Chinese Journal of Integrative Medicine
·
2017
·
IF 1.116
Wei Ping,Tang Qing-fa,Huo Hui-ling,Chen Fei-long,Song Shuai,Xing Xue-feng,Luo Jia-bo
Objective To investigate the pharmacokinetic characteristics of three phenylpropanoids (cinnamic acid, cinnamic alcohol and coumarin) in Ramulus Cinnamomi (GZ) and Ramulus Cinnamomi-Ephedrae Herba (MH) herb-couple (GZMH). Methods Twelve male Sprague-Dawley rats were randomly and equally divided into the GZ and GZMH herb-couple groups. Blood samples were collected at 0, 0.08, 0.25, 0.5, 0.75, 1.5, 3, 4, 6, 8, 12, 24, 36 and 48 h after oral administration. The three phenylpropanoids in rat plasma were quantified using an ultra-performance liquid-chromatography with tandem mass spectrometry (UPLC-MS/MS) method for pharmacokinetic study. Results In GZMH group, the area under the curve (AUC), mean retention time (MRT) of cinnamic acid and coumarin were increased significantly ( P <0.01, respectively), and biological half-life (t 1/2z ) was obviously shorter ( P <0.05) compared with the GZ group. There were no significant differences in the mean retention time from 0 to ∞ (MRT 0-∞ ), the peak concentration (C max ), the time to peak (T max ) and t 1/2z , except for AUC and MRT 0-t (the mean retention time from 0 to t) of cinnamic alcohol in the GZMH group by comparison to the GZ group ( P <0.01, respectively). The AUC, MRT (both P <0.01) and t 1/2z ( P <0.05) of coumarin were increased significantly, while C max , and T max were decreased slightly by comparison to the GZ group ( P >0.05). Conclusions There were statistically significant differences in some pharmacokinetic parameters of the three compounds between GZ and GZMH groups, which meant that MH could affect the absorption and elimination of the three compounds.
研究领域:
中药学
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药理学
·
分析化学
✓ 已验证
DOI
PubMed
高影响因子
Separations
·
2024
·Vol. 11
·期 7
·206
·
IF 2.5
Xiaodong Xin,Xinnong Li,Jiabao Chen,Chuanghui Shen,Xiaohan Shi,Lei Wang,Chunhua Li
Cinnamomi ramulus(CR, Guizhi in Chinese) andZingiberis rhizoma recens(ZRR, Shengjiang in Chinese) are couplet medicines (drug pairs or drug combinations) in traditional Chinese medicine prescriptions. They contain a high amount of volatile oils which endow them with unique flavors and pharmacological activities. Extraction methods have a great influence on the extraction efficiency and composition of volatile oils. Firstly, the volatile oils of CR and ZRR were extracted by steam distillation (SD) and analyzed by GC-MS to obtain their chemical profiles. In total, 35 and 55 compounds were identified in the volatile oils of CR and ZRR, respectively. In order to find a suitable extraction method for the couplet medicine CR-ZRR, subsequently, steam distillation (SD), azeotropic distillation (AD) and supercritical fluid extraction (SFE) were applied to extract the volatile oils from CR-ZRR. The average extraction yields by SD, AD and SFE were 0.573%, 0.62% and 2.135%, respectively. The chemical composition of the volatile oils was then analyzed by GC-MS. In total, 73, 59 and 71 compounds were identified from the extracts obtained by SD, AD and SFE, respectively. Principal component analysis (PCA) and OPLS-DA showed that citral, (E)-cinnamaldehyde dimethyl acetal, zingiberene, cinnamaldehyde and β-sesquiphellandrene were the main contributors to distinguish the volatile oils that were obtained by different processes. Considering the chemical diversity and the total content of the main bioactive components of the volatiles oils, SD was more suitable for CR-ZRR volatile oil extraction. This study provides a basis for elucidating the chemical composition and suitable extraction method for the volatile oils of CR-ZRR.
