and migration, arrested cell cycle and promoted Caspase-dependent apoptosis of cholangiocytes via suppressing the phosphorylation of extracellular regulated protein kinases 1/2 (ERK1/2) and protein kinase B (AKT). While, CEL at equivalent dosage had no obvious hepatotoxicity. Conclusion: We revealed that TG-stimulated liver injury was specifically characterized by cholangiocyte damage and TP might be the decisive ingredient to reflect TG hepatotoxicity. Our results not only provide novel insights into the mechanism underlying the hepatotoxicity effects of TG but also offer reference for clinical rational use of TG.

10 Lithocarpus polystachyus (Sweet Tea) water extract promotes human hepatocytes HL7702 proliferation through activation of HGF/AKT/ERK signaling pathway

Ming Leia , b , Nana Chena , b , Yingshu Xua , Qihai Gongb , Jianmei Gaoa , b

2022, 14(4):576-582. DOI: https://doi.org/10.1016/j.chmed.2021.08.006

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Objective: Sweet Tea (ST), derived from the leaves of Lithocarpus polystachyus, is a Chinese folk medicine with wide pharmacological activities. However, the promotive effects of ST water extract on hepatocytes proliferation and its underlying mechanism remains still unknown. In the present study, the beneficial effects of ST water extract on human hepatocytes and its possible mechanism were investigated. Methods: MTT assay was used to detect the safety range of ST; HL7702 cells were divided into four groups: control group, ST low- (50 μg/mL), medium- (200 μg/mL) and high-concentration (800 μg/mL) groups; BrdU ELISA and EDU staining were used to observe DNA content and cell proliferation; Moreover, flow cytometry was applied to analyze the distribution of cell cycle. Furthermore, the expression of cyclin D1, CDK4, HGF/c-Met, Akt, Erk1/2 were detected by Western blot. Results: It was found that ST water extract concentration-dependent promoted human hepatocytes HL7702 cell proliferation within 72 h through accumulating the cells in S phase and G2/M phase. Furthermore, ST water extract up-regulated expression of Cyclin D1 and CDK4 proteins. Moreover, ST water extract not only increased HGF expression and phosphorylation of c-Met level, but also activated the phosphorylation levels of AKT, ERK1/2. Interestingly, both of AKT inhibitor A6730 and ERK1/2 inhibitor U0126 reversed the promotive effects of ST water extract, which further confirmed that activation of AKT and ERK1/2 were involved. Conclusion: The findings reveal that ST water extract promoted HL7702 cells proliferation through the stimulation of cell cycle mediated by activating the AKT- and ERK1/2-related pathway.

11 Reduning Injection prevents carrageenan-induced inflammation in rats by serum and urine metabolomics analysis

Xia Gaoa , b , c , Jiajia Wanga , b , c , Xialin Chena , b , c , Shanli Wanga , b , c , d , Chaojie Huanga , b , c , d , Quanchang Zhanga , b , c , Liang Caoa , b , c , Zhenzhong Wanga , b , c , Wei Xiaoa , b , c

2022, 14(4):583-591. DOI: https://doi.org/10.1016/j.chmed.2022.01.007

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Objective: To elucidate the anti-inflammatory mechanism of Reduning Injection (RDN) by analyzing the potential biomarkers and metabolic pathways of the carrageenan-induced inflammatory model from the overall metabolic level. Methods: Rat inflammatory model was established by carrageenan. UPLC-Q-TOF/MS was used to detect and analyze changes of endogenous metabolites in the serum and urine of carrageenan-induced inflammatory rats. Combined with multivariate analysis and databases analysis, inflammatory-related potential biomarkers were screened and identified to analyze possible metabolic pathways. The reliability and biological significance of these biomarkers was verified by metabolic network analysis and correlation analysis with pharmacodynamic indicators. Results: A total of 16 potential biomarkers were screened and identified by multivariate analysis and metabolite databases, among which 13 species could be adjusted by RDN. The metabolism pathway analysis revealed that histidine metabolism, sphingolipid metabolism, and tyrosine metabolism were greatly disturbed. Their biomarkers involved urocanic acid, sphingosine, and norepinephrine, all of which showed a callback trend after RDN treatment. The three biomarkers had a certain correlation with some known inflammatory-related small molecules (histamine, arachidonic acid, Leukotriene B4, and PGE2) and pharmacodynamic indicators (IL-6, IL-1β, PGE2 and TNF-α), which indicated that the selected biomarkers had certain reliability and biological significance. Conclusion: RDN has a good regulation of the metabolic disorder of endogenous components in carrageenan-induced inflammatory rats. And its anti-inflammatory mechanism is mainly related to the regulation of amino acid and lipid metabolism. This research method is conducive to the interpretation of the overall pharmacological mechanism of Chinese medicine.

