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Based on the critical plane approach, the Sun-Shang-Bao (SSB) model is analyzed and verified. It is discovered that SSB model cannot take the non-proportional cyclic hardening into account and gives non-conservative fatigue life predictions under the non-proportional loading. To solve this problem, a stress-correlated factor is introduced to describe the degree of the non-proportional cyclic hardening as well as the effect of the non-zero mean stress. The accuracy of the proposed method is systematically checked against the experimental data found in literature for 16 different materials under constant amplitude multiaxial loading paths. [ABSTRACT FROM AUTHOR]

Abstract Phosphoinositide-3-kinase-δ (PI3Kδ) is a key regulator in the process of IgE mediated mast cell degranulation, which directly induces allergic diseases, such as asthma. This study is aimed at discovery of natural PI3Kδ inhibitors from Chinese medicine and evaluating their anti-mast cell degranulation activity. A combined virtual screening based on 3D pharmacophore model and molecular docking was used to screen for bioactive ingredients directly targeting PI3Kδ. Then, an in vitro kinase inhibition assay was conducted to evaluate the PI3Kδ inhibitory activity of the virtual screening hits. Subsequently, a β-hexosaminidase release assay was performed to verify the anti-mast cell degranulation activity of the active compounds. Finally, ginkgoneolic acid was identified as a PI3Kδ inhibitor (IC 50 = 2.49 μM) and exhibited anti-mast cell degranulation activity in vitro (IC 50 = 2.40 μM). Docking studies showed that Glu826, Val827 and Val828 were key amino acid residues for PI3Kδ inhibitory activity. Ginkgoneolic acid may be a potential lead compound for developing effective and safe PI3Kδ-inhibiting drugs. Graphical abstract Image 1 Highlights • Ginkgoneolic acid derived from TCM was identified as a PI3Kδ inhibitor with IC 50 of 2.49μM. • Ginkgoneolic acid significantly inhibited degranulation of mast cellswith an IC 50 of 2.40μM. • The inhibition of ginkgoneolic acid on PI3Kδ was revealed by interacting with residues such as Glu826, Val827 and Val828. [ABSTRACT FROM AUTHOR]

Phosphodiesterase 10A (PDE10A) has been confirmed to be an important target for the treatment of central nervous system (CNS) disorders. The purpose of the present study was to identify PDE10A inhibitors from herbs used in traditional Chinese medicine. Pharmacophore and molecular docking techniques were used to virtually screen the chemical molecule database of Sophora flavescens, a well-known Chinese herb that has been used for improving mental health and regulating the CNS. The pharmacophore model generated recognized the common functional groups of known PDE10A inhibitors. In addition, molecular docking was used to calculate the binding affinity of ligand-PDE10A interactions and to investigate the possible binding pattern. Virtual screening based on the pharmacophore model and molecular docking was performed to identify potential PDE10A inhibitors from S. flavescens. The results demonstrated that nine hits from S. flavescens were potential PDE10A inhibitors, and their biological activity was further validated using literature mining. A total of two compounds were reported to inhibit cyclic adenosine monophosphate phosphodiesterase, and one protected against glutamate-induced oxidative stress in the CNS. The remaining six compounds require further bioactivity validation. The results of the present study demonstrated that this method was a time- and cost-saving strategy for the identification of bioactive compounds from traditional Chinese medicine. [ABSTRACT FROM AUTHOR]

