Strategy and challenge of innovative drug research and development from clinically effective ingredients of traditional Chinese medicine / 中国中药杂志

Novel drug discovery from the active ingredients of traditional Chinese medicine is the most distinctive feature and advantageous field of China, which has provided an unprecedented opportunity. However, there are still problems such as unclear functional substance basis, action targets and mechanism, which greatly hinder the clinical transformation of active ingredients in traditional Chinese medicine. Based on the analysis of the current status and progress of innovative drug research and development in China, this paper aimed to explore the prospect and difficulties of the development of natural active ingredients from traditional Chinese medicine, and to explore the efficient discovery of trace active ingredients in traditional Chinese medicine, and obtain drug candidates with novel chemical structure, unique target/mechanism and independent intellectual property rights, in order to provide a new strategy and a new model for the development of natural medicine with Chinese characteristics.

Efficacy of fenestrated atrial septal defect occulders on pulmonary hypertension dogs / 中华心血管病杂志

Objective: To explore the short-term efficacy of fenestrated atrial septal defect (ASD) occulders in the treatment of pulmonary arterial hypertension (PAH). Methods: Thirty-six healthy dogs were divided into the balloon atrial septostomy (BAS)+fenestrated ASD occulders group (n=12), BAS group (n=12) and non-septostomy group (n=12). PAH was induced by intra-atrial injection of dehydrogenized monocrotaline (1.5 mg/kg) in all dogs. Animals in the BAS+fenestrated ASD occulders group underwent atrial septal puncture and fenestrated ASD occulders implantation. Animals in the BAS group underwent balloon atrial septostomy. The non-septostomy group received no surgical intervention. The hemodynamic indexes and blood N-terminal pro-B-type natriuretic peptide (NT-proBNP) of dogs were measured before modeling, 2 months after modeling, 1, 3, and 6 months after surgery, respectively. Echocardiography was performed to observe the patency of the shunt and atrial septostomy of the dogs in the BAS+fenestrated ASD occulders group and BAS group at 1, 3, and 6 months after surgery. Three dogs were sacrificed in each group at 1, 3, and 6 months after surgery, respectively. Atrial septal tissue and fenestrated ASD occulders were removed to observe the patency and endothelialization of the device. Lung tissues were obtained for hematoxylin-eosin (HE) staining to observe the inflammatory cells infiltration and the thickening and narrowing of the pulmonary arterials. Results: Among 36 dogs, 2 dogs died within 24 hours after modeling, and 34 dogs were assigned to BAS+fenestrated ASD occulders group (n=12), BAS group (n=11), and non-septostomy group (n=11). Compared with BAS group, the average right atrial pressure (mRAP) and NT-proBNP of dogs in the BAS+fenestrated ASD occulders group were significantly reduced at 3 months after surgery (P<0.05), and the cardiac output (CO) was significantly increased at 6 months after surgery, arterial oxygen saturation (SaO2) was also significantly reduced (P<0.05). Compared with non-septostomy group, dogs in the BAS+fenestrated ASD occulders group had significantly lower mRAP and NT-proBNP at 1, 3, and 6 months after surgery (P<0.05), and higher CO and lower SaO2 at 6 months after surgery (P<0.05). Compared with the non-septostomy group, the dogs in the BAS group had significantly lower mRAP and NT-proBNP at 1 month after surgery (P<0.05), and there was no significant difference on mRAP and NT-proBNP at 3 and 6 months after surgery (P>0.05). Echocardiography showed that there was a minimal right-to-left shunt in the atrial septum in the BAS group at 1 month after the surgery, and the ostomy was closed in all the dogs in the BAS group at 3 months after the surgery. There was still a clear right-to-left shunt in the dogs of BAS+fenestrated ASD occulders group. The shunt was well formed and satisfactory endothelialization was observed at 1, 3 and 6 months after surgery. The results of HE staining showed that the pulmonary arterials were significantly thickened, stenosis and collapse occurred in the non-septostomy group. Pulmonary microvascular stenosis and inflammatory cell infiltration in the pulmonary arterials were observed in the non-septostomy group. Pulmonary arterial histological results were comparable between BAS+fenestrated ASD occulders group and non-septostomy group at 6 months after surgery . Conclusions: The fenestrated ASD occulder has the advantage of maintaining the open fistula hole for a longer time compared with simple balloon dilation. The fenestrated ASD occulder can improve cardiac function, and it is safe and feasible to treat PAH in this animal model.

