Effects of Cinnamon Granules on Pharmacokinetics of Berberine in Rhizoma Coptidis Granules in Healthy Male Volunteers

The effects of Cinnamon granules on pharmacokinetics of berberine in Rhizoma Coptidis granules in healthy male volunteers,and the compatibility mechanism of Jiao-Tai-Wan（JTW） composed of Rhizoma Coptidis granules and Cinnamon granules were investigated.The concentration of berberine in plasma of healthy male volunteers was determined directly by high performance liquid chromatogra-phy（HPLC） after an oral administration of Rhizoma Coptidis granules alone or combined with Cinnamon granules（JTW）.The plasma concentration-time curves of berberine were plotted.The data were analyzed with Drug and Statistics（DAS） 2.0 pharmacokinetic program（Chinese Pharmacology Society） to obtain the main pharmacokinetic parameters.The results showed that the plasma concentration-time curve of berberine was described by a two-compartment model.The Cmax,Tmax,t1/2 and CLz/F of berberine in Rhizoma Coptidis granules were 360.883 μg/L,2.0 h,3.882 h,119.320 L.h-1.kg-1 respectively,and those of berberine in JTW were 396.124 μg/L,1.5 h,4.727 h,57.709 L.h-1.kg-1 respectively.It was suggested that Rhizoma Coptidis granules combined with Cinnamon granules could increase the plasma concentration of berberine,promote berberine absorption and lengthen the detention time of berberine in healthy male volunteers.

Active Ingredients and Mechanism of Action of Rhizoma Coptidis against Type 2 Diabetes Based on Network-Pharmacology and Bioinformatics

A pharmacological network of"component/target/pathway"for Rhizoma coptidis against type 2 diabetes(T2D)was established by network-pharmacology,and the active components of Rhizoma coptidis and its mechanism were explored.A literature-based and database study of the components of Rhizoma coptidis was carried out and screened by ADME paramcters.The targets of Rhizoma coptidis were predicted by the ligand similarity method.Related pathways were analyzed with databases,and software was used to construct a "component/target path" network.The mechanism was further confirmed by GEO database with R software.A total of 12 active components were screened from Rhizoma coptidis,involving 57 targets including MAPKI,STAT3,INSR,and 38 signaling pathways were associated with T2D.Related signaling pathways included essential pathways for T2D such as insulin resistance,and pathways that had indirect effect on T2D.It was suggested that Rhizoma coptidis may exert its effects against T2D through multi-component,multi-target,and multi-pathway forms.

Rapid and simultaneous determination of moisture and berberine content in Coptidis Rhizoma and Phellodendri Chinensis Cortex by near-infrared spectroscopy and chemometrics

Coptidis Rhizoma(Chinese:Huanglian)and Phellodendri Chinensis Cortex(Chinese:Huangbo)are widely used Traditional Chinese Medicine,and often used in combination because of their similar pharmacological effects in clinical practice.However,the quality control methods of the two drugs are different and complicated,which is time consuming and laborious in practical application.In this paper,rapid and simultaneous determination of moisture and berberine in Coptidis Rhizoma(CR)and Phellodendri Chinensis Cortex(PC)was realized by near-infrared spectroscopy(NIRs)combined with global models.Competitive adaptive reweighted sampling(CARS)and successive projection algorithm(SPA)method were applied for variable selection.Principal component analysis(PCA)and partial least squares regression method(PLSR)were applied for qualitative and quantitative analysis,respectively.The characteristic variables of berberine showed similarity and consistency in distribution,providing basis for the global models.For moisture content,the global model had relative standard error of prediction set(RSEP)value of 3.04%and 2.53%for CR and PC,respectively.For berberine content,the global model had RSEP value of 5.41%and 3.97%for CR and PC,respectively.These results indicated the global models based on CARS-PLS method achieved satisfactory prediction for moisture and berberine content,improving the determination e±ciency.Furthermore,the greater range and larger number of samples enhanced the reliance of the global model.The NIRs combined with global models could be a powerful tool for quality control of CR and PC.

