Characterization and identification of chemical components in traditional Chinese medicine Psoraleae Fructus based on UHPLC-Q-TOF-MS / 中国中药杂志

This study was designed to comprehensively characterize and identify the chemical components in traditional Chinese medicine Psoraleae Fructus by establishing an ultra-high performance liquid chromatography/quadrupole time-of-flight mass spectrometry(UHPLC-Q-TOF-MS) method in combination with in-house library. The chromatographic separation conditions(stationary phase, column temperature, mobile phase, and elution gradient) and key MS monitoring parameters(capillary voltage, nozzle voltage, and fragmentor) were sequentially optimized via single-factor experiments. A BEH C_(18) column(2.1 mm×100 mm, 1.7 μm) was finally adopted, with the mobile phase consisting of 0.1% formic acid in water(A) and acetonitrile(B) at the flow rate of 0.4 mL·min~(-1) and column temperature of 30 ℃. Auto MS/MS was utilized for data acquisition in both positive and negative ion modes. By comparison with reference compounds, analysis of the MS~2 fragments, in-house library retrieval and literature research, 83 compounds were identified or tentatively characterized from Psoraleae Fructus, including 58 flavonoids, 11 coumarins, 4 terpenoid phenols, and 10 others. Sixteen of them were identified by comparison with reference compounds, and ten compounds may have not been reported from Psoraleae Fructus. This study achieved a rapid qualitative analysis on the chemical components in Psoraleae Fructus, which provided useful reference for elucidating its material basis and promoting the quality control.

Three-dimensional multi-component analysis of Aurantii Fructus quality and research on influencing factors / 中国中药杂志

The present study explored the consistency of the content proportions of active components of Aurantii Fructus and analyzed the influencing factors based on three-dimensional multi-component analysis. A total of 839 Aurantii Fructus samples in 65 research articles were analyzed using the three-dimensional multi-component analysis mode. The content data of flavonoid components(naringin, hesperidin, neohesperidin, narirutin, and nobiletin), coumarin components(meranzin and gluconolactone), and alkaloid(synephrine) in 386 samples which met the criteria of 2020 edition of the Chinese Pharmacopoeia were extracted and adjusted to percentages, and the content ratios between components were calculated. The influencing factors of Aurantii Fructus quality were analyzed. The results showed content ratios of components as follows: neohesperidin∶naringin in the range of 0.4-1.2; narirutin∶naringin in the range of 0.02-0.16; hesperidin∶naringin in the range of 0.01-0.3; nobiletin∶naringin in the range of 0.000 588 3-0.069 68; synephrine∶naringin in the range of 0.02-0.042; gluconolactone∶naringin in the range of 0.001-0.01; meranzin∶naringin in the range of 0.000 4-0.035. The quality of Aurantii Fructus was closely related to the origin, variety, harvesting time, and processing method of medicinal materials. Harvesting time had a greater impact on the quality of Aurantii Fructus, and the origin and variety had a certain impact on the quality of Aurantii Fructus. The findings of this study indicated that the ratios between flavonoid components, flavonoids and coumarin components, and flavonoids and alkaloids fluctuated. The production base should optimize the varieties, harvesting period, and processing methods of Aurantii Fructus to provide a scientific basis for the production of high-quality Aurantii Fructus.

Expression of β-glucosidase An-bgl3 from Aspergillus niger for conversion of scopolin / 生物工程学报

Scopoletin is a coumarin compound with various biological activities including detumescence and analgesic, insecticidal, antibacterial and acaricidal effects. However, interference with scopolin and other components often leads to difficulties in purification of scopoletin with low extraction rates from plant resource. In this paper, heterologous expression of the gene encoding β-glucosidase An-bgl3 derived from Aspergillus niger were carried out. The expression product was purified and characterized with further structure-activity relationship between it and β-glucosidase analyzed. Subsequently, its ability for transforming scopolin from plant extract was studied. The results showed that the specific activity of the purified β-glucosidase An-bgl3 was 15.22 IU/mg, the apparent molecular weight was about 120 kDa. The optimum reaction temperature and pH were 55 ℃ and 4.0, respectively. Moreover, 10 mmol/L metal ions Fe2+ and Mn2+ increased the enzyme activity by 1.74-fold and 1.20-fold, respectively. A 10 mmol/L solution containing Tween-20, Tween-80 and Triton X-100 all inhibited the enzyme activity by 30%. The enzyme showed affinity towards scopolin and tolerated 10% methanol and 10% ethanol solution, respectively. The enzyme specifically hydrolyzed scopolin into scopoletin from the extract of Erycibe obtusifolia Benth with a 47.8% increase of scopoletin. This demonstrated that the β-glucosidase An-bgl3 from A. niger shows specificity on scopolin with good activities, thus providing an alternative method for increasing the extraction efficiency of scopoletin from plant material.