研究领域:
中药学
·
分析化学
✓ 已验证
产品关联
DOI
高影响因子
Journal of Food Measurement and Characterization
·
2024
·
IF 2.9
Zhou Zhen,Liu Shengkai,Cui Liying,Liu Zhongkai,Li Xiaoyu,Liu Zhiguo,Fu Yujie
This study explored the ultrasonic-microwave synergistic extraction technique for obtaining cinnamaldehyde and cinnamic acid from cinnamon twigs, and determined the most favorable extraction conditions. The optimization of extraction parameters, including extraction time, ethanol concentration, liquid-to-solid ratio, and microwave power, was achieved through single-factor experiments and the response surface method. The results of the significance analysis indicated that ethanol concentration and extraction power were the two primary factors affecting the extraction rates of cinnamaldehyde and cinnamic acid. Under the optimal conditions—600 W microwave power, 75% ethanol concentration, a liquid-to-solid ratio of 1:15, and a 20-min extraction time——the extraction efficiency of cinnamaldehyde and cinnamic acid was significantly improved compared to traditional methods. Moreover, the use of the ultrasonic-microwave synergistic extraction technique demonstrated higher efficiency and lower environmental impact due to reduced waste production. The study also revealed that cinnamaldehyde and cinnamic acid in cinnamon twigs exhibited strong polarity characteristics and microwave absorption capacity, contributing to enhanced cell disruption and increased natural product release. These findings provide a robust basis for the development of an efficient and environmentally friendly extraction process for these valuable bioactive compounds.
研究领域:
化学工程
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药学
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环境科学
✓ 已验证
产品关联
DOI
高影响因子
Frontiers in Pharmacology
·
2025
·
IF 4.8
Yuhang Xu,Jing Li,Mengyao Cui,Xiaoliang Li,Hongyan Zhai,Deling Wu,Xiaoqin Chu
Introduction: Cinnamomi Ramulus (CR) is the dried bark of Cinnamomum cassia Presl, Lauraceae. Puerariae Lobatae Radix (PLR) is the dried root of the Pueraria lobata (Wild.) Ohwi, Leguminosae. This Chinese herb couple come from the classic formula “Gui Zhi Ge Gen Tang,” which is included in the TCM classic “Treatise on Febrile Diseases.” Our previous studies have found that CR related herbal compound and PLR related herbal compound are useful in improving type 2 diabetes mellitus (T2DM), which is expected to be an antidiabetic candidate with fewer side effects. However the mechanism of action of CR-PLR on T2DM has not yet been fully elucidated.Methods: The decoction of CR-PLR was prepared by aqueous extraction method and the composition of it was analyzed using UPLC-Q-TOF-MS and HPLC. The T2DM model was established by intraperitoneal injection of streptozotocin, and the groups of drug administration were metformin, CR, PLR and CR-PLR groups, with continuous gastric gavage for 6 weeks, and the serological indexes were detected by ELISA. The abundance of rats’ gut flora was detected by 16s rDNA sequencing, and changes in the content of short-chain fatty acids (SCFAs) in feces of rats were detected by GC-MS; and the expression of G protein-coupled receptor43 (GPR43) and glucagon-like peptide-1 (GLP-1) proteins in colonic tissues of rats were detected by Western Blot. The pharmacokinetic behavior of CR-PLR was investigated in both normal and T2DM model rats. Caco-2/HT29 co-culture cell model was established in vitro, transepithelial electrical resistance (TEER) and ALP activity of epithelial cells were measured to evaluate cell model integrity and cell polarization, Alcian blue staining was used to verify the presence of mucus production, and CCK-8 was used to screen drug safe concentration. The bidirectional transport of puerarin was studied to investigate the transport mechanism of puerarin and the effect of leuric acid on puerarin transport.Results and discussion: The results indicated that CR-PLR can stimulate intestinal flora, increase the content of SCFAs, activate intestinal GPR43 protein, and promote the secretion of GLP-1 in intestinal L cells, which plays a therapeutic role in the treatment of T2DM. Additionally, cytology and pharmacokinetics experiments have proved that cinnamic acid (CA) can enhance the absorption and transport of puerarin (PUR) by inhibiting the efflux effects mediated by P-gp and MRP efflux transporters. The present study exhibites the scientific and reasonable menaning of this novel Chinese herb couple treating T2DM from the perspecives of pharmacodynamics and pharmacokinetics.