Qualitative and Quantitative Analysis for the Quality Control of Rhizoma Coptidis by HPLC-DAD and HPLC-ESI-MS

For quality control purpose, an approach of fingerprinting and simultaneous quantification of five major bioactive constituents of Rhizoma Coptidis was established via a high-performance liquid chromatograph coupled with a photodiode array UV detector（HPLC-DAD） and an electrospray ionization mass spectrometer（HPLC-ESI/MS） The compounds were identified on the basis of the comparison of their mass spectra with literature data and those of standard samples and quantified by the HPLC-DAD method. Baseline separation was achieved on an XTerra C18 column（5 μm, 250 mm×4.6 mm i. d.） with linear gradient elution of formate buffer（consisting of 0.5% formic acid, adjusted to pH=4.5 with ammonia） and acetonitrile（consisting of 0.2% formic acid and 0.2% triethylamine）. The me- thod was validated for linearity（r^2〉0.9995）, repeatability（RSD〈3.1%）, intra- and inter-day precision（RSD〈1.8%） with recovery（99.9%-105.1%）, limits of detection（0.15-0.35 μg/mL）, and limits of quantification（0.53-0.82 μg/mL）. The similarities of 32 batches of Rhizoma Coptidis and their classification according to their manufacturers were based on the retention time and peak areas of the characteristic compounds. The five compounds were selected for quality assessment ofRhizoma coptidis via partial least squares analysis（PLS）.

Network pharmacology-based analysis of effective components and mechanism of Rhizoma coptidis in treating diabetes

Objective:To identify the active ingredients,potential targets,and mechanism of Rhizoma coptidis by bioinformatics method,and to explore the hypoglycemic effect of Rhizoma coptidis by in vitro experiments.Methods:The chemical components of Rhizoma coptidis were collected through database search,and oral bioavailability and drug-likeness were used for preliminary screening.The targets of Rhizoma coptidis and diabetes-related targets were collected by database retrieval and reverse docking techniques,and the biological process of cross-set proteins was analyzed.The inhibitory effects of Rhizoma coptidis onα-glucosidase,α-amylase activity,and advanced glycation end products(AGEs)were determined via in vitro experiments.In addition,the effects of Rhizoma coptidis on preadipocyte differentiation,absorption of glucose by adipocytes,and the level of intracellular triglyceride were investigated using the adipocyte differentiation model.Results:There were 11 potentially active ingredients in Rhizoma coptidis.IL-6,caspase-3,epidermal growth factor receptor(EGFR),MYC,and estrogen receptor 1 were considered as the key genes.The bioinformatics analysis showed that Rhizoma coptidis played an antidiabetic role mainly via biological processes and signaling pathways including hormone receptor activity,glutathione binding,steroid binding,etc.In vitro experiments showed that the extract of Rhizoma coptidis inhibited the activities ofα-glucosidase andα-amylase,and the generation of AGEs;meanwhile,the extract promoted the absorption of glucose by adipocytes.In addition,the extract of Rhizoma coptidis decreased triglyceride level.Conclusions:Our network pharmacology and in vitro experiments demonstrate the anti-diabetic effects and possible underlying mechanisms of Rhizoma coptidis extract.

Associated Bacteriostasis Research of Coptidis Rhizoma-Folium Isatidis and Coptidis Rhizoma-Flos Poprli against Escherichia coli O2

[Objective] The paper was to explore the combined inhibitory effect of rhizoma coptidis-folium isatidis and rhizoma coptidis-flos poprli against Escherichia coli O2.[Method] Contrast test of single and associated bacteriostasis against known serotype E. coli O2 was conducted using microcheckerboard method.[Result] The MIC of rhizoma coptidis, folium isatidis and flos poprli were 1/8 extracting liquid, 1/8 extracting liquid and 1/2 extracting liquid, respectively. When combined with folium isatidis or flos poprli, the MIC of rhizoma coptidis was 1/8 extracting liq-uid or 1/16 extracting liquid compared with single use. When combined with rhizoma coptidis, the MIC of folium isatidis and flos poprli were 1/8 extracting liquid and 1/16 extracting liquid.[Conclusion] When rhizoma coptidis was combined with folium isatidis or flos poprli, the FIC values were 2 and 0.625, performing independent action and additive effect, respectively.

