Targeted bile acids metabolomics in cholesterol gallbladder polyps and gallstones: From analytical method development towards application to clinical samples

Bile acids(BAs)are synthesized by the liver from cholesterol through several complementary pathways and aberrant cholesterol metabolism plays pivotal roles in the pathogeneses of cholesterol gallbladder polyps(CGP)and cholesterol gallstones(CGS).To date,there is neither systematic study on BAs profile of CGP or CGS,nor the relationship between them.To explore the metabolomics profile of plasma BAs in healthy volunteers,CGP and CGS patients,an ultra-performance liquid chromatography-tandem mass spectrometry(UPLC-MS/MS)method was developed and validated for simultaneous determination of 42 free and conjugated BAs in human plasma.The developed method was sensitive and reproducible to be applied for the quantification of BAs in the investigation of plasma samples.The results show that,compared to healthy volunteers,CGP and CGS were both characterized by the significant decrease in plasma BAs pool size,furthermore CGP and CGS shared aberrant BAs metabolic characteristics.Chenodeoxycholic acid,glycochenodeoxycholic acid,l-muricholic acid,deoxycholic acid,and 7-ketolithocholic acid were shared potential markers of these two cholesterol gallbladder diseases.Subsequent analysis showed that clinical characteristics including cysteine,ornithine and body mass index might be closely related to metabolisms of certain BA modules.This work provides metabolomic information for the study of gallbladder diseases and analytical methodologies for clinical target analysis and efficacy evaluation related to BAs in medical institutions.

The Prospect of Application of Extractive Reference Substance of Chinese Herbal Medicines

The emerging development of Extractive Reference Substance (ERS) is a methodology that meets the needs for quality control for Chinese Herbal Medicines (CHM) and respects the holistic viewpoint of Traditional Chinese Medicine (TCM) and its clinical use of multiple ingredients with synergistic effects. The convention of using just a selected few Chemical Reference Substances (CRS) cannot adequately assess the quality of intact CHM. A validated chemical spectrum of an ERS provides the global characteristics in order to more specifically identify and assess targeted CHM. This paper describes the fundamental concepts, potential significance, and basic criteria of ERS, along with methods of preparation and calibration. Given the diversity of CHM, the various problems that will occur in establishing the proper process of ERS will need to be solved in a step by step manner. The ERSs of Ziziphi spinosae semen and ERS of Fritillaria thunbergii bulbus are given as examples of the development of ERS and demonstrate why we are optimistic about the utility of this approach.

Using satellite altimetry leveling to assess the marine geoid

Based on the concept of Global Position System(GPS)/leveling,the satellite altimetry leveling(SAL) is first proposed to evaluate the marine geoid.SAL is derived by the difference among the mean sea surface(MSS),mean dynamic ocean topography(MDT),and leveling origin.In this study,(1) the original satellite altimetry data are processed to infer the vertical deflection and gravity anomaly,(2) the Chinese coastal marine geoids(CMG) are determined by using the differe nt methods(including Molodensky,least square collocation,Stokes formula,and two-dimensional fast Fourier transformation(FFT) with the vertical deflection and gravity anomaly data),(3) CMG are evaluated by using the results from above different methods,the Gravity field and steady-state Ocean Circulation Explorer(GOCE) gravity potential model(GGPM),and SAL.The results show that(1) CMG from the Molodensky method has the highest precision by using vertical de flection data,(2) the accuracy of CMG indicate good consistency between the SAL and GGPM,(3) SAL can be used as a new method for assessing marine geoid.

Hand Gestures Recognition Based on One-Channel Surface EMG Signal

This paper presents an experiment using OPENBCI to collect data of two hand gestures and decoding the signal to distinguish gestures. The signal was extracted with three electrodes on the subiect’s forearm and transferred in one channel. After utilizing a Butterworth bandpass filter, we chose a novel way to detect gesture action segment. Instead of using moving average algorithm, which is based on the calculation of energy, We developed an algorithm based on the Hilbert transform to find a dynamic threshold and identified the action segment. Four features have been extracted from each activity section, generating feature vectors for classification. During the process of classification, we made a comparison between K-nearest-neighbors (KNN) and support vector machine (SVM), based on a relatively small amount of samples. Most common experiments are based on a large quantity of data to pursue a highly fitted model. But there are certain circumstances where we cannot obtain enough training data, so it makes the exploration of best method to do classification under small sample data imperative. Though KNN is known for its simplicity and practicability, it is a relatively time-consuming method. On the other hand, SVM has a better performance in terms of time requirement and recognition accuracy, due to its application of different Risk Minimization Principle. Experimental results show an average recognition rate for the SVM algorithm that is 1.25% higher than for KNN while SVM is 2.031 s shorter than that KNN.

