Discovery of the relationship between bitter taste and bitter flavor (efficacy) based on hTAS2Rs

Objective:To explore the relationship between bitter taste and bitter flavor(efficacy),their character-istics were analyzed at the target and pharmacodynamic points.Methods:Compounds with bitter receptor activity were obtained by high-throughput screening models of the human bitter taste receptors(hTAS2Rs),which were used to analyze bitter taste.The efficacy of anti-asthma medications was used as an example to research bitter flavor(efficacy).The pharmacological effects of bitter taste and bitter flavor(efficacy)were classified according to the functional modules.The coverage for the same targets or pharmacological effects in the overall protein interaction network(PIN)of bitter taste and bitter flavor(efficacy)was analyzed to reveal their relationship.The effect of the compound polydatin with anti-asthma activation on hTAS2R14 was studied to verify the reliability of the aforementioned idea.Results:A total of 121 Chinese materia medica(CMM)compounds that activate hTAS2R10,hTAS2R14,and hTAS2R49 were obtained.The analysis results indicated that 108 same targets for bitter taste and bitter flavor(efficacy)were obtained,accounting for 13.9%in the PIN of bitter taste and 72.5%in the PIN of bitter flavor(efficacy).The pharmacological effects shared by bitter taste and bitter flavor(efficacy)accounted for 79%of the PIN of bitter taste and 81%of the PIN of bitter flavor(efficacy).The activating effect of the anti-asthma compound polydatin on hTAS2R14 was dose-dependent with EC 50 of 4.3 m M.Conclusion:In this study,the relationship between bitter taste and bitter flavor(efficacy)has been demonstrated from the target and pharmacodynamic points,which are based on hTAS2Rs and anti-asthma effect.Bitter taste and bitter flavor(efficacy)exhibited a high correlation.This study provides a theoretical and scientific basis for the hypothesis that“the property theory of CMM is the clinical pharmacodynamics of CMM.”

Color spaces of safflower (Carthamus tinctorius L.) for quality assessment

Objective:In this study,safflower(Carthamus tinctorius L.)was taken as a representative example to examine the application of color characteristics to evaluate quality.Methods:A computer vision system was established for the objective and nondestructive assessment of color using image processing algorithms.Color parameters were investigated based on the RGB,L*a*b and HSV color spaces.The content of hydroxysafflor yellow A(HSYA),a major bioactive constituent of safflower,was determined by high-performance liquid chromatography.The relationship between HSYA content and color values was investigated by Pearson correlation analysis.A multiple linear regression model was established to predict the HSYA content from color values.Results:The red color and lightness of safflower were found to be significantly related to HSYA content.The prediction equation obtained by multiple regression was reliable with an R2 value of 0.805(P<.01).Conclusion:The results suggest that the computer vision technique could be used as a promising and non-destructive technology for color measurement and quality evaluation of CHM.

Property theory of Chinese materia medica: Clinical pharmacodynamics of traditional Chinese medicine

The property theory of Chinese materia medica is one of the foundations of traditional Chinese medicine.The property of Chinese materia medica(PCMM)is a multi-dimensional expression of the effect of Chinese materia medica(CMM),and it is related to the clinical prescription that fully reflects the clinical effect evaluation of CMM in a holistic,systematic,and scientific way.This paper discusses the source,development,and application of the PCMM by considering not only the five dimensions that constitute the PCMM but also the recognition of the human body and disease as given in traditional Chinese medicine.This paper aims to provide theoretical guidance for the rational use and development of CMM.

Near-infrared chemical imaging for quantitative analysis of chlorpheniramine maleate and distribution homogeneity assessment in pharmaceutical formulations

Near infrared chemical imaging(NIR-CI)combines conventional near infrared(NIR)spectros-copy with chemical imaging,thus provides spectral and spatial information simult aneously.It could be utilized to visualize the spatial distribution of the ingredients in a sample.The data acquired using NIR CI instrument are hyperspectral data cube(hypercube)containing thousands of spectra.Chemometric methodologies are necessary to transform spectral information into chemical information.Partial least squares(PLS)method was performed to extract chemical information of chlorpheniramine maleate in pharmaceutical formulations.A series of samples which consisted of different CPM concentrations(w/w)were compressed and hypercube data were measured.The spectra extracted from the hypercube were used to establish the PLS model of CPM.The results of the model were R^(2)_(val)0.981,RMSEC 0.384%,RMSECV 0.483%,RMSEP 0.631%,indicating that this model was reliable.