Three new coumarins and a new coumarin glycoside from Micromelum integerrimum / 中国天然药物

Three new coumarins, integmarins A-C (1-3), and a new coumarin glycoside, integmaside A (4) were isolated from the leaves and stems of Micromelum integerrimum. Their structures were elucidated on the basis of 1D and 2D NMR and MS data, and their absolute configurations were assigned according to the ECD data of the in situ formed transition metal complexes and comparison of experimental and calculated ECD data. Compounds 1 and 2 are two rare coumarins with butyl and propyl moieties at the C-6 position; compound 3 is a novel coumarin with a highly oxidized prenyl group, and compound 4 is a rare bisdihydrofuranocoumarin glycoside.

Study on metabolic dynamics,metabolic enzyme phenotype and species difference of hepatic and intestinal microsome of psoralidin / 中国中药杂志

This study aims to investigate metabolic activities of psoralidin in human liver microsomes( HLM) and intestinal microsomes( HIM),and to identify cytochrome P450 enzymes( CYPs) and UDP-glucuronosyl transferases( UGTs) involved in psoralidin metabolism as well as species differences in the in vitro metabolism of psoralen. First,after incubation serial of psoralidin solutions with nicotinamide adenine dinucleotide phosphate( NADPH) or uridine 5'-diphosphate-glucuronic acid( UDPGA)-supplemented HLM or HIM,two oxidic products( M1 and M2) and two conjugated glucuronides( G1 and G2) were produced in HLM-mediated incubation system,while only M1 and G1 were detected in HIM-supplemented system. The CLintfor M1 in HLM and HIM were 104. 3,and57. 6 μL·min~(-1)·mg~(-1),respectively,while those for G1 were 543. 3,and 75. 9 μL·min~(-1)·mg~(-1),respectively. Furthermore,reaction phenotyping was performed to identify the main contributors to psoralidin metabolism after incubation of psoralidin with NADPH-supplemented twelve CYP isozymes( or UDPGA-supplemented twelve UGT enzymes),respectively. The results showed that CYP1 A1( 39. 5 μL·min~(-1)·mg~(-1)),CYP2 C8( 88. 0 μL·min~(-1)·mg~(-1)),CYP2 C19( 166. 7 μL·min~(-1)·mg~(-1)),and CYP2 D6( 9. 1 μL·min~(-1)·mg~(-1)) were identified as the main CYP isoforms for M1,whereas CYP2 C19( 42. 0 μL·min~(-1)·mg~(-1)) participated more in producing M2. In addition,UGT1 A1( 1 184. 4 μL·min~(-1)·mg~(-1)),UGT1 A7( 922. 8 μL·min~(-1)·mg~(-1)),UGT1 A8( 133. 0 μL·min~(-1)·mg~(-1)),UGT1 A9( 348. 6 μL·min~(-1)·mg~(-1)) and UGT2 B7( 118. 7 μL·min~(-1)·mg~(-1)) played important roles in the generation of G1,while UGT1 A9( 111. 3 μL·min~(-1)·mg~(-1)) was regarded as the key UGT isozyme for G2. Moreover,different concentrations of psoralidin were incubated with monkey liver microsomes( MkLM),rat liver microsomes( RLM),mice liver microsomes( MLM),dog liver microsomes( DLM) and mini-pig liver microsomes( MpLM),respectively. The obtained CLintwere used to evaluate the species differences.Phase Ⅰ metabolism and glucuronidation of psoralidinby liver microsomes showed significant species differences. In general,psoralidin underwent efficient hepatic and intestinal metabolisms. CYP1 A1,CYP2 C8,CYP2 C19,CYP2 D6 and UGT1 A1,UGT1 A7,UGT1 A8,UGT1 A9,UGT2 B7 were identified as the main contributors responsible for phase Ⅰ metabolism and glucuronidation,respectively. Rat and mini-pig were considered as the appropriate model animals to investigate phase Ⅰ metabolism and glucuronidation,respectively.