12 Variation of photosynthesis, secondary metabolites and antioxidant activities in third generation of spaceflight-induced Salvia miltiorrhiza

Liang Penga , c , Mei Rud , Zongsuo Liangb , c

2022, 14(4):592-601. DOI: https://doi.org/10.1016/j.chmed.2022.02.005

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Objective: Spaceflight has long been perceived as an effective way to improve the quantity and quality of plants with wide applications. In order to obtain stable and inheritable descendants of spaceflight-induced Salvia miltiorrhiza lines, we investigated and analyzed four lines m16, m50, m51, m57 (three individuals of each line) and the ground control (three individuals) of the third generation of spaceflight-induced S. miltiorrhiza from primary/secondary metabolism and antioxidative abilities. Methods: A portable photosynthesis system (Li-6400) with red/blue LED light source was used to perform the photosynthetic characteristics to evaluate their primary productivity. The secondary metabolites (phenolic acids, tanshinones, total phenolics and flavonoids) and antioxidant activity of roots were analyzed to assess their quality. Results: Compared with control, line m16 presented weak photosynthetic ability, but high apparent quantum yield (AQY), higher contents of secondary metabolites, and stronger antioxidative abilities. Line m57 had a strong gas exchange ability, relatively higher secondary metabolites contents, and ascending antioxidative abilities. Lines m50 and m51 were in the middle level of lines m16 and m57. The principal component analysis for all the original data revealed three components including a root-related index, a leaf-related index, and a CO2 response parameter could be used to distinguish spaceflight-induced S. miltiorrhiza lines. Conclusion: Line m57 could be an appropriate material for the investigation of targeted breeding towards high production, and line m16 could be used to identify essential genes and unravel sophisticated pathways underlying the secondary metabolisms.

13 Metabolic regulation mechanism of Aconiti Radix Cocta extract in rats based on 1H-NMR metabonomics

Wenfang Jina , Jianli Bia , Sheng Xua , Mengfan Rao , Qi Wangb , Yan Yuana , Baolei Fana

2022, 14(4):602-611. DOI: https://doi.org/10.1016/j.chmed.2022.07.002

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Objective To establish a metabonomics research technique based on the combination of 1H-NMR and multivariate statistical analysis, so as to explore the metabolic regulation mechanism of Aconiti Radix Cocta extract (ARCE) in rat tissues and serum. Methods SD rats were randomly divided into blank group, female group and male group. The 1H-NMR technique was used to collect the information of rat tissues and serum samples in each group. The principal component analysis (PCA), partial least squares discriminant analysis (PLS-DA) and other methods were used for data pattern recognition, so as to screen out potential differential metabolites and metabolic pathways, and then network analysis and KEGG database were used to analyze the relationship between metabolites, metabolic pathways and diseases. Results The external features and 1H-NMR analysis showed that the sex of rats had no obvious effect on the drug action. A total of 15 potential differential metabolites and six metabolic pathways were screened out through data pattern recognition. Through network analysis and KEGG pathway analysis, three target diseases closely related to differential metabolites were found, and the metabolic pathway related to lung cancer was the central carbon metabolism of cancer. Conclusion This study shows that Aconiti Radix Cocta (ARC) may regulate the energy metabolism of the body by influencing arginine synthesis, so as to play the roles of anti-inflammation, analgesia, anti-tumor and immune regulation.

14 Identification of Q-Markers from Hedan Tablet by employing "spider-web" mode and taking compounds hepatotoxicity into account

Xiaoyu Zhang a , Zhenzuo Jiang a , Lei Zhang a , Cheng Xue a , Xiafei Feng b , Xin Chai a , Yuefei Wang a