Experimental Study of Emilia Sonchifolia Combined with Coptidis Rhizoma for the Prevention and Treatment of Oral Ulcer

Objective: This paper aims to investigate the therapeutic effect of the combination of Emilia Sonchifolia and Coptidis Rhizoma on oral ulcer rats. Methods: 36 SD rats of half male and half female were kept for 7 days, and 6 rats among them were selected as normal group by random sampling method, and the rest rats were randomly divided into model group, positive control group, Emilia Sonchifolia group, Coptidis Rhizoma group and combined group after the establishment of oral ulcer model. The normal group and model group were given blank film, the positive control group was given Guilin Watermelon Frost, and the Emilia Sonchifolia group, Coptidis Rhizoma group and combined group were given the corresponding oral film, which was administered to the ulcer for 7 days continuously, 2 times per day. The healing of oral ulcer was assessed at the end of the last day of administration, and the ulcer area was calculated on the 1st, 3rd, 5th and 7th days after successful modeling, and the serum levels of IL-2 and TNF-α in rats were detected by Emilia Sonchifolia. Results: The grading of ulcer healing in the positive control group and the combined group was better than the other groups, and the difference was statistically significant when compared with the model group (p Coptidis Rhizoma group, Emilia Sonchifolia group, combined group and positive control group was smaller than that in the model group, and the difference was statistically significant (p Emilia Sonchifolia group, Coptidis Rhizoma group and combined group were all effective in reducing the area of oral ulcer, among which the combined group was more effective. The level of pro-inflammatory factor TNF-α was reduced and the level of anti-inflammatory factor IL-2 was increased in the Emilia Sonchifolia group, Coptidis Rhizoma group and combined group, and the difference was statistically significant (p Conclusion: The combination of Coptidis Rhizoma and Emilia Sonchifolia is effective in the treatment of oral ulcer in rats, and the effect of the combination is better than that of the drug alone.

Main alkaloids of Rhizoma Coptidis improved palmitic acidinduced insulin resistance in HepG2 cells via AMPK and MAPK signaling pathway

Rhizoma Coptidis,a traditional Chinese herbal medicine,has been used for treating diabetes for thousands of years.However,the molecular basis for this action has not been elucidated.In the present study,the effects of seven main alkaloids of Rhizoma Coptidis on glycometabolism were investigated and the related molecular mechanism of five active compounds on insulin resistant(IR)cell model was explored for the first time.Results showed that berberine,palmatine,epiberberine,columbamine and groenlandicine enhanced glucose consumption in the palmitic acid(PA)-induced IR-HepG2 cells,indicating that these compounds could improve IR.In addition,we found that among these active alkaloids,berberine,columbamine,epiberberine and groenlandicine could inhibit the activation of ERK and p38 pathway,while berberine,columbamine,palmatine and epiberberine could activate AMPK pathway.Moreover,palmatine and columbamine regulated the mRNA expression of GLUT2 to ameliorate IR via activating AMPK and inactivating p38 MAPK signal pathway.To sum up,berberine,columbamine,palmatine,epiberberine and groenlandicine might be the active reagents,which contribute to the glucose lowering effects of Rhizoma Coptidis.

Summary of Professor Tong Xiaolin's clinical experience of applying Rhizoma Coptidis(Huang Lian)

With the advantages of less toxicity and side effects, traditional Chinese medicine(TCM) is showing a bright future with a good clinical practice. Chinese herbal medicine, which usually contains various active ingredients, could provide multiple therapeutic effects. Professor Tong Xiaolin has accumulated abundant experience during many years of clinical practice and applies Rhizoma Coptidis(RC) well with the treatment of diabetes and its complications. Rhizoma coptidis is a classical natural herb which is used frequently by professor Tong Xiaolin. In this review, we summarize Tong Xiaolin's clinical experience of applying Rhizoma Coptidis(Huang Lian) in the treatment of disease from two aspects as well as introducing some traditional Chinese medical theory and clinical experience, with a prospect of guiding clinician to use RC more suitably and reasonably.

A review on pharmacological effects of Rhizoma Coptidis(Huang lian)

Huang Lian(Rhizoma coptidis, RC), which has effects on clearing damp-heat, quenching fie, and counteracting poison, is a herb frequently used in many traditional formulas. At present, there are many researches on the pharmacological effects of RC. In this review, we summarize the research progress on pharmacological effects of RC from four main aspects, in order to guide clinical application and explore the prospects of the application of RC.

