Long-term outcome of percutaneous endovascular stenting in external iliac artery endofibrosis.

BACKGROUND: External iliac artery endofibrosis (EIAE) is a rare vascular disease which has been traditionally seen in avid cyclists. The conventional approach has been surgery, although no high-quality evidence suggests superiority of surgery over percutaneous endovascular intervention. There are limited data on the efficacy of stenting in EIAE. METHODS: Over a 14-year period, we treated 10 patients (13 limbs) with EIAE with stents. These patients had declined surgery. The mean follow up was 8.4 ± 3.3 years. There were eight women. Five patients were competitive runners, three were cyclists, and two were triathletes. The mean age was 40.7 ± 2.9 years and body mass index was 19.46 ± 1.6. Intravascular ultrasound (IVUS) was used in eight limbs. RESULTS: Procedural success was achieved in all. The recurrence of symptoms occurred in three patients at a mean of 9.3 ± 2.1 months postindex intervention. The other seven patients remained symptom free. IVUS revealed a pathognomonic finding which we termed 'perfect circle appearance'. It results from symmetric or asymmetric hypertrophy of one or more layers of the arterial wall leading to negative remodeling, which creates a distinct echo dense structure contrasting itself from the luminal blood's echoluscent appearance. It is identical to IVUS images of diffuse venous stenosis with important implications in the treatment technique. CONCLUSIONS: We conclude that stenting in EIAE is safe and effective with a good long-term outcome. It can be an alternative to surgery, particularly in those patients who refuse a surgical approach. The IVUS image is pathognomonic and 'sine qua non' of EIAE.

In silico induced effect of N-ε-lysine acetylation on microtubule stability and subsequent interaction of microtubule-associated proteins.

Plant systems have been considered valuable models for addressing fundamental questions of microtubule (MT) organization due to their considerable practical utility. Protein acetylation is a very common protein modification, and therate of acetylation can be modulated in cells in different biological states, and these changes can be detected at a molecular level. Here, we focused on K40, K112, and K394 residues as putative acetylation sites, which were shown to exist in both plants and mammals. Such residual effect of acetylation causes critical but unclear effect on MT stability. In turn, it was shown that acetylation indirectly affects the probability of interaction with different MAPs (Microtubule-associated proteins). In a multiscale study using an all-atom force field to reproduce several lattice-forming elements found on the surface the microtubule, we assembled a fragment of a plant microtubule composed of nine tubulins and used it as a model object along with the existing human complex. Triplets of tubulins assembled in a lattice cell were then simulated for both human and plant protein complexes, using a coarse-grained force field. We then analyzed the trajectories and identified some critical deformations of the MAP interaction surface. The initial coordinates were used to investigate the structural scenario in which autophagy-related protein 8 (ATG8) was able to interact with the MT fragment.

Effective biosorption of Al ions from drinking water by lignocellulosic biomass rice straw.

High concentration of aluminum (Al) in drinking water is a major intake source of it and can result in serious diseases. Rice straw (RS) as lignocellulosic biomasses has great potential to peak up metal ions from aqueous environment, however, feasibility of Al3+ removal by RS has not been investigated yet. The present study aimed to evaluate the capacity of RS as a novel biosorbent for Al3+ from drinking water. Biosorption characteristics of RS were surveyed through several biological and physiochemical techniques. Additionally, isotherm, kinetic and thermodynamic studies were evaluated using various common models. BET profiles revealed the presence of textural mesoporosity on heterogeneous surface, which leading to improve the biosorption capacity. SEM-EDS analysis confirmed the morphological changes as irregularly particles of Al3+ on external surface via physical mechanism. The results of bioassays and FTIR analysis showed carboxylic and hydroxyl groups in lignin and pectin as the main Al3+ binding site. The batch experimental results showed the maximum biosorption capacity of 283.09 mg/g and removal efficiency of 94.86% for Al3+ at biosorbent dosage of 0.05 g/100 mL, contact time of 50 min, pH 7.5, and temperature of 30 °C. The Freundlich model has the best match and suggests the biosorption process as a multi-layer. According to the results of free activation energy, biosorption process was also physical. As thermodynamic result, the biosorption behavior was found spontaneous and endothermic. Consequently, results showed RS as an economical biosorbent for reducing Al3+ of drinking water. Meanwhile, it can be considered as one of the most appropriate methods for management of rice paddies waste.