2022, 14(4):612-621. DOI: https://doi.org/10.1016/j.chmed.2021.08.007

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Objective: As a classic prescription in traditional Chinese medicine, Xuefu Zhuyu Decoction (XFZYD) has been widely used in the clinical treatment of cardiovascular and cerebrovascular diseases. In order to unveil the potentially effective compounds, a rapid ultra-performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF/MS) method was established to identify prototype components and their metabolites from XFZYD in rats' serum. Methods: The serum from rats after intragastric administration of XFZYD aqueous extract was analyzed by UPLC-Q-TOF/MS method. The prototype components and their metabolites were identified by comparison with the reference standards and tentatively characterized by comprehensively analyzing the retention time, MS data, characteristic MS fragmentation pattern and retrieving literatures. Results: A total of 175 components (24 prototype components and 151 metabolites) were identified and tentatively characterized. The metabolic pathways of prototype components in vivo were also summarized, including glucuronidation, hydrolyzation, sulfation, demethylation, and hydroxylation, and so on. Conclusion: In this study, a UPLC-Q-TOF/MS technique was developed to analyze prototype components and their metabolites from XFZYD in serum, which would provide the evidence for further studying the effective compounds of XFZYD.

15 Trace heavy metals and harmful elements in roots and rhizomes of herbs: Screening level analysis and health risk assessment

Xiaoli Wu , Peiling Wu , Mengying Gu , Jian Xue

2022, 14(4):622-629. DOI: https://doi.org/10.1016/j.chmed.2021.11.004

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Objective: Heavy metal and harmful element contamination are frequently reported in Chinese herbal medicines (CHMs), and roots and rhizomes parts showed a higher content than other parts. To investigate the residue level and assess the potential human health risk of heavy metals and harmful elements in roots and rhizomes, 720 batches of the sample representing 20 species of herbs from different sources were collected. Methods: The content of Pb, Cd, As, Hg, and Cu in the digests was determined using ICP-MS. The chronic hazard index estimate based on non-cancer hazard quotient (HQ) was applied for potential health risk assessment of Pb, Cd, As, Hg, and Cu via consumption of CHMs. Results: Compared with the Chinese limit standard (Chinese Pharmacopoeia Commission, 2020 edition) of Pb, Cd, As, Hg, and Cu in Ginseng Radix et Rhizoma, the exceedance percentage of Pb in total samples was 14.1%, which were generally far higher than Cd, As, Hg, and Cu. Health risk assessment results based on hazard quotient calculating showed that total HQ of Cu, Pb, As, Cd, and Hg in Pulsatillae Radix and Clematidis Radix et Rhizoma exceeded 1, with the value of 1.543 and 1.235. Besides, Arsenic had the highest HQ value (0.957) in Pulsatillae Radix. Conclusion: Consuming raw materials of Pulsatillae Radix and Clematidis Radix et Rhizoma may pose a potential risk and Arsenic residues in Pulsatillae Radix deserved special attention.

16 Comparative study on brain pharmacokinetics of Buyang Huanwu Decoction in normal and cerebral ischemia rats using brain microdialysis combined with LC-MS/MS

Wanyi Liu , Keqi Zeng , Xin Zhou , Yingfeng Zhang , Cong Nie

2022, 14(4):630-637. DOI: https://doi.org/10.1016/j.chmed.2022.03.007

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Abstract:
Objective: To conduct a comparative study on the brain pharmacokinetics of seven ingredients (i. e. senkyunolide A, ferulic acid, formononetin, calycosin, ononin, calycosin-O-β-D-glucopyranoside, and paeoniflorin), which were the compounds of Buyang Huanwu Decoction (BHD), in normal and cerebral ischemia rats administrated intragastrically with BHD. Methods: The samples of normal and permanent middle cerebral artery occlusion (pMCAO) rats were collected by using brain microdialysis technique. The concentrations of seven ingredients were determined by the HPLC-MS/MS method. After the BHD were administrated intragastrically to the rats for seven consecutive days, brain microdialysis probes were inserted into the hippocampus of rats, and then the brain microdialysates were collected at 20 min time intervals for 5 h. The separation of the seven ingredients and internal standard (IS) was carried out on an ACQUITY UPLC BEH C18 (2.1 mm × 100 mm, 1.7 μm) chromatographic column, using a mobile phase consisting of acetonitrile (containing 0.1% formic acid) and water (containing 0.1% formic acid) for gradient elution within 13 min. The ionization was conducted using an ESI source in positive ion mode. Multiple reaction monitoring mode was used for quantification of ingredients in BHD. Results: Linearity, accuracy, precision, matrix effect and stability of LC-MS/MS method were all satisfactory, successfully applied to compare the pharmacokinetics of the analytes between normal and model rats after intragastric administration of BHD. Compared with the normal group, the model group after the administration of the BHD showed that T1/2 of formononetin and ononin were longer, and except for calycosin-O-β-D-glucopyranoside (P < 0.01), there was no significant difference between the normal group and the model group. The Cmax of senkyunolide A and calycosin of model group were increased, while the Tmax of senkyunolide A was decreased, and except for the Tmax of PF, the differences between the two groups were statistically significant (P < 0.01). Conclusion: The LC-MS/MS method combined with microdialysis was successfully applied to the comparative study of brain pharmacokinetics of seven ingredients in BHD. After intragastric administration of BHD, there were differences in the pharmacokinetics of seven ingredients in the brain hippocampus between normal rats and model rats, probably related to the characteristics of the ingredients and the effects of cerebral ischemia on the absorption and distribution of the ingredients.