转录组测序分析黄连总碱抗脑缺血的作用机制

背景:黄连清热燥湿、泻火解毒,黄连及其成分对脑缺血有显著的保护作用,基于网络药理学和转录组测序探究黄连总碱抗脑缺血的作用机制。目的:在明确黄连总碱对脑缺血大鼠保护作用的基础上,基于网络药理学和转录组测序技术探讨黄连总碱干预脑缺血的作用机制。方法:将SD大鼠随机分为假手术组、缺血再灌注组、阳性药物组和黄连总碱组,后3组采用改良线栓法制备大脑中动脉阻塞的缺血再灌注模型,假手术组不插入线栓,其余手术操作相同。通过TTC染色、Longa 5神经功能缺损评分、苏木精-伊红染色、尼氏染色评价黄连总碱对脑缺血再灌注模型大鼠的脑保护作用。对假手术组、缺血再灌注组、黄连总碱组大鼠脑组织进行转录组测序,通过差异表达基因筛选、基因本体论分析、京都基因与基因组百科全书分析以及转录组学与网络药理学关联分析,阐明黄连总碱干预脑缺血的作用特点,最后通过ELISA检测及免疫荧光染色对黄连总碱干预脑缺血的关键靶点进行验证。结果与结论:①黄连总碱可降低缺血再灌注模型大鼠Longa 5神经功能缺损评分及脑梗死面积,增加神经元、尼氏小体数目;②黄连总碱治疗后差异表达基因的基因本体论功能富集分析包括炎症反应、分裂原活化蛋白激酶级联的正调控等生物学过程;京都基因与基因组百科全书通路富集分析主要涉及白细胞介素17信号通路、神经活性配体-受体相互作用、环磷腺苷信号通路等通路;③转录组分析发现黄连总碱主要调控的基因有前列腺素内过氧化物合酶2、脑源性神经营养因子、瞬间受体电位A1等;④采用网络药理学分析发现,黄连总碱中9个成分可能通过87个成分靶点关联到过氧化物合酶2、脑源性神经营养因子及瞬间受体电位A1而发挥作用;⑤ELISA检测及免疫荧光染色结果进一步证实,黄连总碱调控脑缺血再灌注模型大鼠过氧化物合酶2、脑源性神经营养因子和瞬间受体电位A1的表达;⑥提示黄连总碱能明显改善脑缺血再灌注模型大鼠损伤,可能通过调控过氧化物合酶2、脑源性神经营养因子和瞬间受体电位A1而发挥作用。

基于“毒损脑络”理论探讨黄连改善卒中后认知功能障碍的研究

中医学认为,卒中后认知功能障碍(PSCI)病位在脑,“毒损脑络”为PSCI病因病机。从“毒损脑络”角度出发,阐述“毒邪”理论与卒中后认知功能的相关性。并以“解毒通络”为着手点,针对“热毒”“糖毒”“脂毒”“瘀毒”,分别探讨“毒邪”致PSCI的病机,逐步验证“毒损脑络”学说为PSCI的病因病机,为PSCI的中医诊疗提供思路。梳理解毒中药黄连改善认知障碍的文献记载,探析其理论内涵,开拓黄连临证辨证思路,提高解毒中药改善认知障碍的认识。

In vitro studies on the multi-target anti-Alzheimer activities of berberine-like alkaloids from Coptidis Rhizoma

Coptidis Rhizoma, a well known heat-clearing Chinese Materia Medica, exhibited multi-target anti-Alzheimer effectsin vitro through inhibition of AI342 aggregation, ACHE, and BACE1. Six berberine-like alkaloids were found to be the majoractive constituents of Coptidis Rhizoma by HPLC analysis along with activity assays. A standard combination of the six majoralkaloids was demonstrated to fully reproduce the in vitro effects of Coptidis Rhizoma. Molecular docking studies revealed thatberberine-like alkaloids could directly bind at the active sites of AI342, ACHE, and BACE1 through hydrophobic interactions,aromatic stacking, and electrostatic interactions.