Effects of Osthole on Apoptosis and Autophagy of Human Tongue Cancer Tca8113 Cells / 中国医学科学院学报

Objective To investigate the effects of osthole on the proliferation,apoptosis,and autophagy of human tongue cancer Tca8113 cells and explore its possible mechanism of action. Methods Tca8113 cells were cultured

Phenylpropanoids from Zanthoxylum species and their pharmacological activities: a review / 中国中药杂志

Phenylpropanoids are one of the major chemical constituents in Zanthoxylum species. They include simple phenylpropanoids, coumarins, and lignans and possess anti-tumor, anti-inflammatory, anti-platelet aggregation, anti-bacterial, anti-viral, insecticidal, and antifeedant activities. This review summarizes the chemical constituents and pharmacological activities from the Zanthoxylum plants in hopes of providing reference for the research and application of phenylpropanoids from this genus.

One new coumarin from seeds of Herpetospermum pedunculosum / 中国中药杂志

This paper aims to investigate the chemical constituents of the seeds of Herpetospermum pedunculosum. One new coumarin and two known lignans were isolated from the ethanolic extract of the seeds of H. pedunculosum with thin layer chromatography(TLC), silica gel column chromatography, Sephedax LH-20 chromatography, Semi-preparative high performance liquid chromatography and recrystallization, etc. Their structures were elucidated as herpetolide H(1), phyllanglaucin B(2), and buddlenol E(3) by analysis of their physicochemical properties and spectral data. Among them, compound 1 was a new compound, and compounds 2 and 3 were isolated from this genus for the first time. In vitro anti-inflammatory activity test showed that herpetolide H had certain NO inhibitory activity for LPS-induced RAW 264.7 cells, with its IC_(50) value of(46.57±3.28) μmol·L~(-1).

Studies on absorption and transportation of coumarins in Angelica dahurica 'Yubaizhi' across human intestinal epithelial by using human Caco-2 cell monolayers / 中国中药杂志

The absorption is the key to the resulted efficacy of orally administered drugs and the small intestine is the main site to absorb the orally administered drug. In this paper, internationally recognized human colon adenocarcinoma cell line(Caco-2) monola-yer model which can simulate small intestinal epithelial cell was used to comparatively study the absorption and transportation diffe-rences of total coumarins and main individual coumarin in Angelica dahurica 'Yubaizhi' by separately using 6-and 12-well plates. It was found that apparent permeability coefficient(P_(app)) values of oxypeucedanin hydrate, byakangelicin and phellopterin were at the quantitative degree of 1 × 10~(-5) cm·s~(-1) when the individual administration was conducted independently, indicating that they were well-absorbed compounds. P_(app) ratio of their bi-directional transportation was close to 1, indicating that they can be absorbed across Caco-2 monolayer by passive diffusion mechanism without carrier mediation during the transportation. The similar trend of transportation was also observed for imperatorin, isoimperatorin and bergapten. The P_(app) values of oxypeucedanin hydrate, byakangelicin and bergapten were at quantitative degree of 1 × 10~(-5) cm·s~(-1) when the administration of total coumarins in Angelica dahurica 'Yubaizhi' was conducted, indicating that they were well-absorbed compounds. The results were consistent with those of independent administration of individual coumarins. Whereas, the P_(app) values of imperatorin, phellopterin and isoimperatorin in the total coumarins decreased, indicating that the interaction between compounds may exist although the P_(app) value ratio of bi-directional transportation was between 0.5 and 1.5. The results laid the foundation for intestinal absorption study of Angelica dahurica 'Yubaizhi' coumarins in compound Chinese medicine.