This article provides a new interdisciplinary horizon at the border of plant biochemistry, agriculture, water treatment industry, and environmental protection. This study covers different aspects including biosorption, cell wall network as well as the usefulness of agricultural by-products in biosorption of Al-polluted drinking water. Findings of the present study revealed that rice straw cell wall polysaccharides have specific Al³⁺ binding sites, therefore can be effectively used in water treatment and reduce Al³⁺ content below the standard permissible limit of WHO (0.2 mg/L). This can be a foundation for future research to evaluate agricultural wastes management in the industry of water as natural biosorbent. This method also effectively converts RS from an unwanted agricultural waste to high-value products.

Physiological, biochemical, and molecular responses of Linum album to digested cell wall of Piriformospora indica.

Plants synthesize a variety of metabolites in response to biotic elicitors. To comprehend how the digested cell wall of Piriformospora indica affects the response of ROS burst, antioxidant enzymes, amino acids profiling, and phenylpropanoid compounds such as lignans, phenolic acids, and flavonoids in Linum album hairy roots; we accomplished a time-course analysis of metabolite production and enzyme activities in response to CDCW and evaluated the metabolic profiles. The results confirms that CDCW accelerates the H2O2 burst and increases SOD and GPX activity in hairy roots. The HPLC analysis of metabolic profiles shows that the H2O2 burst shifts the amino acids, especially Phe and Tyr, fluxes toward a pool of lignans, phenolic acids, and flavonoids through alterations in the behavior of the necessary enzymes of the phenylpropanoid pathway. CDCW changes PAL, CCR, CAD, and PLR gene expression and transiently induces PTOX and 6MPROX as the main-specific products of PAL and PLR genes expression. The production of phenolic acids (e.g., cinnamic, coumaric, caffeic, and salicylic acid) and flavonoids (e.g., catechin, diosmin, kaempferol, luteolin, naringenin, daidzein, and myricetin) show different behaviors in response to CDCW. In conclusion, our observations show that CDCW elicitation can generate H2O2 molecules in L. album hairy roots and consequently changes physiological, biochemical, and molecular responses such as antioxidant system and the specific active compounds such as lignans. Quantification of metabolic contents in response to CDCW suggests enzyme and non-enzyme defense mechanisms play a crucial role in L. album hairy root adaptation to CDCW. A summary revealed that the correlation between H2O2 generation and L. album hairy root defense system under CDCW. Increase of H2O2 generation led plant to response against oxidative conditions. SOD, and GPX modulated H2O2 content, Phe, and Tyr shifted to the phenylpropanoid compounds as a precursor of PAL and TAL enzyme, the predominant phenylpropanoid compounds controlled oxidative conditions, and the other amino acids responsible for amino acid synthesis and development stages.

Time-dependent behavior of phenylpropanoid pathway in response to methyl jasmonate in Scrophularia striata cell cultures.

KEY MESSAGE: MeJA triggers a time-dependent behavior of the phenylpropanoid compounds. Plant cells produce a large number of metabolites in response to environmental factors. The cellular responses to environmental changes are orchestrated by signaling molecules, such as methyl jasmonate (MeJA). To understand how the MeJA changes the behavior of amino acids, carbohydrates, and phenylpropanoid compounds such as phenolic acids, phenylethanoid-glycosides, and flavonoids in Scrophularia striata cells; we monitored the metabolic responses for different times of exposure. In this study, we performed a time course analysis of metabolites and enzymes in S. striata cells exposed to MeJA (100 µM) and evaluated the metabolic flux towards carbon-rich secondary metabolites production. Moreover, we calculated the biosynthetic energy cost for free amino acids. Our results indicated that MeJA accelerates the sucrose degradation and directs the metabolic fluxes towards a pool of flavonoids and phenylethanoid glycosides through a change in enzyme behavior in the entry point and center of the phenylpropanoid pathway. MeJA also decreased and then raised the amino acid biosynthesis cost in S. striata cells in a time-dependent manner, indicating the cells evolve to utilize amino acids more economically by reducing cell growth. Finally, we classified the marked changes in the metabolites level and enzyme activities into three groups including early-, late-, and oscillatory-response groups to MeJA and summarized our findings as a model depicting pathway interactions during MeJA elicitation. Determination of metabolic levels in response to MeJA suggests that the changes in metabolic responses are time-dependent.