Analysis of peptides and proteins from Asini Corii Colla using nano LC-Q-Exactive-MS/MS / 中国中药杂志

This paper aims to systematically analyze the peptides and proteins from Asini Corii Colla(ACC) through shotgun proteomics. After high-pH reversed-phase fractionation, the proteins and peptides in the hydrolysate of ACC were further separated by nano LC-Q-Exactive-MS/MS under the following conditions: Thermo Scientific EASY column(100 μm×2 cm, 5 μm, C_(18)) as precolumn, Thermo Scientific EASY column(75 μm×100 mm, 3 μm, C_(18)) for solid phase extraction, gradient elution with 0.1% formic acid in water(mobile phase A) and 84% acetonitrile in water containing 0.1% formic acid(mobile phase B), and MS in positive ion mode. Based on Uniprot_Equus caballus, MS data, and literature, 2 291 peptides were identified from ACC by MaxQuant, with 255 Maillard reactions(AML, CML, CEL)-modified peptides identified for the first time. Through alignment, the peptides were found to belong to 678 equine proteins. In conclusion, the combination of nano LC-Q-Exactive-MS/MS and shotgun proteomics achieved rapid and accurate identification of the proteins and peptides in ACC, which provides the key information and new insights for further investigation of chemicals and effective substances in ACC.

Effect of neuregulin-1 on cardiac glucose metabolism in rats with experimental myocardial infarction / 中华心血管病杂志

Objective: To investigate the effect of neuregulin-1(NRG-1) on cardiac glucose metabolism in Sprague Dawley (SD) rats with experimental myocardial infarction (MI). Methods: Adult male SD rats were randomly divided into three groups: the sham-operated group, MI group, and MI+NRG1 group. The rat MI model was established via ligation of the left anterior descending coronary artery. Two weeks after operation, echocardiography was performed, MI rats with left ventricular ejection fraction (LVEF) between 0.3-0.5 were selected and randomly assigned to MI group and MI+NRG-1 group. Rats in MI+NRG-1 group were treated with recombinant human NRG-1β (100 μg/kg) via tail vein at 2 weeks after operation (twice per week for 6 weeks); while rats in sham-operated group and MI group received equal volume of physiological saline. By the end of administration, echocardiography and small animal positron emission tomography (PET) were performed to detect cardiac function and myocardial glucose uptake. Myocardial morphology and collagen volume fraction, cardiomyocyte apoptosis and reactive oxygen species (ROS) production were evaluated by histopathologic analysis. Myocardial pyruvate dehydrogenase (PDH) and citrate synthase (CS) activity, as well as ATP production were detected by commercial kits. The mRNA and protein expression levels of NRG-1, p-ErbB4, and key factors involved in glucose metabolism (including Glut-4, HK2, PDK4, PDH, CS) were detected by quantitative real-time PCR (qRT-PCR) and Western blot assay, respectively. Results: With the MI model successfully established, the left ventricular ejection fraction(LVEF) and left ventricular shortening fraction(LVFS) were significantly lower in MI group and MI+NRG-1 group than that in sham group (both P<0.01), while there was no significant difference between MI group and MI+NRG-1 group(all P>0.05). After 6 weeks of NRG-1β intervention, the LVEF and LVFS were significantly higher in MI+NRG-1 group than in MI group (both P<0.01). By the end of experiment, PET imaging showed that the mean standardized uptake value (SUVmean) were lower in MI+NRG-1 group than in the sham group (4.06±0.28 vs. 5.18±0.37, P<0.01), while significantly higher than that in MI group (4.06±0.28 vs.2.86±0.49, P<0.01). Histopathological analysis showed that compared with MI group, rats in MI+NRG-1 group exhibited significantly decreased left ventricle collagen volume fraction ((7.83±1.24) % vs. (18.31±3.58) %, P<0.01), cardiomyocyte apoptosis((37.98±4.26)% vs. (67.04±5.38)%, P<0.01), and DHE fluorescence intensity(0.057 28±0.007 06 vs. 0.076 94±0.008 46, P<0.01), indicating that NRG-1β could reduce ROS production. PDH activity, CS activity, and ATP production were significantly higher in MI+NRG-1 group than in MI group (all P<0.05). qRT-PCR demonstrated an upregulated Glut-4, HK2 and CS, but downregulated PDK4 mRNA expression in MI+NRG-1 group compared with MI group (all P<0.01). Western blot assay showed significantly higher protein expression of NRG-1, p-ErbB4, Glut-4, HK2, PDH, CS in MI+NRG-1 group than in MI group (all P<0.01). Conclusion: NRG-1 could improve glucose uptake and utilization in myocardium by activating phosphorylation of myocardial ErbB4 receptor in MI rats, thus providing a therapeutic option for improving energy metabolism after MI.