Study on fragmentation patterns of coumarins in Notopterygium inchum with ultrahigh performance liquid chromatography combined with quadrupole time-of-flight mass spectrometry / 中国中药杂志

To demonstrate the fragmentation patterns of simple coumarins furanocourmarin(C_7-C_8), furanocourmarin(C_6-C_7) and dihydrofuran coumarin by mass spectrometry, with fraxin, scopoletin, isopsoralen, pimpinellin, isoimperatorin, notopterol and noda-kenin as study subjects, so as to provide a basis for rapid identification of compounds in different subtypes of coumarins. Ultrahigh performance liquid chromatography combined with quardrupole time-of-flight mass spectrometry(UPLC-Q-TOF-MS) was implemented in both positive and negative ion modes. Masslynx software was employed to provide the elemental constituents of each detected ion based on its accurate molecular weight. Chemdraw 2014 was used to cultivate mass number of each inferred structure. The fragment pattern of each compound was determined based on the structures inferred from all the relevant ions. And the patterns were drawn by Chemdraw 2014. The deviation between the calculated molecular weight of the inferred structure and the detected value of the ions was used to assess the correctness of the inferred structures in the fragmentation patterns. The results showed that with UPLC-Q-TOF, neutral loss of CO_2 and CO was reflected in lactone and furan skeletons from the courmarin structure. An even mass was attributed to the loss of an odd number of methyl radicals from compounds with a methoxy substituent. Furanocourmarin(C_7-C_8) produced a protonated molecular ion([M+H]~+), while the other courmarin subtypes produced either a sodium adduct of the molecular ion([M+Na]~+) or a sodium adduct of the molecular ion([M+Na]~+) with a protonated molecular ion([M+H]~+). The m/z 203.03 was a diagnostic ion for furanocourmarin(C_6-C_7), and the m/z 147.04 was supplementary evidence for furanocourmarin(C_6-C_7) identification. The characteristic ion of furanocourmarin(C_7-C_8) was m/z 131.05, while m/z 187.04 was the characteristic ion of dihydrofuran coumarin. The m/z 203.03 ion for furanocourmarin(C_7-C_8) was pretty weak. In negative ion mode, furanocourmarin(C_7-C_8) did not have any signals that were different from the other subtypes of courmarins. The fragmentation patterns in negative ion mode for the other subtypes of courmarins were similar to those in positive ion mode. Four types of fragmentation patterns were identified as forcourmarins from Notopterygium inchum. This study provides the basis for the rapid identification of courmarin subtypes by mass spectrometry.

Stability of hydroalcoholic extracts of two species of guaco; Mikania glomerata SPRENG. and Mikania laevigata SCHULTZ. (Asteraceae), by UHPLC-MS

It is important to study the stability of plant extracts used as active ingredients in phytotherapic medicine, as degradation of the active principles directly affects the efficacy and safety of these products. Therefore, a stability study of the hydroalcoholic extract of the species: Mikania glomerata and Mikania laevigata was conducted in order to determine the speed of degradation and shelf life of these extracts, which are incorporated in cough syrup in Brazil. Leaves of both species were dried in an oven or by lyophilization (freeze-dried). Hydroalcoholic extracts underwent both accelerated stability study of six months and long-term stability study for 12 months. Samples were stored at different temperatures and every three months were analysed by ultra-high performance liquid chromatography-mass spectrometry (UHPLC-MS) to monitor their chemical profile, quantifying coumarin and chlorogenic acid. For all conditions of the study, a reduction of the content of the chemical marker of this species, coumarin, greater than 5% was observed, so a shelf life of two years cannot be assigned to the hydroalcoholic extracts of these species as observed in commercial extracts.

Identification and attribution of chemical constituents of Qingfei Paidu Decoction based on UHPLC-LTQ-Orbitrap-MS technology / 中国中药杂志

UHPLC-LTQ-Orbitrap-MS was developed for the identification of chemical constituents in Qingfei Paidu Decoction, which will clarify its material basis. ACQUITY UHPLC HSS T3 chromatography column(2.1 mm×100 mm, 1.8 μm) was used with 0.1% formic acid(B)-acetonitrile(A) as the mobile phase in gradient elution. The decoction was detected by high-resolution liquid chromatography-mass spectrometry equipped with an ESI ion source in positive and negative mode. Based on the accurate mass measurements, retention time, mass fragmentation patterns combined with comparison of reference and literature reports, a total of 87 major compounds including 43 flavonoids, 9 alkaloids, 4 triterpenoid saponins, 1 sesquiterpene, 2 coumarins, 10 phenolic acids and 18 other compounds were tentatively screened and characterized. UHPLC-LTQ-Orbitrap-MS was employed to comprehensively elucidate the chemical components in Qingfei Paidu Decoction, which basically covered 20 Chinese medicines except gypsum in Qingfei Paidu Decoction. These collective results provide a scientific basis for further research on the quality control standard of Qingfei Paidu Decoction.