17 Camganoids A and B, two new sesquiterpenes with different carbon skeletons isolated from fruits of Cinnamomum migao

Yongzhen Xiaoa , Ishaq Muhammada , Xianpeng Mac , Huajun Yuc , Shikai Yana , b , Xue Xiaod , Huizi Jina , b

2022, 14(4):638-642. DOI: https://doi.org/10.1016/j.chmed.2021.09.016

[Abstract](306) [HTML](0) [PDF 0.00 Byte](0)

Abstract:
Objective: To isolate and identify the undescribed compounds from the fruits of Cinnamomum migao and evaluate its nitric oxide inhibition potential. Methods: The chromatographic techniques of silica gel, sephadex, and HPLC were used for isolation and purification of the compounds, while HR-ESI-MS, 1D-NMR, 2D-NMR, ECD, and X-ray diffraction techniques were used to characterize and confirm the isolated compounds. Moreover, the anti-inflammatory activity of the isolated compounds was carried out to check inhibitory potential against the production of nitric oxide with RAW264.7 cells stimulated by LPS. Results: Camganoid A (1), a novel sesquiterpene possessing an unprecedented skeleton, and camganoid B (2), containing a unique eight-membered sesquiterpene moiety with a new carbon skeleton, were isolated and identified from the fruits of C. migao. The absolute configurations of 1 and 2 were confirmed by single crystal X-ray diffraction and electronic circular dichroism (ECD) calculations. Among these compounds, compound 1 exhibited potent inhibitory activity against the production of nitric oxide with IC50 value of 4.59 μmol/L in RAW264.7 cells stimulated by LPS. Conclusion: The isolation of two new skeletons from the fruits part of C. migao possessed unique skeletons which have not been reported before.

18 Effect of date palm pollen supplementation on female sexual function in non-menopausal women: A double blind randomized clinical trial

Roghayeh Salmania , Khadijeh Nasirib , Yousef Javadzadehc , Roya Salmanid , Cain C. T. Clarke , Vahideh Aghamohammadif

2022, 14(4):643-648. DOI: https://doi.org/10.1016/j.chmed.2022.02.004

[Abstract](696) [HTML](0) [PDF 0.00 Byte](0)

Abstract:
Objective: Despite numerous experimental studies in the literature, there are few clinical trials regarding the effect of date palm pollen (DPP) supplementation on sexual function improvement. In the present study, we sought to evaluate the impact of DPP on female sexual function in Iranian non-menopausal women. Methods: Between October 2019 and December 2019, health centers in the city of Khalkhal, volunteers meeting the inclusion criteria were recruited in randomized clinical trials. Sixty-eight women were randomly stratified and assigned to one of the two study groups: placebo group (n = 35) and palm pollen group (n = 35), and received a starch or palm pollen capsule (300 mg per day), respectively, for 35 d. The Female Sexual Function Index (FSFI) instrument was used to assess female sexual function. Results: After DPP supplementation, the increase in desire, lubrication, and the overall score, was statistically significant compared to the placebo group (P = 0.002, P = 0.000, and P = 0.042; respectively); Whilst there was no significant differences in the remaining domains (arousal: P = 0.763; orgasm: P = 0.370; satisfaction: P =0.474; pain: P = 0.259). There was a statistically significant positive correlation between the coitus and preintervention levels of desire (r = 0.298, P = 0.038), arousal (r = 0.328, P = 0.021), lubrication (r = 0.361, P = 0.011), orgasm (r = 0.320, P = 0.025), satisfaction (r = 0.327, P = 0.022), and overall scores (r = 0.338, P = 0.018). Conclusion: This study suggests that DPP (300 mg supplementation for 35 d), given to non-menopausal women, could improve the lubrication and desire domains of FSFI.

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