Impact of transcatheter aortic valve replacement on renal function in patients with severe aortic stenosis / 中华心血管病杂志

Objective: To explore the impact of transcatheter aortic valve replacement (TAVR) on renal function in patients with severe aortic stenosis. Methods: This is a single-center retrospective study. Consecutive patients with severe aortic valve stenosis and received TAVR in Zhongshan Hospital from December 2014 to December 2019 were included. The patients were divided into four groups according to the estimate glomerular filtration rate (eGFR) measured at one day before TAVR, namely eGFR>90 ml·min-1·1.73m-2 group, 60<eGFR≤90 ml·min-1·1.73m-2 group, 30<eGFR≤60 ml·min-1·1.73m-2 group and eGFR≤30 ml·min-1·1.73m-2 group. The patients were also divided into acute renal function recovery (AKR) group, acute kidney injury (AKI) group and no change in renal function group according to renal function changes at 72 hours after TAVR. AKR was defined as eGFR increased by more than 25% of the baseline value at 72 hours after TAVR, and AKI was defined as eGFR decreased more than 25% of the baseline value at 72 hours after TAVR. The clinical data of each group were compared, and multivariate logistic regression analysis was performed to analyze the determinants responsible for renal function changes after TAVR. Results: A total of 217 patients were enrolled in this study. The age was (76.7±7.4) years and there were 86 females. The Society of Thoracic Surgeons score was (9.5±5.8). The proportions achieved AKR after TAVR were 0, 30.2% (35/116), 58.6% (41/70) and 75.0% (9/12) respectively in eGFR>90 ml·min-1·1.73m-2 group, 60<eGFR≤90 ml·min-1·1.73m-2 group, 30<eGFR≤60 ml·min-1·1.73m-2 group and eGFR≤30 ml·min-1·1.73m-2 group. A total of 3 patients (1.4%) suffered AKI, including 2 patients in 30<eGFR≤60 ml·min-1·1.73m-2 group and 1 patient in 60<eGFR≤90 ml·min-1·1.73m-2 group. The incidence of AKI in eGFR<60 ml·min-1·1.73m-2 group was 2.4% (2/82). Among the 217 patients, AKR occurred in 85(39.2%) patients, 3(1.4%) experienced AKI and renal function remained unchanged in 129 (59.4%) patients post TAVR. Body mass index (BMI), left ventricular end diastolic dimension (LVEDD) and preoperative eGFR were statistically different between the 3 groups (P<0.05). Multivariate logistic regression analysis showed that BMI (OR=5.54, 95%CI 1.04-29.58, P=0.045), preoperative LVEDD (OR=1.22, 95%CI 1.09-1.38, P=0.001) and preoperative eGFR (OR=2.23, 95%CI 2.04-2.55, P=0.004) were associated with non-AKR post TAVR. Conclusions: After TAVR, most patients show no change or improvement of renal function. BMI, preoperative LVEDD and eGFR are related to renal function change after TAVR.

Analytical methodologies for sensing catechol-O-methyltransferase activity and their applications / 药物分析学报

Mammalian catechol-O-methyltransferases(COMT)are an important class of conjugative enzymes,which play a key role in the metabolism and inactivation of catechol neurotransmitters,catechol es-trogens and a wide range of endobiotics and xenobiotics that bear the catechol group.Currently,COMT inhibitors are used in combination with levodopa for the treatment of Parkinson's disease in clinical practice.The crucial role of COMT in human health has raised great interest in the development of more practical assays for highly selective and sensitive detection of COMT activity in real samples,as well as for rapid screening and characterization of COMT inhibitors as drug candidates.This review summarizes recent advances in analytical methodologies for sensing COMT activity and their applications.Several lists of biochemical assays for measuring COMT activity,including the probe substrates,along with their analytical conditions and kinetic parameters,are presented.Finally,the challenges and future perspec-tives in the field,such as visualization of COMT activity in vivo and in situ,are highlighted.Collectively,this review article overviews the practical assays for measuring COMT activities in complex biological samples,which will strongly facilitate the investigations on the relevance of COMT to human diseases and promote the discovery of COMT inhibitors via high-throughput screening.