研究领域:
中药学
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代谢病研究
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药理学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Analytical Methods
·
2015
·Vol. 7
·期 22
·9489-9494
·
IF 1.821
Lishuang Yu,Shiyao Lin,Mei Sha,Zhaoxia Sun,Huifeng Xu,Lili Wang,Wei Xu,Zongbao Chen,Guonan Chen
A method using microemulsion electrokinetic chromatography (MEEKC) coupled with large volume sample stacking was developed for the quantitative analysis of five compounds, namely liquiritin, glycyrrhizin, cinnamic acid, gallic acid and protocatechuic acid in Gualou Guizhi granules. The effect of the microemulsion components, such as the oil phase, surfactant and cosurfactant on the resolution of the analytes was studied. The baseline separation of the five analytes was achieved within 10 min by using a microemulsion buffer containing 0.5% (w/v, 17 mmol L−1) sodium dodecyl sulfate, 5.0% (v/v) butan-1-ol, 0.5% (v/v) ethyl acetate and 94.5% (v/v) 5 mmol L−1 borate–10 mmol L−1 phosphate buffer (pH 9.0). After combining with on-line preconcentration via large volume sample stacking (LVSS), the detection limits (defined as S/N = 3) for the analytes could be as low as 0.05 μg mL−1. MEEKC-LVSS was successfully applied to the determination of four analytes in Gualou Guizhi granules; the recoveries ranged from 94.51% to 97.53%, and good reproducibilities were obtained with relative standard deviations (RSDs) less than 5%.
研究领域:
药学
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分析化学
✓ 已验证
产品关联
DOI
高影响因子
Scientific Reports
·
2016
·
IF 5.228
Shufang Wang,Haiqiang Wang,Yining Liu,Yi Wang,Xiaohui Fan,Yiyu Cheng
The traditional activity-guided approach has the shortcoming of low accuracy and efficiency in discovering active compounds from TCM. In this work, an approach was developed by integrating activity index (AI), liquid chromatography - mass spectrometry (LC-MS), and nuclear magnetic resonance (NMR) to rapidly predict and identify the potential active constituents from TCM. This approach was used to discover and identify the anti-inflammatory constituents from a TCM formula, Gui-Zhi-Jia-Shao-Yao-Tang (GZJSYT). The AI results indicated that, among the 903 constituents detected in GZJSYT by LC-MS, 61 constituents with higher AI values were very likely to have anti-inflammatory activities. And eight potential active constituents of them were isolated and validated to have significant inhibitory effects against NO production on LPS-induced RAW 264.7 cell model. Among them, glycyrrhisoflavone (836), glisoflavanone (893) and isoangustone A (902) were reported to have anti-inflammatory effects for the first time. The proposed approach could be generally applicable for rapid and high efficient discovery of anti-inflammatory constituents from other TCM formulae or natural products.
研究领域:
药理学
·
分析化学
·
中医药
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Frontiers in Pharmacology
·
2021
·
IF 5.811
Zhang Yu,Su Na,Liu Weiyi,Wang Qingqing,Sun Jianguo,Peng Ying
Dysmenorrhea refers to a kind of uterine cramping pain that occurs in women during the period of menstrual. Guizhi Fuling Capsules are mainly used for the treatment of various pain syndromes and especially effective in treating primary dysmenorrhea. However, the research on its modern pharmacology and mechanism of action have not been thoroughly carried out. It is not clear about the main active ingredients, potential targets and metabolic pathways involved in its efficacy. Therefore, this research project employed estradiol benzoate sensitization combined with oxytocin pain to construct the cold coagulation syndrome dysmenorrhea model, observed the anti-dysmenorrhea effect of Guizhi Fuling Capsules, and used the metabolomics to explore its mechanism. The results showed that Guizhi Fuling Capsules could considerably reduce the number of writhing times in dysmenorrhea rats, increasing the level of PGE2 and β-EP and reducing the contents of PGF2α in rat serum. Pathological sections of uterus and ovaries also showed that Guizhi Fuling Capsules could significantly relieve endometrial hyperplasia and improve ovarian function. The LC/MS-based metabolomics of rat uterine indicated that the model group has a great deviation from the control group. Compared with the model group, the Guizhi Fuling Capsules group had a tendency to shift to the control group, and the main metabolic changes was mainly concentrated on saturated and unsaturated fatty acids. Among them, arachidonic acid is in a pivotal position, and the expression of its rate-limiting enzyme (COX-2) involved in its cyclooxygenase metabolic pathway was significantly up-regulated in the model group, but significantly decreased after the intervention of Guizhi Fuling Capsules. In conclusion, Guizhi Fuling Capsules can effectively relieve primary dysmenorrhea, and this effect may be attributed to the regulation effects of Guizhi Fuling Capsules on endogenous metabolism, such as inhibiting arachidonic acid converted to prostaglandins through downregulate the expression of COX-2, which plays an anti-inflammatory effect.