Coumarin analogue 3-methyl-7H-furo[3,2-g]chromen-7-one as a possible antiparkinsonian agent / El análogo de cumarina 3-metil-7H-furo[3,2-g]cromen-7-ona, un posible agente antiparkinsoniano

Abstract Introduction: Parkinson's disease is the second most common neurodegenerative disease. Monoamine oxidase B inhibitors are used in the treatment of this disease concomitantly with levodopa or as monotherapy. Several substituted coumarins have shown activity as inhibitors of monoamine oxidase B. Objective: To evaluate the possible antiparkinsonian effects of the coumarin analogue FCS005 (3-methyl-7H-furo[3,2-g]chromen-7-one) in mouse models, as well as its inhibitory activity towards monoamine oxidases (MAO) and its antioxidant activity. Materials and methods: FCS005 was synthesized and the reversal of hypokinesia was evaluated in the reserpine and levodopa models. Moreover, in the haloperidol model, its anticataleptic effects were evaluated. Additionally, the monoamine oxidase inhibitory activity and antioxidant activity of FCS005 were evaluated using in vitro and ex vivo studies, respectively. Results: FCS005 (100 mg/kg) caused the reversal of hypokinesia in the reserpine and levodopa models. This furocoumarin also presented anti-cataleptic effects at the same dose. Besides, it showed selective inhibitory activity towards the MAO-B isoform and antioxidant activity. Conclusion: These results attribute interesting properties to the compound FCS005. It is important to continue research on this molecule considering that it could be a potential antiparkinsonian agent.

Resumen Introducción. El segundo trastorno neurodegenerativo más común es la enfermedad de Parkinson. Los inhibidores de la monoamino oxidasa B se emplean en el tratamiento de esta enfermedad en monoterapia o concomitantemente con levodopa. Varios compuestos cumarínicos han mostrado actividad como inhibidores de la monoamino oxidasa B. Objetivo. Evaluar los posibles efectos antiparkinsonianos del análogo de la cumarina FCS005 (3-methyl-7H-furo [3,2-g ] chromen-7-one) en modelos de ratones, la actividad inhibitoria frente a las monoamino oxidasas (MAO) y la actividad antioxidante. Materiales y métodos. Se sintetizó la furanocumarina FCS005 y, en los modelos de reserpina y levodopa, se evaluó si producía reversión de la hipocinesia; en el modelo de haloperidol se evaluaron sus efectos anticatalépticos. Además, se evaluó in vitro la actividad inhibidora de MAO y, ex vivo, la actividad antioxidante del compuesto FCS005. Resultados. El compuesto FCS005 en dosis de 100 mg/kg produjo la remisión de la hipocinesia en los modelos de reserpina y de levodopa. Esta furanocumarina presentó efectos anticatalépticos con la misma dosis. Además, mostró tener actividad inhibitoria selectiva sobre la MAO B, así como efectos antioxidantes. Conclusión. Los resultados evidenciaron propiedades interesantes del compuesto FCS005. Es importante continuar investigando esta molécula porque puede ser un potencial agente antiparkinsoniano.