Ethnopharmacology, chemodiversity, and bioactivity of Cephalotaxus medicinal plants / 中国天然药物

Cephalotaxus is the only genus of Cephalotaxaceae family, and its natural resources are declining due to habitat fragmentation, excessive exploitation and destruction. In many areas of China, folk herbal doctors traditionally use Cephalotaxus plants to treat innominate swollen poison, many of which are cancer. Not only among Han people, but also among minority ethnic groups, Cephalotaxus is used to treat various diseases, e.g., cough, internal bleeding and cancer in Miao medicine, bruises, rheumatism and pain in Yao medicine, and ascariasis, hookworm disease, scrofula in She medicine, etc. Medicinal values of some Cephalotaxus species and compounds are acknowledged officially. However, there is a lack of comprehensive review summarizing the ethnomedicinal knowledge of Cephalotaxus, relevant medicinal phytometabolites and their bioactivities. The research progresses in ethnopharmacology, chemodiversity, and bioactivities of Cephalotaxus medicinal plants are reviewed and commented here. Knowledge gaps are pinpointed and future research directions are suggested. Classic medicinal books, folk medicine books, herbal manuals and ethnomedicinal publications were reviewed for the genus Cephalotaxus (Sanjianshan in Chinese). The relevant data about ethnobotany, phytochemistry, and pharmacology were collected as comprehensively as possible from online databases including Scopus, NCBI PubMed, Bing Scholar, and China National Knowledge Infrastructure (CNKI). "Cephalotaxus", and the respective species name were used as keywords in database search. The obtained articles of the past six decades were collated and analyzed. Four Cephalotaxus species are listed in the official medicinal book in China. They are used as ethnomedicines by many ethnic groups such as Miao, Yao, Dong, She and Han. Inspirations are obtained from traditional applications, and Cephalotaxus phytometabolites are developed into anticancer reagents. Cephalotaxine-type alkaloids, homoerythrina-type alkaloids and homoharringtonine (HHT) are abundant in Cephalotaxus, e.g., C. lanceolata, C. fortunei var. alpina, C. griffithii, and C. hainanensis, etc. New methods of alkaloid analysis and purification are continuously developed and applied. Diterpenoids, sesquiterpenoids, flavonoids, lignans, phenolics, and other components are also identified and isolated in various Cephalotaxus species. Alkaloids such as HHT, terpenoids and other compounds have anticancer activities against multiple types of human cancer. Cephalotaxus extracts and compounds showed anti-inflammatory and antioxidant activities, immunomodulatory activity, antimicrobial activity and nematotoxicity, antihyperglycemic effect, and bone effect, etc. Drug metabolism and pharmacokinetic studies of Cephalotaxus are increasing. We should continue to collect and sort out folk medicinal knowledge of Cephalotaxus and associated organisms, so as to obtain new enlightenment to translate traditional tips into great therapeutic drugs. Transcriptomics, genomics, metabolomics and proteomics studies can contribute massive information for bioactivity and phytochemistry of Cephalotaxus medicinal plants. We should continue to strengthen the application of state-of-the-art technologies in more Cephalotaxus species and for more useful compounds and pharmacological activities.

Comprehensive profiling and characterization of the absorbed components and metabolites in mice serum and tissues following oral administration of Qing-Fei-Pai-Du decoction by UHPLC-Q-Exactive-Orbitrap HRMS / 中国天然药物