研究领域:
药理学
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中医药学
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代谢组学
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妇科学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Molecular Medicine Reports
·
2014
·Vol. 10
·期 1
·248-254
·
IF 1.484
Xianwen Chen,Huang Li,Mingqing Huang,Mei Huang,Wei Xu,Kedan Chu,Lidian Chen,Yuqin Zhang
Gua Lou Gui Zhi decotion (GLGZD) has been reported to be an effective treatment for post‑apoplectic limb spasm in the clinic. The present study aimed to investigate whether GLGZD had an affect on cerebral injuries induced by middle cerebral artery occlusion (MCAO) in rats and its possible mechanism. High‑performance liquid chromatography was performed to analyze GLGZD. Furthermore, a model was established to assess the efficacy of GLGZD. Neurological defect scores and screen tests were analyzed. Brain ischemic infarct volume was measured using 2,3,5‑triphenyl tetrazolium chloride staining and glutamic acid (Glu), aspartic acid (Asp) and glycine (Gly) levels in the cerebrospinal fluid were measured using the Hitachi automatic amino acid analyzer. Immunohistochemistry was performed to determine the expression of the α‑amino‑3‑hydroxy‑5‑methyl‑4‑isoxazole‑propionic acid (AMPA) and N‑methyl‑D‑aspartic acid (NMDA) glutamate receptors, and to analyze histopathological change. GLGZD was found to improve neurological performance and reduce infarct volumes in MCAO rats. In addition, GLGZD was observed to enhance motor performance, which was assessed using the screen test. Furthermore, GLGZD was found to reduce Glu, Asp and Gly levels in the cerebrospinal fluid and downregulate the protein expression of the AMPA and NMDA glutamate receptors. Thus, it was demonstrated that GLGZD may exert neuroprotective effects through the modulation of excitatory amino acids, and AMPA and NMDA receptor expression.
研究领域:
神经科学
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中药学
·
药理学
✓ 已验证
DOI
PubMed
高影响因子
PHYTOMEDICINE
·
2022
·
IF 6.656
Baogui Xu,Jiawen Zheng,Xiaoxiao Tian,Falei Yuan,zhongliang Liu,Yafeng Zhou,Zuisu Yang,Xianjun Ding
Background Chemical or drug-induced kidney damage has been recognized as a critical cause of kidney failure. The oxidative stress, inflammation, and imbalance of intestinal flora caused by carbon tetrachloride (CCl 4 ) play a fundamental role in chronic kidney damage. Guizhi Fuling pills (GZFL) is a traditional formula consisting of five traditional Chinese medicinal herbs, which can promote blood circulation and improve kidney function. The underlying mechanisms of GZFL improving kidney damage are not fully understood yet. Aim The current study aimed to explore the effects of GZFL on CCl 4 -induced kidney damage and intestinal microbiota in mice. Methods Male ICR mice were intraperitoneally administered with 20% CCl 4 (mixed in a ratio of 1:4 in soybean oil) twice a week, for 4 weeks to induce kidney damage. Creatinine (CRE), urea nitrogen, antioxidant enzymes, and inflammatory cytokines were measured and the histology of the kidney, jejunum, and colon examination to assess kidney and intestinal damage. The expressions of nuclear factor-erythroid 2-related factor 2 (Nrf2) family members, nucleotide-binding domain and leucine-rich repeat protein 3 (NLRP3) inflammasome in kidney tissues, and the tight junction proteins in colonic tissues were detected by Western blot. The gut microbiota was analyzed through 16S rRNA gene sequencing. Results GZFL treatment decreased the serum CRE and urea nitrogen levels. Moreover, GZFL reduced the levels of pro-inflammatory cytokines and increased antioxidant enzyme activities in kidney and colonic tissues. GZFL improved the kidney, jejunum, and colon histology. Furthermore, GZFL inhibited the expressions of NLRP3, ASC, and cleaved-Caspase-1, while Nrf2, HO-1, NQO1, GCLM, and tight junction proteins were increased. The dysbiosis of intestinal microbiota improved after GZFL treatment. Conclusions This study showed that GZFL could improve kidney damage, which might be mainly via the integrated regulations of the Nrf2 pathway, NLRP3 inflammasome, and composition of intestinal microbiota.