The analytical methodologies for evaluation of multi-component system in traditional Chinese medicines (TCMs) have been inadequate or unacceptable. As a result, the unclarity of multi-component hinders the sufficient interpretation of their bioactivities. In this paper, an ultra-high-performance liquid chromatography coupled with linear ion trap–Orbitrap (UPLC–LTQ–Orbitrap)-based strategy focused on the comprehensive identification of TCM sequential constituents was developed. The strategy was characterized by molecular design, multiple ion monitoring (MIM), targeted database hits and mass spectral trees similarity filter (MTSF), and even more isomerism discrimination. It was successfully applied in the HRMS data-acquisition and processing of chlorogenic acids (CGAs) in Flos Lonicerae Japonicae (FLJ), and a total of 115 chromatographic peaks attributed to 18 categories were characterized, allowing a comprehensive revelation of CGAs in FLJ for the first time. This demonstrated that MIM based on molecular design could improve the efficiency to trigger MS/MS fragmentation reactions. Targeted database hits and MTSF searching greatly facilitated the processing of extremely large information data. Besides, the introduction of diagnostic product ions (DPIs) discrimination, C log P analysis, and molecular simulation, raised the efficiency and accuracy to characterize sequential constituents especially position and geometric isomers. In conclusion, the results expanded our understanding on CGAs in FLJ, and the strategy could be exemplary for future research on the comprehensive identification of sequential constituents in TCMs. Meanwhile, it may propose a novel idea for analyzing sequential constituents, and is promising for quality control and evaluation of TCMs. [ABSTRACT FROM AUTHOR]

Abstract: A highly sensitive and effective strategy for rapid screening and identification of target constituents has been developed using full scan-parent ions list-dynamic exclusion (FS-PIL-DE) acquisition coupled to diagnostic product ions (DPIs) analysis on a hybrid LTQ-Orbitrap mass spectrometer. The FS-PIL-DE was adopted as a survey scan to trigger the MS/MS acquisition of all the predictable constituents contained in traditional Chinese medicines. Additionally, DPIs analysis can provide a criterion to judge the target constituents detected into certain chemical families. Results from analyzing polymethoxylated flavonoids (PMFs) in the leaves of Citrus reticulata Blanco demonstrated that FS-PIL-DE was capable of targeting a greater number of constituents than FS, FS-PIL and FS-DE, thereby increasing the coverage of constituent screening. As a result, 135 PMFs including 81 polymethoxyflavones, 54 polymethoxyflavanones or polymethoxychalcones were identified preliminarily. And this was the first time to systematically report the presence of PMFs in the leaves of Citrus reticulata Blanco, especially for polymethoxylated flavanones and chalcones, most of which were new compounds. The results indicated that the developed FS-PIL-DE coupled to DPIs analysis methodology could be employed as a rapid, effective technique to screen and identify target constituents from TCMs extracts and other organic matter mixtures whose compounds contained can also be classified into families based on the common carbon skeletons. [Copyright &y& Elsevier]

Abstract: A method of modified diagnostic fragment-ion-based extension strategy (DFIBES) coupled to DFIs (diagnostic fragmentation ions) intensity analysis was successfully established to simultaneously screen and identify the chlorogenic acids (CGAs) in Flos Lonicerae Japonicae (FLJ) by HPLC-ESI-MSn. DFIs, such as m/z 191 [quinic acid-H]−, m/z 179 [caffeic acid-H]− and m/z 173 [quinic acid–H–H2O]− were determined or proposed from the fragmentation patterns analysis of corresponding reference substances for every chemical family of CGAs. A “structure extension” method was then proposed based on the well-demonstrated fragmentation patterns and was successively applied into the rapid screening of CGAs in FLJ. Considering that substitution isomerism is a common phenomenon, a full ESI-MSn fragmentation analysis according to the intensity of DFIs has been performed to identify the CGA isomers. Based on the DFIs and intensity analysis, 41 peaks attributed to CGAs including 4 caffeoylquinic acids (CQA), 7 CQA glycosides, 6 dicaffeoylquinic acids (DiCQA), 10 DiCQA glycosides, 1 tricaffeoylquinic acids (TriCQA), 4p-coumaroylquinic acids (pCoQA), 3 feruloylquinic acids (FQA) and 6 caffeoylferuloylquinic acids (CFQA) were identified preliminarily in a 65-min chromatographic run. It was the first time to systematically report the presence of CGAs in FLJ, especially for CQA glycosides, DiCQA glycosides, TriCQA, pCoQA and CFQA. All the results indicated that the method of developed DFIBES coupled to DFIs analysis was feasible, reliable and universal for screening and identifying the constituents with the same carbon skeletons especially the isomeric compounds from the complex extract of TCMs. [Copyright &y& Elsevier]