Qing-Fei-Pai-Du decoction (QFPDD) is a Chinese medicine compound formula recommended for combating corona virus disease 2019 (COVID-19) by National Health Commission of the People's Republic of China. The latest clinical study showed that early treatment with QFPDD was associated with favorable outcomes for patient recovery, viral shedding, hospital stay, and course of the disease. However, the effective constituents of QFPDD remain unclear. In this study, an UHPLC-Q-Orbitrap HRMS based method was developed to identify the chemical constituents in QFPDD and the absorbed prototypes as well as the metabolites in mice serum and tissues following oral administration of QFPDD. A total of 405 chemicals, including 40 kinds of alkaloids, 162 kinds of flavonoids, 44 kinds of organic acids, 71 kinds of triterpene saponins and 88 kinds of other compounds in the water extract of QFPDD were tentatively identified via comparison with the retention times and MS/MS spectra of the standards or refereed by literature. With the help of the standards and in vitro metabolites, 195 chemical components (including 104 prototypes and 91 metabolites) were identified in mice serum after oral administration of QFPDD. In addition, 165, 177, 112, 120, 44, 53 constituents were identified in the lung, liver, heart, kidney, brain, and spleen of QFPDD-treated mice, respectively. These findings provided key information and guidance for further investigation on the pharmacologically active substances and clinical applications of QFPDD.

Transcriptional profiling and network pharmacology analysis identify the potential biomarkers from Chinese herbal formula Huosu Yangwei Formula treated gastric cancer in vivo / 中国天然药物

Huosu Yangwei (HSYW) Formula is a traditioanl Chinese herbal medicine that has been extensively used to treat chronic atrophic gastritis, precancerous lesions of gastric cancer and advanced gastric cancer. However, the effective compounds of HSYW and its related anti-tumor mechanisms are not completely understood. In the current study, 160 ingredients of HSYW were identified and 64 effective compounds were screened by the ADMET evaluation. Furthermore, 64 effective compounds and 2579 potential targets were mapped based on public databases. Animal experiments demonstrated that HSYW significantly inhibited tumor growth in vivo. Transcriptional profiles revealed that 81 mRNAs were differentially expressed in HSYW-treated N87-bearing Balb/c mice. Network pharmacology and PPI network showed that 12 core genes acted as potential markers to evaluate the curative effects of HSYW. Bioinformatics and qRT-PCR results suggested that HSYW might regulate the mRNA expression of DNAJB4, CALD, AKR1C1, CST1, CASP1, PREX1, SOCS3 and PRDM1 against tumor growth in N87-bearing Balb/c mice.

Construction and application of pharmacophore model of human carboxylesterase 2 inhibitors / 中国中药杂志

According to human carboxylesterase 2(hCE2) inhibitors reported in the literature, the pharmacophore model of hCE2 inhibitors was developed using HipHop module in Discovery Studio 2016. The optimized pharmacophore model, which was validated by test set, contained two hydrophobic, one hydrogen bond acceptor, and one aromatic ring features. Using the pharmacophore model established, 5 potential hCE2 inhibitors(CS-1,CS-2,CS-3,CS-6 and CS-8) were screened from 20 compounds isolated from the roots of Paeonia lactiflora, which were further confirmed in vitro, with the IC_(50) values of 5.04, 5.21, 5.95, 6.64 and 7.94 μmol·L~(-1), respectively. The results demonstrated that the pharmacophore model exerted excellent forecasting ability with high precision, which could be applied to screen novel hCE2 inhibitors from Chinese medicinal materials.

Investigation of modulating effect of Qingfei Paidu Decoction on host metabolism and gut microbiome in rats / 中国中药杂志

This study is to explore the effect of Qingfei Paidu Decoction(QPD) on the host metabolism and gut microbiome of rats with metabolomics and 16 S rDNA sequencing. Based on 16 S rDNA sequencing of gut microbiome and metabolomics(GC-MS and LC-MS/MS), we systematically studied the serum metabolites profile and gut microbiota composition of rats treated with QPD for continued 5 days by oral gavage. A total of 23 and 43 differential metabolites were identified based on QPD with GC-MS and LC-MS/MS, respectively. The involved metabolic pathways of these differential metabolites included glycerophospholipid metabolism, linoleic acid metabolism, TCA cycle and pyruvate metabolism. Meanwhile, we found that QPD significantly regulated the composition of gut microbiota in rats, such as enriched Romboutsia, Turicibacter, and Clostridium_sensu_stricto_1, and decreased norank_f_Lachnospiraceae. Our current study indicated that short-term intervention of QPD could significantly regulate the host metabolism and gut microbiota composition of rats dose-dependently, suggesting that the clinical efficacy of QPD may be related with the regulation on host metabolism and gut microbiome.