Serotonergic-like profile of 4-propyl-2hbenzo[h]-chromen-2-one (FCS-304) in mice and rats / Perfil de tipo serotoninérgico de 4-propil-2h-benzo[h]-cromen-2-ona (FCS-304) en ratones y ratas

Background: 4-propil-2H-benzo[h]-cromen-2-ona (FCS-304) is a semisynthetic coumarin with MAO-A inhibitory activity and positive results in forced swimming and tail suspension test in mice, but until now, it has not been studied in other screening antidepressant models in mice and rats. Objectives: The aim of this work was to assess the serotonin like effect of FCS-304 in the 5-hydroxytryptophan (5-HTP) test in mice, in the behavioral despair test in rats, and in the reserpine test in rats. Methods: Potentiation of 5-HTP (100 mg/kg, i.p.), induced head twitches were assessed in mice, previously treated with FCS-304 (50-75-150 mg/kg, p.o.). The behavioral despair test was performed in rats treated with FCS-304, recording the immobility time attained by the animals subjected to forced swimming. Antagonism of reserpine-induced ptosis was examined in rats, assessing the level of palpebral closure. Imipramine (30 mg/kg, p.o.) and vehicle (canola oil) served as positive and negative controls, respectively. Results: FCS-304 significantly potentiated 5-HTP induced head twitches in mice, in a dose dependent manner. In rats, FCS-304 significantly decreased the immobility time in the behavioral despair test and antagonized reserpine induced ptosis. Conclusions: These results add support to propose that FCS-304 could elicit antidepressant effects related to MAO-A inhibitory activity.

Antecedentes: 4-propil-2H-benzo[h]-cromen-2-ona (FCS-304) es una cumarina semisintética inhibidora de MAO-A con efectos positivos en las pruebas de nado forzado y suspensión por la cola en ratones, sin embargo, hasta ahora no se había estudiado en otros modelos de tamizado antidepresivo en ratones y ratas. Objetivos: el objetivo de este trabajo fue evaluar el efecto de tipo serotoninérgico de FCS-304 en la prueba de potenciación de 5-hidroxitriptofano (5-HTP) en ratones, y su respuesta en la prueba de desesperanza conductual en ratas y en la prueba de reserpina en ratas. Métodos: se evaluó la potenciación de las sacudidas de cabeza inducidas por 5-HTP (100 mg/kg, i.p.), en ratones tratados con FCS-304 (50-75-150 mg/Kg, v.o.). La prueba de desesperanza conductual se realizó en ratas tratadas con FCS-304, expuestas a nado forzado. El antagonismo de la ptosis palpebral inducida por reserpina se examinó en ratas determinando el grado de apertura ocular. Imipramina (30 mg/kg, v.o.) y el vehículo (aceite de canola, 0,1 mL/10 g), sirvieron como controles positivo y negativo, respectivamente. Resultados: FCS-304 incrementó significativamente el recuento de sacudidas de cabeza inducidas por 5-HTP en ratones, en función de la dosis. En ratas, FCS-304 fue efectiva para disminuir el tiempo de inmovilidad en la prueba de desesperanza inducida por nado forzado y el grado de ptosis palpebral inducido por reserpina. Conclusiones: estos resultados dan soporte para proponer que FCS-304 ejercería efectos de tipo antidepresivo relacionados con la inhibición de MAO-A.

Ethnobotany, Phytochemistry, and Pharmacology of Angelica decursiva Fr. et Sav

Angelica decursiva Fr. et Sav. (Umbelliferae) has traditionally been used to treat different diseases due to its antitussive, analgesic, and antipyretic activities. It is also a remedy for thick phlegm, asthma, and upper respiratory infections. Recently, the leaf of A. decursiva has been consumed as salad without showing any toxicity. This plant is a rich in different types of coumarin derivatives, including dihydroxanthyletin, psoralen, dihydropsoralen, hydroxycoumarin, and dihydropyran. Its crude extracts and pure constituents possess anti-inflammatory, anti-diabetic, anti-Alzheimer disease, anti-hypertension, anti-cancer, antioxidant, anthelmintic, preventing cerebral stroke, and neuroprotective activities. This valuable herb needs to be further studied and developed not only to treat these human diseases, but also to improve human health. This review provides an overview of current knowledge of A. decursiva metabolites and their biological activities to prioritize future studies.