Abstract: Ethnopharmacological relevance: Interpreting the molecular interactions in Chinese herbal medicine will help to understand the molecular mechanisms of Traditional Chinese medicines (TCM) and predict the new pharmacological effects of TCM. Yet, we still lack a method which could integrate the concerned pieces of parsed knowledge about TCM. Materials and methods: To solve the problem, a new method named TCM grammar systems was proposed in the present article. The possibility to study the interactions of TCM at the molecular level using TCM grammar systems was explored using Herba Ephedrae Decoction (HED) as an example. Results: A platform was established based on the formalism of TCM grammar systems. The related molecular network of Herba Ephedrae Decoction (HED) can be extracted automatically. The molecular network indicates that Beta2 adrenergic receptor, Glucocorticoid receptor and Interleukin12 are the relatively important targets for the anti-anaphylaxis asthma function of HED. Moreover, the anti-anaphylaxis asthma function of HED is also related with suppressing inflammation process. The results show the feasibility using TCM grammar systems to interpret the molecular mechanism of TCM. Although the results obtained depend on the database absolutely, recombination of existing knowledge in this method provides new insight for interpreting the molecular mechanism of TCM. Conclusions: TCM grammar systems could aid the interpretation of the molecular interactions in TCM to some extent. Moreover, it might be useful to predict the new pharmacological effects of TCM. The method is an in silico technology. In association with the experimental techniques, this method will play an important role in the understanding of the molecular mechanisms of TCM. [Copyright &y& Elsevier]

Abstract: Based on the critical plane approach, the Shang–Wang fatigue damage parameter is analyzed. It is discovered that the effect of the additional cyclic hardening on fatigue life cannot be reflected by the normal strain excursion well. In order to solve this problem, this fatigue damage parameter is modified by using the Huber–Mises criterion. The modified damage parameter combined maximum shear strain range with normal strain range on the critical plane, and a new stress-correlated factor is introduced to account for the additional cyclic hardening. It is demonstrated that the modified criterion gives satisfactory results for all the six checked materials. [Copyright &y& Elsevier]

Abstract: Based on the critical plane approach, a new damage parameter for multiaxial fatigue damage is presented. Both components of strain and stress are considered in this parameter. Thus, a new multiaxial fatigue damage model is given based on the critical plane approach. The capability of fatigue life prediction for the proposed fatigue damage model is checked against the experimental data of Hot-rolled 45 Steel, S460N Steel, 1045HR Steel, 30CrMnSiNi2A alloy steel, and GH4169 alloy at elevated temperature, and the predicted results are compared with results from common multiaxial fatigue model. It is demonstrated that the proposed criterion gives better satisfactory results for all the five checked materials. [Copyright &y& Elsevier]

Abstract: In order to theoretically estimate the cyclic yield strength and fatigue limit, 27 alloy steel test data are taken as the basic data, the equation that relates the cyclic yield strength with two conventional mechanical performance parameters are established firstly. Then, the formula that expresses fatigue limit by the cyclic yield strength is presented. Theoretical results from the deduced expressions are compared with test data as well. By comparing the equations and data, the deduced expressions can be used to theoretically estimate the cyclic yield strength and fatigue limit for alloy steels in cases with a lack of data. [Copyright &y& Elsevier]