High performance thin layer chromatography as an effective tool for rapid screening of 5α-reductase inhibitors

Benign prostatic hyperplasia(BPH)is a common disease in men,and is known to be related to 5α-reductase,which can affect steroid metabolism.Under the promotion of 5α-reductase,testosterone can be converted into dihydrotestosterone(DHT),and excessive DHT will cause related diseases.Since BPH seriously affects the quality of life of patients,it is essential to discover effective 5α-reductase inhibitors.In this study,the simple analytical method of high performance thin layer chromatography(HPTLC)was used to screen active compounds,and seven compounds with strong activity were screened out.This research will provide a reference for studying the material basis of drugs for the treatment of BPH.

Isotoosendanin exerts inhibition on triple-negative breast cancer through abrogating TGF-β-induced epithelial—mesenchymal transition via directly targeting TGFβR1

As the most aggressive breast cancer,triple-negative breast cancer(TNBC) is still incurable and very prone to metastasis.The transform growth factor β(TGF-β)-induced epithelial—mesenchymal transition(EMT) is crucially involved in the growth and metastasis of TNBC.This study reported that a natural compound isotoosendanin(ITSN) reduced TNBC metastasis by inhibiting TGF-β-induced EMT and the formation of invadopodia.ITSN can directly interact with TGF-β receptor type-1(TGFβR1) and abrogated the kinase activity of TGFβR1,thereby blocking the TGF-β-initiated downstream signaling pathway.Moreover,the ITSN-provided inhibition on metastasis obviously disappeared in TGFβR1-overexpressed TNBC cells in vitro as well as in mice bearing TNBC cells overexpressed TGFβR1.Furthermore,Lys232 and Asp351 residues in the kinase domain of TGFβR1 were found to be crucial for the interaction of ITSN with TGFβR1.Additionally,ITSN also improved the inhibitory efficacy of programmed cell death 1 ligand 1(PD-L1) antibody for TNBC in vivo via inhibiting the TGF-β-mediated EMT in the tumor microenvironment.Our findings not only highlight the key role of TGFβR1 in TNBC metastasis,but also provide a leading compound targeting TGFβR1 for the treatment of TNBC metastasis.Moreover,this study also points out a potential strategy for TNBC treatment by using the combined application of anti-PD-L1 with a TGFβR1 inhibitor.

Bile acid nuclear receptor FXR and digestive system diseases

Bile acids(BAs) are not only digestive surfactants but also important cell signaling molecules,which stimulate several signaling pathways to regulate some important biological processes. The bileacid-activated nuclear receptor, farnesoid X receptor(FXR), plays a pivotal role in regulating bile acid,lipid and glucose homeostasis as well as in regulating the inflammatory responses, barrier function and prevention of bacterial translocation in the intestinal tract. As expected, FXR is involved in the pathophysiology of a wide range of diseases of gastrointestinal tract, including inflammatory bowel disease, colorectal cancer and type 2 diabetes. In this review, we discuss current knowledge of the roles of FXR in physiology of the digestive system and the related diseases. Better understanding of the roles ofFXR in digestive system will accelerate the development of FXR ligands/modulators for the treatment of digestive system diseases.

Notoginsenoside Ft1 acts as a TGR5 agonist but FXR antagonist to alleviate high fat diet-induced obesity and insulin resistance in mice

Obesity and its associated complications are highly related to a current public health crisis around the world.A growing body of evidence has indicated that G-protein coupled bile acid(BA) receptor TGR5(also known as Gpbar-1) is a potential drug target to treat obesity and associated metabolic disorders.We have identified notoginsenoside Ftl(Ftl) from Panax notoginseng as an agonist of TGR5 in vitro.However,the pharmacological effects of Ftl on diet-induced obese(DIO) mice and the underlying mechanisms are still elusive.Here we show that Ftl(100 mg/100 diet) increased adipose lipolysis,promoted fat browning in inguinal adipose tissue and induced glucagon-like peptide-1(GLP-1) secretion in the ileum of wild type but not Tgr5^(-/-) obese mice.In addition,Ftl elevated serum free and taurineconjugated bile acids(BAs) by antagonizing Fxr transcriptional activities in the ileum to activate Tgr5 in the adipose tissues.The metabolic benefits of Ftl were abolished in Cyp27 al^(-/-) mice which have much lower BA levels.These results identify Ftl as a single compound with opposite activities on two key BA receptors to alleviate high fat diet-induced obesity and insulin resistance in mice.