Research progress in application and mechanism of Schisandrae Chinensis Fructus for prevention and treatment of liver diseases / 中国中药杂志

Schisandra is the mature fruit of Schisandra chinensis(known as "north Schisandra") or S. shenanthera(known as "south Schisandra"). S. chinensis contains a variety of lignans, volatile oils, polysaccharides, organic acids and other chemical constituents; among them, lignans are recognized as the characteristic active components. Clinical studies have found that Schisandra and Schisandra-related products have a better effect in the prevention and treatment of viral hepatitis, drug-induced liver injury, liver cirrhosis, liver failure and other liver diseases. Modern pharmacological studies have demonstrated that Schisandra has a variety of pharmacological activities, such as anti-inflammation, antioxidation, anticancer, regulation of nuclear receptor, antivirus, regulation of cytochrome P450 enzyme, inhibition of liver cell apoptosis and promotion of liver regeneration. This paper reviews the studies about the applications and mechanism of Schisandra in the prevention and treatment of liver diseases, in the expectation of providing guidance for the development of hepatoprotective drugs from Schisandra and the clinical applications of Schisandra-related products.

Clinical Practice Guideline of Integrative Chinese and Western Medicine for Acute Myocardial Infarction / 中国结合医学杂志

With increasing morbidity and mortality, acute myocardial infarction (AMI) has become one of the major causes of human death, leading to heavy burdens to individuals, families and society. Previous researches have found that though large amount of resources and great effort were devoted, no significant improvements were achieved in reducing the in-hospital mortality of AMI patients. Meanwhile, extensive studies about Chinese medicine (CM) have found that CM has special advantages in treating AMI patients. However, there is no standardized and unified clinical practice guideline (CPG) of CM for AMI. Therefore, a CPG with strict standard and generally acknowledgement is urgent to be established. This guideline was developed following the methodological process established by the World Health Organization Handbook for Guideline Development. Extensive search on clinical evidences including systematic review (SR), randomized controlled trial (RCT), observational study and case reports was launched, covering evidence of CM for AMI on several aspects, such as diagnosis, CM patterns, CM interventions on AMI and complications, cardiac rehabilitation and clinical pathway management. Besides, the application of Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach enabled the evaluation of evidence and formulation of grade of recommendation (GOR) and level of evidence (LOE). With the help of GOR and LOE, this CPG recommends the integrative CM and WM treatment method in AMI patients and provides useful information on medical decision for clinical physicians.

Pancreatic lipase inhibitory constituents from Fructus Psoraleae / 中国天然药物

Pancreatic lipase (PL), a crucial enzyme in the digestive system of mammals, has been proven as a therapeutic target to prevent and treat obesity. The purpose of this study is to evaluate and characterize the PL inhibition activities of the major constituents from Fructus Psoraleae (FP), one of the most frequently used Chinese herbs with lipid-lowering activity. To this end, a total of eleven major constituents isolated from Fructus Psoraleae have been obtained and their inhibition potentials against PL have been assayed by a fluorescence-based assay. Among all tested compounds, isobavachalcone, bavachalcone and corylifol A displayed strong inhibition on PL (IC < 10 μmol·L). Inhibition kinetic analyses demonstrated that isobavachalcone, bavachalcone and corylifol A acted as mixed inhibitors against PL-mediated 4-methylumbelliferyl oleate (4-MUO) hydrolysis, with the K values of 1.61, 3.77 and 10.16 μmol·L, respectively. Furthermore, docking simulations indicated that two chalcones (isobavachalcone and bavachalcone) could interact with the key residues located in the catalytic cavity of PL via hydrogen binding and hydrophobic interactions. Collectively, these finding provided solid evidence to support that Fructus Psoraleae contained bioactive compounds with lipid-lowering effects via targeting PL, and also suggested that the chalcones in Fructus Psoraleae could be used as ideal leading compounds to develop novel PL inhibitors.