三黄膏质量标准提升研究

目的:提升三黄膏的质量标准。方法:制备三黄膏,进行性状观察和粒度检查,采用薄层色谱法对该制剂中的黄连药材进行定性鉴别,采用高效液相色谱法测定该制剂中的小檗碱、表小檗碱、黄连碱、巴马汀含量并规定其总含量限度。结果:本研究所制得的三黄膏为黄色至棕黄色的软膏;粒度检查符合相关规定;建立的薄层色谱法专属性强,可准确鉴别黄连药材;小檗碱、表小檗碱、黄连碱、巴马汀的平均总含量为4.01 mg/g,其含量限度不得少于3.21 mg/g。结论:本研究建立的三黄膏质量标准稳定、可行,可有效控制该制剂的质量。

黄连生物碱超声辅助低共熔溶剂提取工艺优化

目的优化黄连生物碱超声辅助低共熔溶剂提取工艺。方法以葡萄糖-乳酸(1∶5)为低共熔溶剂。在单因素试验基础上,以提取时间、含水量、液料比为影响因素,生物碱得率为评价指标,Box-Behnken响应面法优化提取工艺。结果最佳条件为提取时间35 min,含水量26%,液料比33∶1,生物碱得率为7.22%。结论该方法稳定可靠,切实可行,可为黄连开发利用提供参考。

黄连的化学成分及药理作用研究进展

黄连是毛茛科植物黄连、三叶黄连及云连的干燥根茎,临床广泛使用。近年来国内外研究者对黄连的化学成分及药理作用不断深入探索,黄连的临床应用更加丰富。黄连的化学成分包括生物碱、黄酮、木脂素、有机酸、挥发油等,具有抗动脉粥样硬化、抗心肌缺血、抗脑缺血、抗心律失常、降血压、抗焦虑抗抑郁、降血糖、抗炎、抗肿瘤、抑菌等药理作用。本文对黄连的化学成分及其药理作用研究进展进行综述,以期为未来黄连的研究提供依据。

小檗碱调节糖脂代谢作用机制研究进展

随着生活质量的提高,糖脂代谢紊乱导致的疾病如糖尿病、高脂血症、肥胖症、胰岛素抵抗、脂肪肝等的发生率逐年上升。中药黄连在治疗糖脂代谢紊乱相关疾病方面有着显著疗效。小檗碱为黄连中含量最高、代表性最强的活性成分,属异喹啉类生物碱,能通过保护胰岛β细胞,改善胰岛素抵抗、调节胰岛素分泌、促进胰高血糖素样肽1(GLP-1)分泌、调节肠道菌群调节糖代谢,通过减少脂质沉积、促进脂质清除等调节脂代谢,还可通过AMPK通路、肠道菌群等共同调节糖脂代谢。其来源广泛、作用安全,在防治糖脂代谢紊乱导致的相关疾病中有着多通路、多效应的优势。该文归纳总结国内外相关文献,对小檗碱调节糖脂代谢作用机制进行综述,以期为中医药改善糖脂代谢紊乱提供一定的思路和理论依据。

Cytotoxicity effects of Rhizoma Coptidis on L929 murine fibroblast cells

Rhizoma Coptidis （RC）, a widely used traditional Chinese medicine, is commonly believed to be non-toxic. However, little is known about its cytotoxicity and relevant mechanisms at cellular and genetic levels. The present study aimed to explore the cytotoxicity of RC and its possible mechanisms related to cell cycle arrest, DNA damage and reactive oxygen species （ROS） level in L929 murine fibroblast cells. The cells were cultured in vitro and treated with different RC concentrations for 24 h. Cell viability was determined by CCK-8 method, morphological changes were observed with an inverted microscope, cell cycle and ROS level were examined by flow cytometry, and DNA damages were detected by comet assay. Our results showed that cell viability was significantly decreased in a dose-dependent manner when the RC concentration was higher than 1 mg/mL. ARC concentration above 1 mg/mL altered the morphology of L929 cells. Both cells at G2/M phase and the ROS level increased in the 2 mg/mL group. Each DNA damage indicator score increased in the groups with the RC concentration of above 0.05 mg/mL. Taken together, our study suggested that RC at a high dosage exhibited cytotoxicity on L929 cells, which was likely to be the consequences of cell cycle arrest, DNA damage and accumulation of intracellular ROS.