A new coumarin derivative, 4-acetatecoumarin, with antifungal activity and association study against Aspergillus spp

Abstract Fungal infections have become a concern for health professionals, and the emergence of resistant strains has been reported for all known classes of antifungal drugs. Among the fungi causing disease, we highlight those that belong to the genus Aspergillus. For these reasons, the search for new antifungals is important. This study examines the effects of a coumarin derivative, 4-acetatecoumarin (Cou-UMB16) both alone and together with antifungal drugs, and its mode of action against Aspergillus spp. Cou-UMB16 was tested to evaluate its effects on mycelia growth, and germination of Aspergillus spp. fungal conidia. We investigated its possible action on cell walls, on the cell membrane, and also the capacity of this coumarin derivative to enhance the activity of antifungal drugs. Our results suggest that Cou-UMB16 inhibits Aspergillus spp. virulence factors (mycelia growth and germination of conidia) and affects the structure of the fungal cell wall. When applying Cou-UMB16 in combination with azoles, both synergistic and additive effects were observed. This study concludes that Cou-UMB16 inhibits mycelial growth and spore germination, and that the activity is due to its action on the fungal cell wall, and that Cou-UMB16 could act as an antifungal modifier.

Synthesis of some novel pyrimidine, thiophene, coumarin, pyridine and pyrrole derivatives and their biological evaluation as analgesic, antipyretic and anti-inflammatory agents

Pyrimidine derivative 3 was afforded through the reaction of compound (1) with 5-ureidohydantion (2). Product 3 underwent a cyclization to produce fused pyrimidine derivative 7, although the latter product 7 was synthesized through one step via the reaction of compound (1) with 5-ureidohydantion (2) using another catalyst. Compound 3 was oriented to react with cyclic ketones 8a,b in the presence of elemental sulfur, salicylaldehyde (10), aryldiazonium chlorides 12a,b and ω-bromo-4-methoxy- acetophenone (14), which afforded, fused thiophene derivatives 9a,b, coumarin derivative 11, arylhdrazono derivatives 13a,b and 4-methoxyphenyl butenyl derivative 15, respectively. The latter product 15 was reacted with either potassium cyanide (16a) or potassium thiocyanide (16b) to form cyano and thiocyano derivatives 17a,b, respectively. Compound 17a underwent further cyclization to afford pyridopyrimidine derivative 19. Compound 15 was reacted with either hydrazine (20a) or phenylhydrazine (20b) to produce hydrazo derivatives 21a,b and these products were cyclize to produce pyrrole derivatives 23a,b. Finally, 5-ureidohydantion (2) was reacted with compounds 24a,b,c to afford pyrimidine derivatives 25a,b,c. The structures of the synthesized compounds were confirmed using IR, 1H NMR, 13C NMR and mass spectrometry techniques. Compounds 11 and 19 have promising as analgesic and antipyretic activities

Antiproliferative effect of urolithin A, the ellagic acid-derived colonic metabolite, on hepatocellular carcinoma HepG2. 2. 15 cells by targeting Lin28a/let-7a axis

An abnormality in the Lin28/let-7a axis is relevant to the progression of hepatitis B virus (HBV)-positive hepatocellular carcinoma (HCC), which could be a novel therapeutic target for this malignant tumor. The present study aimed to investigate the antiproliferative and anti-invasive effects of urolithin A in a stable full-length HBV gene integrated cell line HepG2.2.15 using CCK-8 and transwell assays. The RNA and protein expressions of targets were assessed by quantitative PCR and western blot, respectively. Results revealed that urolithin A induced cytotoxicity in HepG2.2.15 cells, which was accompanied by the cleavage of caspase-3 protein and down-regulation of Bcl-2/Bax ratio. Moreover, urolithin A suppressed the protein expressions of Sp-1, Lin28a, and Zcchc11, and elevated the expression of microRNA let-7a. Importantly, urolithin A also regulated the Lin28a/let-7a axis in transient HBx-transfected HCC HepG2 cells. Furthermore, urolithin A decelerated the HepG2.2.15 cell invasion, which was involved in suppressing the let-7a downstream factors HMGA2 and K-ras. These findings indicated that urolithin A exerted the antiproliferative effect by regulating the Lin28a/let-7a axis and may be a potential supplement for HBV-infected HCC therapy.