Rapid analysis of spatial distribution of PVPP and hardness of Yinhuang dispersible tablets by NIR-CI

The present study aimed at investigating the relationship between tablet hardness and homogeneity of different Yinhuang dispersible tablets by near-infrared chemical imaging(NIR-CI)technology.The regularity of best hardness was founded between tablet hardness and the spatial distribution uniformity of Yinhuang dispersible tablets.The ingredients homogeneity of Yinhuang dispersible tablets could be spatially determined using basic analysis of correlation between analysis(BACRA)method and binary image.Then different hardnesses of Yinhuang dispersible tablets were measured.Finally,the regularity between tablet hardness and the spatial distribution uniformity of Yinhuang dispersible tablets was illuminated by quantifying the agglomerate of polyvinyl poly pyrrolidone(PVPP).The result demonstrated that the distribution of PVPP was unstable when the hardness was too large or too small,while the agglomerate of PVPP was smaller and more stable when the best tablet hardness was 75 N.This paper provided a novel methodology for selecting the best hardness in the tabletting process of Chinese Medicine Tablet.

Rapid analysis of dyed safflowers by color objectification and pattern recognition methods

Objective:Rapid discrimination of three classes of safflowers,dyed safflower,adulterated safflower,and pure safflower using computer vision and image processing algorithms.Methods:A low cost computer vision system(CVS)was designed to measure the color of safflowers in the RGB(red,green,blue),L^*a^*b^*,and HSV(hue,saturation,vale)color spaces.The color moments in these three color spaces were extracted from the acquired images as color features of safflower.In addition,five kinds of pigments that are commonly used to dye safflowers were identified by high-performance liquid chromatography as a reference.Pattern recognition methods were investigated for rapid discrimination,including an unsupervised principal component analysis(PCA)algorithm and a supervised partial least squares discriminant analysis(PLS-DA)algorithm.Results:The mean error(e)between color values measured with the colorimeter and calculated with the CVS was 2.4%,with a high correlation coefficient(r)of 0.9905.This result indicated that the established CVS was reliable for color estimation of safflowers.The PLS-DA model,which had a total accuracy of 91.89%,outperformed the PCA model in classifying pure,adulterated,and dyed safflowers.Conclusion:The color objectification is a promising tool for rapid identification of dyed and adulterated safflowers.

Identification of berbamine dihydrochloride from barberry as an anti-adipogenic agent by high-content imaging assay

Objective:Lipid droplet(LD)deposition in adipose tissue is a critical factor leading to metabolic dysfunction.Various herbal medicines in traditional Chinese medicine(TCM)are used to treat hyperlipidemia,type 2 diabetes,obesity,and other diseases.The objective of this study was to identify potential anti-adipogenic agents from TCM herbal compounds.Methods:One hundred and twenty compounds were evaluated in terms of their effect on adipocyte differentiation through image-based high content screening.Anti-adipogenic effects of identified hits were further confirmed at various concentrations.In addition,drug-induced liver injury assay was performed with HepG2 cells to test the hepatotoxicity of hit compounds.Results:Berbamine(BBM),a chemical isolated from barberry,and a derivative of BBM,berbamine dihydrochloride(BBMD),reduced LDs formation by more than 50%.Dose-dependent effects were observed and the IC50 values of the two hits,BBM and BBMD,were determined as 1.88 mM and 0.95 mM,respectively.Moreover,BBM induced mild HepG2 cell injury,while its dihydrochloridedBBMD did not exhibit hepatotoxicity within 40 mM.Conclusion:This study demonstrates that BBMD may be a potential therapeutic candidate for disorders associated with elevated LDs accumulation.