黄连大黄药对调控ROS/NF-κB/GSDMD信号通路对2型糖尿病大鼠胰岛β细胞焦亡的影响

目的基于活性氧(reactive oxygen species,ROS)/核转录因子κB(nuclear transcription factor-κB,NF-κB)/消皮素D(gasdermin D,GSDMD)焦亡信号通路探讨黄连大黄药对发挥2型糖尿病(type 2 diabetes mellitus,T2DM)胰岛β细胞保护作用的分子机制。方法选取自发性T2DM大鼠—Goto-Kakizaki(GK)大鼠构建动物模型,24只符合成模标准的GK大鼠随机分为模型组、二甲双胍组(0.1 g·kg^(-1)·d^(-1))、黄连大黄高剂量组(4.72 g·kg^(-1)·d^(-1))及低剂量组(2.36 g·kg^(-1)·d^(-1)),并随机选取6只正常Wistar大鼠设为正常组,连续灌胃干预8周后采用免疫荧光法检测大鼠胰腺组织胰岛素(insulin,INS)阳性表达,RT-PCR法检测细胞增殖相关细胞周期蛋白D1(cyclin D1,CCND1)、髓细胞瘤病毒癌基因(cellular-myelocytomatosis viral oncogene,c-Myc)mRNA表达,TUNEL染色检测胰岛细胞死亡,流式细胞术检测ROS水平,Western blot法检测NF-κB p65、GSDMD及消皮素D N端片段(gasdermin D-N,GSDMD-N)蛋白的表达,ELISA法检测白介素1β(interleukin 1β,IL^(-1)β)水平。结果与正常组比较,模型组大鼠胰腺组织INS平均光密度值显著降低,CCND1、c-Myc mRNA表达显著下调,TUNEL阳性率、ROS水平和NF-κB p65、GSDMD-N蛋白表达以及IL-1β水平均显著升高(P均<0.01);与模型组比较,黄连大黄低剂量组INS平均光密度值有效升高,CCND1、c-Myc mRNA表达有效上调,TUNEL阳性率、ROS水平以及NF-κB p65、GSDMD-N蛋白表达、IL-1β水平均明显降低(P<0.01,P<0.05),黄连大黄高剂量组仅c-Myc mRNA表达有效上调,NF-κB p65蛋白表达明显降低(P均<0.05)。结论黄连大黄药对可能通过ROS/NF-κB/GSDMD信号通路抑制细胞焦亡,促进增殖进而起到保护T2DM大鼠胰岛β细胞的作用。

黄连防治鸭病毒性肠炎机制的网络药理学分析及动物试验验证

旨在探讨黄连防治鸭病毒性肠炎(duck viral enteritis,DVE)的作用机制,本研究首先应用中药系统药理学分析平台(Traditional Chinese Medicine System Pharmacology Analysis Platform,TCMSP)筛选黄连活性成分及作用靶点,GeneCards数据库分析DVE相关靶点,Venny和Cytoscape3.7.2软件绘制黄连与DVE交集靶点及构建“药物-成分-疾病-靶点”网络,利用STRING数据库建立蛋白相互作用网络(protein interaction network,PPI),借助DAVID数据库进行靶点GO功能富集分析和KEGG通路富集分析,然后分正常对照组、病毒感染组和黄连防治组进行动物干预试验,采集组织样本进行病理组织学观察和相关细胞因子测定,结果表明:筛选出黄连14个活性成分和212个作用靶点,其中,与DVE交集的靶点25个,涉及RNA聚合酶Ⅱ启动子转录、序列特异性DNA结合转录因子活性、免疫应答、炎症反应和细胞凋亡等生物学过程,富集在Toll样受体信号通路、炎症性肠病、细胞因子-细胞因子受体相互作用、单纯疱疹病毒感染等信号通路,核心靶点是IL-6、IL-10和STAT1;病毒感染组鸭肝、脾和十二指肠发生不同程度的病理损伤,且这些组织中IL-6含量较正常对照组鸭显著提升(P≤0.05),IL-10和STAT1含量显著降低(P≤0.05),而黄连防治组鸭肝、脾和十二指肠组织病理损伤明显减轻,IL-6、IL-10和SYAT1含量趋于正常水平。由此可见,黄连能有效缓解鸭病毒性肠炎所致的鸭机体组织病理损伤,其作用机制涉及到多种炎症反应信号通路。