Abstract: Aconitine is an effective ingredient in Aconite tuber, an important traditional Chinese medicine. Aconitine is also known to be a highly toxic diterpenoid alkaloid with arrhythmogenic effects. In the present study, we have characterized the properties of arrhythmic cytotoxicity and explored the possible mechanisms of aconitine-induced cardiomyocytes. Results show that aconitine induces significant abnormity in the spontaneous beating rate, amplitude of spontaneous oscillations and the relative intracellular Ca2+ concentration. Also, mRNA transcription levels and protein expressions of SR Ca2+ release channel RyR2 and sarcolemmal NCX were elevated in aconitine-induced cardiomyocytes. However, co-treatment with ruthenium red (RR), a RyR channel inhibitor, could reverse the aconitine-induced abnormity in intracellular Ca2+ signals. These results demonstrate that disruption of intracellular Ca2+ homeostasis in the cardiac excitation–contraction coupling (EC coupling) is a crucial mechanism of arrhythmic cytotoxicity in aconitine-induced cardiomyocytes. Moreover, certain inhibitors appear to play an important role in the detoxification of aconitine-induced Ca2+-dependent arrhythmias. [Copyright &y& Elsevier]

Background: Cancer is the second most common cause of death globally. The anticancer effects of Tanshinone IIA (Tan IIA) has been confirmed by numerous researches. However, the underlying mechanism remained to be integrated in systematic format. Systems biology embraced the complexity of cancer; therefore, a system study approach was proposed in the present study to explore the anticancer mechanism of Tan IIA based on network pharmacology. Method: Agilent Literature Search (ALS), a text-mining tool, was used to pull protein targets of Tan IIA. Then, pharmacological clustering was applied to classify obtained hits, the anticancer module was analysed further. The top ten essential nodes in the anticancer module were obtained by ClusterONE. Functional units in the anticancer module were catalogued and validated by Gene Ontology (GO) analysis. Meanwhile, KEGG and Cell Signalling Technology Pathway were employed to provide pathway data for potential anticancer pathways construction. Finally, the pathways were plotted using Cytoscape 3.5.1. Furthermore, in vitro experiments with five carcinoma cell lines were conducted. Results: A total of 258 proteins regulated by Tan IIA were identified through ALS and were visualized by protein network. Pharmacological clustering further sorted 68 proteins that intimately involved in cancer pathogenesis based on Gene Ontology. Subsequently, pathways on anticancer effect of Tan IIA were delineated. Five functional units were clarified according to literature: including regulation on apoptosis, proliferation, sustained angiogenesis, autophagic cell death, and cell cycle. The GO analysis confirmed the classification was statistically significant. The inhibiting influence of Tan IIA on p70 S6K/mTOR pathway was revealed for the first time. The in vitro experiments displayed the selectivity of Tan IIA on HeLa, MDA-MB-231, HepG2, A549, and ACHN cell lines, the IC50 values were 0.54 μM, 4.63 μM, 1.42 μM, 17.30 μM and 204.00 μM, respectively. This result further reinforced the anticancer effect of Tan IIA treatment. Conclusions: The current study provides a systematic methodology for discovering the coordination of the anticancer pathways regulated by Tan IIA via protein network. And it also offers a valuable guidance for systematic study on the therapeutic values of other herbs and their active compounds. [ABSTRACT FROM AUTHOR]

In multivariate calibration using a spectral dataset, it is difficult to optimize nonsystematic parameters in a quantitative model, i.e., spectral pretreatment, latent factors and variable selection. In this study, we describe a novel and systematic approach that uses a processing trajectory to select three parameters including different spectral pretreatments, variable importance in the projection (VIP) for variable selection and latent factors in the Partial Least-Square (PLS) model. The root mean square errors of calibration (RMSEC), the root mean square errors of prediction (RMSEP), the ratio of standard error of prediction to standard deviation (RPD), and the determination coefficient of calibration (Rcal2) and validation (Rpre2) were simultaneously assessed to optimize the best modeling path. We used three different near-infrared (NIR) datasets, which illustrated that there was more than one modeling path to ensure good modeling. The PLS model optimizes modeling parameters step-by-step, but the robust model described here demonstrates better efficiency than other published papers. [ABSTRACT FROM AUTHOR]