研究领域:
药理学
·
毒理学
·
中医
·
肾脏生理学
·
微生物组研究
✓ 已验证
产品关联
DOI
PubMed
高影响因子
JOURNAL OF ETHNOPHARMACOLOGY
·
2021
·
IF 4.36
Min Liu,Hongqiu Zhu,Ying Zhu,Xiaodan Hu
Ethnopharmacological relevance Guizhi Fuling Wan (GFW) is a traditional Chinese medicine used to remove blood stasis and dissipate phlegm for treating gynecological diseases that was invented by Zhang Zhongjing in the Eastern Han dynasty. In recent years, GFW has been widely used to treat patients with polycystic ovary syndrome (PCOS). Clinical and animal studies have shown that it is effective in the treatment of PCOS, but its mechanism is unknown. Generally, it works by regulating autophagy via the PI3K/AKT/mTOR signaling pathway. Aim of the study This study investigated the effects and mechanism of GFW in PCOS rats with insulin resistance (IR) in order to provide better understanding of its observed clinical effects and a theoretical basis for the study of traditional Chinese medicine. Materials and methods Eighty-four female Sprague–Dawley rats were randomly divided into seven groups (n = 12 per group): 1) control, 2) PCOS model, 3) low-dose GFW, 4) medium-dose GFW, 5) high-dose GFW, 6) metformin , and 7) medium-dose GFW plus LY294002 . In all non-control groups, we induced PCOS through daily letrozole combined with intragastric high-fat emulsion for 21 days. After treatment, rats were sacrificed and serum follicle-stimulating hormone (FSH), testosterone (T), progesterone , luteinizing hormone (LH), 17β-estradiol, fasting insulin (FINS), and fasting plasma glucose levels were measured by enzyme-linked immunosorbent assay (ELISA). The LH/FSH ratios and HOMA-IR values were calculated. Ovarian morphology was observed by hematoxylin and eosin staining, and all follicles were counted under a microscope. MDC-positive vesicles were used as markers to detect autophagy, and the expression levels of p62, Beclin1 , and LC3-II were examined by immunostaining. Western blotting was used to measure PI3K/AKT/mTOR pathway activation, granulosa cell apoptosis , and autophagy. Results Compared with the PCOS model group, GFW-treated rats had less atretic and cystic follicles, and more mature follicles and corpus lutea. The GFW-treated rats had lower serum T, LH, and FINS levels than the PCOS model group, as well as lower LH/FSH ratios and HOMA-IR values. GFW treatment resulted in significantly reduced levels of cleaved-Caspase-3, cleaved-Caspase-9, BAX, Beclin1, Atg5, and LC3-II. Phosphorylation of PI3K, AKT, and mTOR was significantly higher in GFW-treated rats compared with the PCOS model group. The phosphorylation of PI3K, AKT, and mTOR was decreased with the use of a PI3K antagonist. Conclusions Our results indicate that GFW inhibited granulosa cell autophagy and promoted follicular development to attenuate ovulation disorder in PCOS-IR rats. This was associated with activation of the PI3K/AKT/mTOR signaling pathway.