Manejo perioperatorio de pacientes con tratamiento anticoagulante crónico / Perioperative management of patients with chronic anticoagulant therapy

Resumen La terapia anticoagulante es ampliamente utilizada en la práctica clínica, como profilaxis en pacientes con riesgo de presentar fenómenos tromboembólicos o como tratamiento en aquellos que han presentado algún evento trombótico. Cada vez es más frecuente enfrentarse a pacientes en tratamiento anticoagulante crónico que serán intervenidos mediante procedimientos quirúrgicos, por lo que es importante y necesario conocer el manejo perioperatorio de los diferentes fármacos anticoagulantes, para disminuir los riesgos y complicaciones asociados a la suspensión o mantención de estos en el período perioperatorio. Para lograr este objetivo se debe evaluar y balancear el riesgo de sangrado versus el riesgo de eventos tromboembólicos, considerando la condición médica de cada paciente y el tipo de procedimiento quirúrgico que recibirá. La recomendación para fármacos anticoagulantes orales antagonistas de vitamina K es mantenerlos en cirugías con bajo riesgo de sangrado y suspenderlos 5 días antes de procedimientos quirúrgicos con riesgo hemorrágico moderado y alto, controlando el international normalized ratio el día previo a la cirugía. Los nuevos anticoagulantes orales no requieren monitorización de rutina, recomendándose suspenderlos a las 24-96 h previas al procedimiento quirúrgico, dependiendo del riesgo hemorrágico de cada cirugía y de la función renal. En relación con los anticoagulantes parenterales, la heparina no fraccionada en infusión intravenosa se recomienda suspenderla 4-5 h antes de la cirugía, mientras que la utilizada vía subcutánea, 12 h previas a la intervención quirúrgica. Las heparinas de bajo peso molecular en dosis de tratamiento se sugiere descontinuarlas 24 h previas a la cirugía, mientras que las usadas en dosis profilácticas, solo 12 h antes.

Anticoagulant therapy is widely used in clinical practice, as prophylaxis in patients at risk of presenting thromboembolic phenomena or as treatment in those who have presented a thrombotic event. It is increasingly the number of patients on chronic anticoagulant therapy to undergo surgical procedures, so it is important and necessary to know the perioperative management of the different anticoagulant drugs to reduce the risks and complications associated with suspension or maintenance of these in the perioperative period. To achieve this goal, the risk of bleeding should be evaluated and balanced against the risk of thromboembolic events, considering the medical condition of each patient and the type of surgical procedure to which they have undergone. The recommendation for vitamin K antagonist oral anticoagulant drugs is to maintain them for surgeries at low risk of bleeding and to suspend them 5 days before surgical procedures with moderate and high bleeding risk, controlling 'International Normalized Ratio' the day before surgery. The new oral anticoagulants do not require routine monitoring, recommending suspending them 24-96 h prior to the surgical procedure, depending on the hemorrhagic risk of each surgery and renal function of patient. In relation to parenteral anticoagulants, unfractionated heparin in intravenous infusion is recommended to be discontinued 4-5 h prior to surgery, while the subcutaneous route, 12 h prior to surgery. Low-molecular-weight heparins in treatment doses should be suspended 24 h prior to surgery, while in prophylactic doses, only 12 h earlier.

Osthole decreases collagen I/III contents and their ratio in TGF-β1-overexpressed mouse cardiac fibroblasts through regulating the TGF-β/Smad signaling pathway / 中国天然药物

The present study was designed to elucidate whether the mechanism by which osthole decreases collagenI/III contents and their ratio is regulating the TGF-β/Smad signaling pathway in TGF-β1-overexpressed mouse cardiac fibroblasts (CFs). These CFs were cultured and treated with different concentrations of osthole. Our results showed that the TGF-β1 expression in the CFs transfected with that the recombinant expression plasmids pcDNA3.1(+)-TGF-β1 was significantly enhanced. After the CFs were treated with 1.25-5 μg·mL of osthole for 24 h, the mRNA and protein expression levels of collagensIand III were reduced. The collagen I/III ratio was also reduced. The mRNA and protein expression levels of TGF-β1, TβRI, Smad2/3, P-Smad2/3, Smad4, and α-SMA were decreased, whereas the expression level of Smad7 was increased. These effects suggested that osthole could inhibit collagen I and III expression and reduce their ratio via the TGF-β/Smad signaling pathway in TGF-β1 overexpressed CFs. These effects of osthole may play beneficial roles in the prevention and treatment of myocardial fibrosis.