In silico investigation of the association of the TRPM8 ion channel with the pungent flavor of Chinese herbs

Objective:Explicating the property and action of traditional Chinese medicine(TCM)in the perspectives of modern science deepens the insight into the property of TCM,and provides the basis for new drug discovery and clinical therapy.In this study,we investigated the relationship between transient receptor potential melastatin 8(TRPM8)and pungent flavor using three-dimensional pharmacophores based on virtual screening methods.Methods:Firstly,an inhouse database was established to identify the related pharmacological action according to the traditional Chinese herbs expressing an action of promoting blood circulation.Then,several therapeutic targets,3-hydroxy-3-methylglutaryl-coenzyme A reductase(HMG-CoAR),cholesteryl ester transfer protein(CETP),Niemann-Pick C1-Like 1(NPC1L1)and platelet-activating factor receptor(PAFR),were selected to screen traditional Chinese herbs,and the common virtual screening hits with various hit scores providing data to reveal the correlation among TRPM8 and therapeutic targets.Results:According to the screening results,TRPM8 agonists were able to identify the effective components of pungent herbs and TRPM8,which shares the common virtual screening hits with the therapeutic targets,was considered to be related to the action of pungent taste.Conclusion:The novel ideas and methods in this study are beneficial to unveil the scientific relationship between a TCM property and its action.

Network analysis of primary active compounds in Danqi analogous formulas for treating cardiovascular disease

Objective:Used extensively to treat cardiovascular disease,Danqi analogous formulas(DQAF)include prescriptions for Danqi(DQ),Fufang Danshen(FFDS)and Qishen Yiqi(QSYQ).Differences in prescription compatibility result in varying emphases of DQAF in clinical application.Methods and results:Based on network analysis in this study,common and distinct mechanisms of DQAF actions on cardiovascular disease were analyzed at a systemic level.Components etargetsepathways models were developed by Cytoscape(http://www.cytoscape.org/);whereby,target information for active compounds was obtained based on the PharmMapper database(http://59.78.96.61/pharmmapper/),which was further used to search pathways using the Kyoto Encyclopedia of Genes and Genomes database(http://www.genome.jp/kegg/).Based on target and network analyses,we discovered RBP4 is a potential common target of DQAF,while mitogen-activated protein kinase 1(MAPK1)and glutathione S-transferase P were potential targets of FFDS and QSYQ,respectively.Furthermore,the potential of DQAF to treat cardiovascular disease occurs through effects on the endocrine,immune,and digestive systems,in addition to lipid,sugar and amino acid metabolic pathways.Whereas FFDS exhibits effects on Toll-like receptor,transforming growth factor beta and MAPK signaling pathways;QSYQ exerts effects on cyclic adenosine monophosphate signaling,as well as metabolism of glutathione and arachidonic acid.

Identification of the material basis of the medicinal properties in Curcuma Longa L. to enhance targeted clinical application

Objective:To identify the relationship between the active compounds in turmeric(Curcuma Longa L.,C.Longa)and their medicinal properties,and clarify the chemical material basis of the medicinal properties in C.Longa.Methods:High throughput screening models of the thermo-transient receptor potentials(thermo-TRPs)and human taste type 2 receptors(hTAS2Rs)were established to evaluate the activity of the active compounds in C.Longa.The biological processes and distributions of the related targets of the active compounds were acquired by data mining.The above results were then used as basic data to comprehensively analyze the material basis of the medicinal properties of turmeric.Results:Curcumin inhibited TRPV1,TRPV2,TRPV3,and TRPA1,while demethoxycurcumin(DMC)inhibited TRPV3,TRPA1,and TRPM8.In terms of the 21 hTAS2Rs,the response values of hTAS2R38,hTAS2R16,and hTAS2R44 intervened by curcumin were ranked top three;the response values of hTAS2R3,hTAS2R1,and hTAS2R9 by DMC were in top three;the response values of hTAS2R47,hTAS2R39,and hTAS2R43 by bisdemethoxycurcumin(BDMC)were in top three.The biological processes related to active compounds primarily involved blood circulation,ossification,and regulation of the inflammatory response.Conclusion:Curcumin,DMC,and BDMC were identified as the material basis of the property of Chinese materia medica of C.Longa.Among these,curcumin and DMC may contribute to its warming effect in the four qi.Curcumin,DMC,and BDMC may lead to its bitter flavor,and the three active compounds were consistent with the meridian entry of C.Longa.Although different compounds play diverse roles in the four qi,five flavors,and meridian entry,they all were relevant to the efficacy of C.Longa.It is helpful to further understand the important role of the property of Chinese materia medica for the clinical application of traditional Chinese medicine.