研究领域:
药理学
·
中医药
·
内分泌学
·
生殖生物学
✓ 已验证
DOI
PubMed
高影响因子
JOURNAL OF ETHNOPHARMACOLOGY
·
2024
·
IF 4.8
Zhuojun Zhang,Jin Gao,Junpeng Wang,Zishuo Mi,Haoyang Li,Zhicen Dai,Yujing Pan,Jiming Dong,Sihan Chen,Shu Lu,Xiaodong Tan,Hao Chen
Ethnopharmacological relevance Zhishi Xiebai Guizhi Decoction (ZSXBGZD) is a traditional herbal manuscript used to treat cardiovascular disease, including atherosclerosis and coronary heart disease. The decoction has demonstrated its capability to protect arteries and resist atherosclerosis. Its mechanisms for anti-atherosclerosis effect, nevertheless, remain unknown. Aims of the study The goal of the present study is to explore the effectiveness of ZSXBGZD acting on atherosclerosis and its key components based on experimental verification and network pharmacology analysis. Materials and methods The ultra-performance liquid chromatography quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF-MS) and databases were used to identify chemical components in ZSXBGZD. Network pharmacological analysis and molecular docking were implemented in order to reveal the possible therapeutic targets of ZSXBGZD. To form the model of atherosclerosis, we gave Apolipoprotein E knocked out mice a high-fat diet. H&E staining was performed to observe the effects of ZSXBGZD on atherosclerosis. Immunofluorescence and Western blot were used to investigate whether ZSXBGZD could affect autophagy, apoptosis, AGE-RAGE signaling pathway and other related mechanisms. Results In total, 30 core compounds were screened through intersecting UPLC-Q-TOF-MS and the databases. The anti-atherosclerotic effect of ZSXBGZD might relate to the AGE-RAGE signaling pathway via network pharmacology analysis. ZSXBGZD could inhibit apoptosis, activate autophagy and ease inflammation by modifying AGE-RAGE signaling pathway to reduce the area of atherosclerotic plaque. Conclusion ZSXBGZD could treat atherosclerosis by regulating autophagy and apoptosis via adjusting the AGE-RAGE signaling pathway.
研究领域:
药理学
·
心血管疾病
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中医药
·
分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Drug Design Development and Therapy
·
2020
·
IF 3.216
Hao-Zhen Zheng,Xiao Shen,Ying-Ying He,Xiang-Li Yan,Sheng-Xin Wang,Ai-Ming Yu,Li-Sheng Wang
Objective The aim of our research was to analyze and compare the pharmacokinetics of paeoniflorin, calycosin, calycosin-7-o-β-d-6-glucoside, and 6-gingerol in the blood and brain tissue of normal and cerebral ischemia-reperfusion injury rats by HPLC-MS/MS method.Methods The blood and brain tissue samples of normal and middle cerebral artery occlusion (MCAO) rats were compared. The blood and brain tissue samples were collected by using microdialysis technique. The concentrations of paeoniflorin, calycosin, calycosin-7-o-β-d-6-glucoside, and 6-gingerol in blood and brain tissues were determined by the HPLC-MS/MS internal standard method.Results Compared with the normal group, the model group after the administration of the Huangqi Guizhi Wuwu Decoction showed that Cmax blood, AUC0-t blood, and AUC0-inf blood of paeoniflorin were increased, CLblood, t1/2 brain, and Vbrain of paeoniflorin were decreased; Cmaxblood, AUC0-tblood, AUC0-infblood, and average residence time (MRTbrain) of calycosin-7-o-β-d-6-glucoside were decreased and the CLblood and Cmax brain of calycosin-7-o-β-d-6-glucoside were increased; Cmax blood of calycosin was decreased, Vblood and Vbrain of calycosin were increased; Cmax blood, AUC0-t blood, AUC0-inf blood, and MRTbrain of 6-gingerol were decreased, CLblood of 6-gingerol was increased.Conclusion This method is simple, rapid, and sensitive. It is suitable for the pharmacokinetic study of Huangqi Guizhi Wuwu Decoction in the blood and brain tissue of rats. Cerebral ischemia-reperfusion injury increased the content of paeoniflorin, calycosin, calycosin-7-o-β-d-6-glucoside, and 6-gingerol in the blood, affecting the clearance rate of paeoniflorin in the brain, the detention time of calycosin-7-o-β-d-6-glucoside and the 6-gingerol in the brain. In normal and cerebral ischemia-reperfusion rats, the content of paeoniflorin and 6-gingerol in the blood was higher than that in brain tissue, while the content of calycosin, calycosin-7-o-β-d-6-glucoside in the brain tissue was higher than that in blood, suggesting that calycosin and calycosin-7-o-β-d-6-glucoside have brain targeting properties.
研究领域:
中药学
·
药理学
·
神经科学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）