An ultra-sensitive and easy-to-use assay for sensing human UGT1A1 activities in biological systems / 药物分析学报

The human UDP-glucuronosyltransferase 1A1 (UGT1A1), one of the most essential conjugative enzymes, is responsible for the metabolism and detoxification of bilirubin and other endogenous substances, as well as many different xenobiotic compounds. Deciphering UGT1A1 relevance to human diseases and characterizing the effects of small molecules on the activities of UGT1A1 requires reliable tools for probing the function of this key enzyme in complex biological matrices. Herein, an easy-to-use assay for highly-selective and sensitive monitoring of UGT1A1 activities in various biological matrices, using liquid chromatography with fluorescence detection (LC-FD), has been developed and validated. The newly developed LC-FD based assay has been confirmed in terms of sensitivity, specificity, precision, quanti-tative linear range and stability. One of its main advantages is lowering the limits of detection and quantification by about 100-fold in comparison to the previous assay that used the same probe substrate, enabling reliable quantification of lower amounts of active enzyme than any other method. The precision test demonstrated that both intra- and inter-day variations for this assay were less than 5.5％. Further-more, the newly developed assay has also been successfully used to screen and characterize the regu-latory effects of small molecules on the expression level of UGT1A1 in living cells. Overall, an easy-to-use LC-FD based assay has been developed for ultra-sensitive UGT1A1 activities measurements in various biological systems, providing an inexpensive and practical approach for exploring the role of UGT1A1 in human diseases, interactions with xenobiotics, and characterization modulatory effects of small mole-cules on this conjugative enzyme.

Three new polyoxygenated bergamotanes from the endophytic fungus Penicillium purpurogenum IMM 003 and their inhibitory activity against pancreatic lipase / 中国天然药物

Purpurolides D-F (1-3), three new polyoxygenated bergamotanes bearing a 6/4/5/5 tetracyclic ring system, were isolated from the endophytic fungus Penicillium purpurogenum IMM 003. Their structures were unambiguously elucidated based on extensive spectroscopic data analyses, C NMR chemical shifts calculations coupled with the DP4+ probability method, and the calculated and experimental electronic circular dichroism (ECD) spectra. Compounds 1-3 showed significant inhibitory activity against pancreatic lipase (PL). The result highlights that the presence of 3-hydroxylated decanoic acid moiety at C-14 is important for increasing the inhibition potency against PL.

Recent advances on pancreatic lipase inhibitors from Chinese herbs / 药学学报

Obesity is an important cause of a panel of metabolic diseases, such as hypertension, hyperlipidemia, arteriosclerosis, type 2 diabetes and various cancers. Discovery of anti-obesity agents has always been a hot spot in the field of new drug research and development. Pancreatic lipase (PL, also named triacylglycerol acyl hydrolase), a key enzyme responsible for the hydrolysis of 50%-70% dietary fats in the gastrointestinal system, which has been recognized as a crucial target for the prevention and treatment of obesity. PL inhibitors can reduce the decomposition and absorption of dietary fat in the digestive organs by decreasing the hydrolytic activity of this key enzyme, which can alleviate the symptoms of metabolic diseases such as obesity and hyperlipidemia. Although a potent PL inhibitor (orlistat) has been marketed, it may trigger gastrointestinal side effects after long-term use. Therefore, it is necessary to develop more new PL inhibitors with strong inhibition potency and safety. In recent years, a large number of studies have found that some Chinese herbal extracts and their constituents can regulate lipid metabolism and treat obesity via inhibiting PL. In this paper, the research progress in the field pancreatic lipase inhibitors, as well as the extracts of Chinese herbs and their constituents with pancreatic lipase inhibitory effects were summarized. Meanwhile, the PL inhibition activities and inhibitory mechanisms of herbal constitutes were also summarized systematically. In addition, the authors also highlight the challenges in this field and the future research directions. All information and knowledge presented in this review will be very helpful for the medicinal chemists to find more potent PL inhibitors from herbs or to develop next generation anti-obesity drugs, as well as helpful for the prevention and treatment of obesity and other related metabolic diseases using herba medicines or related products.

An unexpected electrocardiogram sign of subacute left ventricular free wall rupture: Its early awareness may be lifesaving / 世界急诊医学杂志（英文）

@#BACKGROUND: Post-infarct left ventricular free wall rupture (LVFWR) is not always an immediately catastrophic complication. The rupture can be subacute, allowing time for diagnosis and intervention. Accordingly, early recognition of the entity may be lifesaving. METHODS: We present an electrocardiogram (ECG) change pattern in two cases, which was erroneously attributed to ischemia. Two women in their 80s were admitted to our institute after experiencing the sudden onset of chest pain. They were managed as anterior ST-segment elevation myocardial infarction without reperfusion treatment. Unfortunately, they experienced a recurrence of severe chest pain with cardiogenic shock during hospitalisation. The ECG recorded at that time showed a ST-segment re-elevation in infract-related leads. RESULTS: The two cases were regrettably received a misjudgement of reinfarction at first, and one of the patients even was administrated with tirofi ban. Afterwards the diagnosis of subacute LVFWR was made through antemortem echocardiography. CONCLUSION: New ST-segment elevation (STE) in infarct-associated leads, coupled with recurrence of chest pain and new-onset hypotension, may constitute the premonitory signs of a subacute LVFWR.