Estimation of multivariate detection limits of four quality parameters in licorice using MEMS–NIR spectrometry coupled with two sampling accessories

In this work,multivariate detection limits(MDL)estimator was obtained based on the microelectro-mechanical systems–near infrared(MEMS–NIR)technology coupled with two sampling accessories to assess the detection capability of four quality parameters(glycyrrhizic acid,liquiritin,liquiritigenin and isoliquiritin)in licorice from di®erent geographical regions.112 licorice samples were divided into two parts(calibration set and prediction set)using Kennard–Stone(KS)method.Four quality parameters were measured using high-performance liquid chromatography(HPLC)method according to Chinese pharmacopoeia and previous studies.The MEMS–NIR spectra were acquired from¯ber optic probe(FOP)and integrating sphere,then the partial least squares(PLS)model was obtained using the optimum processing method.Chemometrics indicators have been utilized to assess the PLS model performance.Model assessment using chemometrics indicators is based on relative mean prediction error of all concentration levels,which indicated relatively low sensitivity for low-content analytes(below 1000 parts per million(ppm)).Therefore,MDL estimator was introduced with alpha error and beta error based on good prediction characteristic of low concentration levels.The result suggested that MEMS–NIR technology coupled with fiber optic probe(FOP)and integrating sphere was able to detect minor analytes.The result further demonstrated that integrating sphere mode(i.e.,MDL0:05;0:05,0.22%)was more robust than FOP mode(i.e.,MDL0:05;0:05,0.48%).In conclusion,this research proposed that MDL method was helpful to determine the detection capabilities of low-content analytes using MEMS–NIR technology and successful to compare two sampling accessories.

NIR assignment of isopsoralen by 2D-COS technology and model application in Yunkang Oral Liquid

Near infrared(NIR)assignment of Isopsoralen was performed using deuterated chloroform solvent and two-dimensional correlation spectroscopy(2D-COS)technology.Yunkang Oral Liquid was applied to study Isopsoralen,the characteristic bands by spectral assignment as well as the bands by interval partial least squares(iPLS)and synergy interval partial least squares(siPLS)were used to establish partial least squares(PLS)model.The coefficient of determination in calibration(R^(2)_(cal))were 0.9987,0.9970 and 0.9982.The coefficient of determination in cross validation(R^(2)_(val)) T were 0.9985,0.9921 and 0.9982.The coe±cient of determination in prediction(R^(2)_(pre)) T were 0.9987,0.9955 and 0.9988.The root mean square error of calibration(RMSEC)were 0.27,0.40 and 0.31 ppm.The root mean square error of cross validation(RMSECV)were 0.30,0.67 and 0.32 ppm.The root mean square error of prediction(RMSEP)were 0.23,0.43 and 0.22 ppm.The residual predictive deviation(RPD)were 31.00,16.58 and 32.41.It turned out that the characteristic bands by spectral assignment had the same results with the chemometrics methods in PLS model.It provided guidance for NIR spectral assignment of chemical compositions in Chinese Materia Medica(CMM).

Comparison of the clinical effect features of Han-Ku-Gan and Wen-Xin-Gan based on the efficacy of promoting blood circulation and removing blood stasis