Ginsenosides in Panax genus and their biosynthesis

Ginsenosides are a series of glycosylated triterpenoids which belong to protopanaxadiol(PPD)-,protopanaxatriol(PPT)-,ocotillol(OCT)-and oleanane(OA)-type saponins known as active compounds of Panax genus.They are accumulated in plant roots,stems,leaves,and flowers.The content and composition of ginsenosides are varied in different ginseng species,and in different parts of a certain plant.In this review,we summarized the representative saponins structures,their distributions and the contents in nearly 20 Panax species,and updated the biosynthetic pathways of ginsenosides focusing on enzymes responsible for structural diversified ginsenoside biosynthesis.We also emphasized the transcription factors in ginsenoside biosynthesis and non-coding RNAs in the growth of Panax genus plants,and highlighted the current three major biotechnological applications for ginsenosides production.This review covered advances in the past four decades,providing more clues for chemical discrimination and assessment on certain ginseng plants,new perspectives for rational evaluation and utilization of ginseng resource,and potential strategies for production of specific ginsenosides.

Astragaloside Ⅳ suppresses post-ischemic natural killer cell infiltration and activation in the brain:involvement of histone deacetylase inhibition

Natural killer(NK)cells,a type of cytotoxic lymphocytes,can infiltrate into ischemic brain and exacerbate neuronal cell death.Astragaloside Ⅳ(ASIV)is the major bioactive ingredient of Astragalus membranaceus,a Chinese herbal medicine,and possesses potent immunomodulatory and neuroprotective properties.This study investigated the effects of ASIV on post-ischemic brain infiltration and activation of NK cells.ASIV reduced brain infarction and alleviated functional deficits in MCAO rats,and these beneficial effects persisted for at least 7 days.Abundant NK cells infiltrated into the ischemic hemisphere on day 1 after brain ischemia,and this infiltration was suppressed by ASIV.Strikingly,ASIV reversed NK cell deficiency in the spleen and blood after brain ischemia.ASIV inhibited astrocyte-derived CCL2 upregulation and reduced CCR2+NK cell levels in the ischemic brain.Meanwhile,ASIV attenuated NK cell activating receptor NKG2D levels and reduced interferon-γproduction.ASIV restored acetylation of histone H3 and the p65 subunit of nuclear factor-κB in the ischemic brain,suggesting inhibition of histone deacetylase(HDAC).Simultaneously,ASIV prevented p65 nuclear translocation.The effects of ASIV on reducing CCL2 production,restoring acetylated p65 levels and preventing p65 nuclear translocation were mimicked by valproate,an HDAC inhibitor,in astrocytes subjected to oxygen-glucose deprivation.Our findings suggest that ASIV inhibits post-ischemic NK cell brain infiltration and activation and reverses NK cell deficiency in the periphery,which together contribute to the beneficial effects of ASIV against brain ischemia.Furthermore,ASIV’s effects on suppressing NK cell brain infiltration and activation may involve HDAC inhibition.

Pyrrolizidine alkaloids:An update on their metabolism and hepatotoxicity mechanism

Pyrrolizidine alkaloids(PAs)are among the most hepatotoxic natural compounds that are widely distributed throughout the world.Most PAs are metabolically activated to trigger toxicity.Exposure to herbal medicine containing PAs and food supplements contaminated by PAs is considered to be one of the two main causes of hepatic sinusoidal obstruction syndrome(HSOS),which is a rare hepatic vascular disease with a high mortality rate.PAs-induced HSOS cases have been reported worldwide.However,there is no clinically effective therapy for PAs-induced HSOS,which is partially because the toxic mechanism is not fully understood.This review focuses on updating the information on the metabolism and the molecular mechanisms of PAs hepatotoxicity,including oxidative stress,apoptosis,and dysfunction of bile acid metabolism,and their interactions.

Dust distribution of solid and adhesive mixed dust in a granular bed filter

Granular bed filters can effectively filter adhesive dust in high-temperature flue gas.In this study.polyvinyl chloride(PVC)powder was used as adhesive dust,and the mixture of PVC and ash powder was used to simulate solid and adhesive mixed dust.The effects of gas temperature,velocity,and inlet adhesive dust mass content on dust distribution in granular bed(GBF)were discussed.Results show that the mixed dust mainly accumulates on the upper part of the granular bed,and the mass of the collected dust decreases exponentially from the upper layer to the bottom layer in the GBF.The adhesive dust content collected in each layer differs from that of the incoming dust,and their deviation varies approximately linearly along with the depth of the bed.The total dust distribution and adhesive dust content deviation are influenced by gas temperature and inlet adhesive dust content but independent of gas velocity.The correlations of dust distribution of solid and adhesive mixed dust are presented based on the experimental results.