Efficacy and safety of Shexiang Baoxin pill (MUSKARDIA) in patients with stable coronary artery disease: a multicenter, double-blind, placebo-controlled phase IV randomized clinical trial / 中华医学杂志(英文版)

BACKGROUND@#The Shexiang Baoxin Pill (MUSKARDIA) has been used for treating coronary artery disease (CAD) and angina for more than 30 years in China. Nevertheless, methodologically sound trials on the use of MUSKARDIA in CAD patients are scarce. The aim of the study is to determine the effects of MUSKARDIA as an add-on to optimal medical therapy (OMT) in patients with stable CAD.@*METHODS@#A total of 2674 participants with stable CAD from 97 hospitals in China were randomized 1:1 to a MUSKARDIA or placebo group for 24 months. Both groups received OMT according to local tertiary hospital protocols. The primary outcome was the occurrence of a major adverse cardiovascular event (MACE), defined as a composite of cardiovascular death, non-fatal myocardial infarction (MI), or non-fatal stroke. Secondary outcomes included all-cause mortality, non-fatal MI, non-fatal stroke, hospitalization for unstable angina or heart failure, peripheral revascularization, angina stability and angina frequency.@*RESULTS@#In all, 99.7% of the patients were treated with aspirin and 93.0% with statin. After 2 years of treatment, the occurrence of MACEs was reduced by 26.9% in the MUSKARDIA group (MUSKARDIA: 1.9% vs. placebo: 2.6%; odds ratio = 0.80; 95% confidence interval: 0.45-1.07; P  = 0.2869). Angina frequency was significantly reduced in the MUSKARDIA group at 18 months (P = 0.0362). Other secondary endpoints were similar between the two groups. The rates of adverse events were also similar between the two groups (MUSKARDIA: 17.7% vs. placebo: 17.4%, P = 0.8785).@*CONCLUSIONS@#As an add-on to OMT, MUSKARDIA is safe and significantly reduces angina frequency in patients with stable CAD. Moreover, the use of MUSKARDIA is associated with a trend toward reduced MACEs in patients with stable CAD. The results suggest that MUSKARDIA can be used to manage patients with CAD.@*TRIAL REGISTRATION@#chictr.org.cn, No. ChiCTR-TRC-12003513.

Comparisons of aortic anatomy between aortic stenosis and aortic regurgitation / 中国介入心脏病学杂志

Objective To compare aortic root anatomical characteristics between severe aortic valve stenosis (AS) and aortic regurgitation (AR) patients, and to provide useful information for transcatheter aortic valve replacement (TAVR) device designs and procedural techniques for treatment of AR. Methods Consecutive patients admitted between April 2014 to May 2016 with severe AS or AR and planned to undergo transcatheter aortic valve replacement were included. There were a total of 57 AR and 113 AS patients. All patients underwent multi-detector computed tomographic imaging and echocardiography examinations. Results The mean aortic annulus diameter in AR patients was slightly but significantly larger than AS patients[ (26.4±3.7) mm vs. (25.2±2.9) mm, P=0.001]. The mean diameters of the ascending aorta[ (38.3±6.9) mm vs. (33.9±6.7) mm, P<0.001]and Valsalva sinus[ (38.9±6.9) mm vs. (32.7±4.5) mm, P<0.001] in AR patients were larger than in AS patients. The left coronary ostia height was of no significant difference between the 2 groups [ (12.5±3.7) mm vs. (13.4±3.2) mm, P=0.08] and the right coronary ostia height was higher in the AR group than in the AS group [ (17.5±5.0) mm vs. (15.3±3.3) mm, P=0.001]. Conclusions The anatomical aortic root data from patients with AS or AR in the present study may provide useful information for transcatheter aortic valve replacement device designs and procedural techniques for treatment of AR.