Objective:The application of Chinese materia medica(CMM)in clinical diseases is the embodiment and continuation of the property theory of CMM(PTCMM).However,due to a lack of precise quantitative description methods,it is difficult to systematically analyze the property of CMM(PCMM)and clinical effect features at the micro molecular level.Methods:The therapeutic drugs and targets were obtained from the Drugbank database.The molecular descriptors of these drugs were calculated based on Dragon software.Drug-effect relationships that integrated the molecular descriptors and effect descriptors were plotted as grayscale images.These images were used to train the Le Net-5 model and the Alex Net model.The best-performing model was used to predict the effect features of the CMM compounds.Finally,the effect features of the PCMM combinations were calculated based on the support vector machine recursive feature elimination algorithm.Results:The Alex Net model showed a superior prediction performance.The results showed that its accuracy,precision,sensitivity,F-measure,and Matthews correlation coefficient on the training set were 0.940,0.936,0.945,0.940,and 0.880,respectively,and those of the test set were 0.909,0.901,0.920,0.910,and 0.819,respectively.A total of 399 compounds in the 42 CMMs for promoting blood circulation and removing blood stasis were predicted by this model.The key effect features of the Han-Ku-Gan combination were anti-inflammatory,anti-tumor,anti-atherosclerosis,anti-Parkinson,hypoglycemic,and anti-coagulant properties,as well as excitation of uterine smooth muscle.The key effect features of the Wen-Xin-Gan combination were anti-inflammatory,anti-atherosclerosis,anti-hypertensive,anticoagulant,anti-tumor,and anti-cardiac insufficiency effects,as well as enhanced immunity,sedation and hypnosis,and analgesia.Conclusion:This study provides a new method for the further exploration of the relationship between the PCMM and clinical effect features.

In silico method for studying property combination of traditional Chinese herbs

Objective:This paper discusses the composition of prescription qualitative,quantitative design principles and methods based on herbal property combination,describing the method application in new prescription design.Method:Qualitative property-combination pattern(PP)calculation was based on bipartite graphing and performing a greedy algorithm which was designed to optimize obtaining a new herbal prescription.Quantitative PP calculation was based on the qualitative computation.To calculate the Euclidean distance for the PP of the new prescription,an optimized algorithm for solving the unknown minimum Euclidean distance was used with,the new weighted proportions.Finally,non-linear optimization software was used to find the minimum Euclidean distance.Results:Using the PP of classic prescription Large Yin-Nourishing Pill,applying quantitative PP calculation a new prescription was created.Mathematical algorithms based on property combinations of traditional Chinese herbs can be applied to identify compatibility and synergies of herbs within prescriptions,especially classic formulas.Conclusion:In silico methods can then be used to create new prescriptions or modify existing ones depending on need.This type of automated approach may increase efficiency in designing new drugs based on Chinese herbs.

Property combination patterns of traditional Chinese medicines

Objective:In this study,the property combinations(PCs)of single herbs,two-herb combinations,and multi-herb prescriptions were studied to determine that the propertycombination patterns will be associated with these three levels.Method:By calculating the prescription PC weight,we analyzed the PCs of the single herb coptis rhizome,the two-herb combination of coptis rhizome and scutellaria root,and the classic prescriptions Coptis Decoction to Resolve Toxicity,White Tiger Decoction to Resolve Toxicity,and Peony Decoction,all three of which contain coptis and scutellaria.Results:Calculated results show that cold-bitter-lung,cold-bitter-heart,and cold-bitterstomach are present in both Coptis Decoction and White Tiger Decoction and have the highest PC weights.The weights of coptis and scutellaria in Peony Decoction differs from in their weights in Coptis Decoction and White Tiger Decoction,in that the PCs of highest weights in Peony Decoction are cold-bitter-spleen,cold-bitter-liver,cold-bitter-large intestine,coldsour-liver,and cold-sour-spleen.Conclusion:This novel method for exploring the properties and compatibilities of traditional Chinese herbs helps validate the combination theories of herbs.Application of this method may be valuable in designing new efficacious herbal prescriptions.

Pharmacophore Model Generation of Thrombin Inhibitors

Thrombin, an important factor of clotting system, take part in a variety of physiological actions, such as blood clotting, anticoagulation, thrombosis and fibrinolysis. Inhibiting thrombin is a pivotal and effective step for the prophylaxis of venous and arterial thrombosis, as well as prevent myocardial infarction for high-risk patients. In this study, a three dimensional pharmacophore model was generated for the molecules which are responsible for vasodilation activities targeting thrombin. Ten compounds with known thrombin-inhibiting activity values were selected as training set to generate the hypothesis using GALAHAD program in SYBYL 7.0 software. The best hypothesis comprises five pharmacophore features: four hydrophobes groups and one positively charged group. It has been further validated towards a test set including known activity compounds obtained from Binding Database, the values of effectively active hit A% and comprehensive evaluation index CAI are respectively 63.33% and 2.34, the pharmacophore was proven to be successful in discriminating active and inactive inhibitors. ?Furthermore, the pharmacophore model was used as a 3D query to screen TCMD (Version 2009) database and 6 hit compounds of higher predicted activity were the reported cardiovascular activities, which may be useful for further study.

Molecular dynamics simulation studies of transmembrane transport of chemical components in Chinese herbs and the function of platycodin D in a biological membrane

Objective:To study the transmembrane transport of chemical components of Chinese herbs and to explore the function of platycodin D (PD) on biomembranes.Methods:Interaction between PD and the dipalmitoylphosphatidylcholine (DPPC) bilayer was reproduced by molecular dynamics simulation with the Martini force field.A model validation and methodological study were first performed,and were based on simulation investigations of transmembrane transport for three herbal compounds with distinct hydrophilic properties.Results:PD increased the mobility of the DPPC bilayer since its aglycone strongly interacted with the hydrophobic layer,which broke the structure of the gate layer,and weakened the ordered performance of hydrophobic tails.Conclusion:The Martini force field was successfully applied to the study of the interaction between herbal compounds and a biological membrane.By combining the dynamics equilibrium morphology,the distribution of drugs inside and outside the biomembrane,and the interaction sites of drugs on the DPPC bilayer,factors influencing transmembrane transport of drugs were elucidated and the function of platycodin D in a biological membrane was reproduced.

Data-driven engineering framework with AI algorithm of Ginkgo Folium tablets manufacturing

Smart manufacturing still remains critical challenges for pharmaceutical manufacturing.Here,an original data-driven engineering framework was proposed to tackle the challenges.Firstly,from sporadic indicators to five kinds of systematic quality characteristics,nearly 2,000,000 real-world data points were successively characterized from Ginkgo Folium tablet manufacturing.Then,from simplex to the multivariate system,the digital process capability diagnosis strategy was proposed by multivariate C_(pk)integrated Bootstrap-t.The C_(pk)of Ginkgo Folium extracts,granules,and tablets were discovered,which was 0.59,0.42,and 0.78,respectively,indicating a relatively weak process capability,especially in granulating.Furthermore,the quality traceability was discovered from unit to end-to-end analysis,which decreased from 2.17 to 1.73.This further proved that attention should be paid to granulating to improve the quality characteristic.In conclusion,this paper provided a data-driven engineering strategy empowering industrial innovation to face the challenge of smart pharmaceutical manufacturing.

New sensor technologies in quality evaluation of Chinese materia medica:2010–2015

New sensor technologies play an important role in quality evaluation of Chinese materia medica(CMM) and include near-infrared spectroscopy,chemical imaging,electronic nose and electronic tongue.This review on quality evaluation of CMM and the application of the new sensors in this assessment is based on studies from 2010 to 2015,with prospects and opportunities for future research.

Scale-up of a high shear wet granulation process using a nucleation regime map approach

Scale-up of the high shear wet granulation （HSWG） process is considered a challenge because HSWG is complex and influenced by numerous factors, including equipment, formulation, and process variables. For a system of microcrystalline cellulose and water, HSWG experiments at three scales （1, 2, and 4 L working vessel） were conducted with a granulator. Scale-up was implemented on the basis of a nucleation regime map approach. To keep dimensionless spray flux and drop penetration time constant, water addition time at three processing scales were 300, 442, and 700 s, respectively. The other process parameters were kept unchanged. Granule size distributions were plotted and compared, and scanning electron microscopy was used to analyze granule surface morphology. Physical characterization was undertaken using a modified SeDeM method. At nearly all scales, granule yield was greater than 85% and all the cosine values were larger than 0.89. At the same experiment points, granules at all scales had similar surface morphology and similar physical characteristics. The results demonstrate that a rational scaling-up of the HSWG process is feasible using a regime map approach.