Structural and functional features of lysine acetylation of plant and animal tubulins.

The study of the genome and the proteome of different species and representatives of distinct kingdoms, especially detection of proteome via wide-scaled analyses has various challenges and pitfalls. Attempts to combine all available information together and isolate some common features for determination of the pathway and their mechanism of action generally have a highly complicated nature. However, microtubule (MT) monomers are highly conserved protein structures, and microtubules are structurally conserved from Homo sapiens to Arabidopsis thaliana. The interaction of MT elements with microtubule-associated proteins and post-translational modifiers is fully dependent on protein interfaces, and almost all MT modifications are well described except acetylation. Crystallography and interactome data using different approaches were combined to identify conserved proteins important in acetylation of microtubules. Application of computational methods and comparative analysis of binding modes generated a robust predictive model of acetylation of the ϵ-amino group of Lys40 in α-tubulins. In turn, the model discarded some probable mechanisms of interaction between elements of interest. Reconstruction of unresolved protein structures was carried out with modeling by homology to the existing crystal structure (PDBID: 1Z2B) from B. taurus using Swiss-model server, followed by a molecular dynamics simulation. Docking of the human tubulin fragment with Lys40 into the active site of α-tubulin acetyltransferase, reproduces the binding mode of peptidomimetic from X-ray structure (PDBID: 4PK3).

Retrospective comparison of ultrasound facilitated catheter-directed thrombolysis and systemically administered half-dose thrombolysis in treatment of pulmonary embolism.

This study retrospectively compared the outcomes of patients who received ultrasound facilitated catheter-directed thrombolysis (UFCDT) versus systemically administered 'half-dose' thrombolysis (HDT) in 97 patients with PE. The outcomes assessed included changes in baseline pulmonary artery systolic pressure (PASP), right ventricle/left ventricle ratio (RV/LV), cost and duration of hospitalization, death, bleeding, and recurrent venous thromboembolism in the short and intermediate term follow-up. Analyses were performed using a covariance adjustment propensity score approach to address baseline differences between groups in variables associated with PASP and RV/LV, covarying baseline scores. The baseline mean ± SE PASP dropped from 49.3 ± 1.1 to 32.5 ± 0.3 mmHg at 36 hours in the HDT group, and from 50.6 ± 1.2 to 35.1 ± 0.4 mmHg in the UFCDT group; group × time interaction p-value = 0.007. Corresponding drops in the RV/LV were from a baseline of 1.26 ± 0.05 to 1.07 ± 0.01 in the HDT group and from 1.30 ± 0.05 to 1.14 ± 0.01 in the UFCDT group at 36 hours; group × time interaction p-value = 0.269. Statistically significant decreases were noted in PASP and RV/LV for both the HDT and UFCDT at 36 hours and follow-up. PASP through follow-up was significantly lower in the HDT than the UFCDT group. Likewise, RV/LV was lower in the HDT group. The duration and cost of hospitalization were lower in the HDT group (6.2 ± 1.4 days vs 1.9 ± 0.3 days, p < 0.001; US$12,000 ± $3000 vs $74,000 ± $6000, p < 0.001). We conclude that both UFCDT and HDT lead to rapid reduction of PASP and RV/LV, whereas HDT leads to a lower duration and cost of hospitalization.

Molecular Networking-Based Analysis of Cytotoxic Saponins from Sea Cucumber Holothuria atra.

The saponin composition of a specimen of black sea cucumber, Holothuria atra collected in the Persian Gulf was studied by a combined approach including LC-MS/MS, Molecular Networking, pure compound isolation, and NMR spectroscopy. The saponin composition of Holothuria atra turned out to be more complex than previously reported. The most abundant saponins in the extract (1⁻4) were isolated and characterized by 1D- and 2D-NMR experiments. Compound 1 was identified as a new triterpene glycoside saponin, holothurin A5. The side chain of the new saponin 1, unprecedented among triterpene glycosides, is characterized by an electrophilic enone function, which can undergo slow water or methanol addition under neutral conditions. The cytotoxic activity of compounds 1⁻4, evaluated on the human cervix carcinoma HeLa cell line, was remarkable, with IC50 values ranging from 1.2 to 2.5 µg/mL.

Piriformospora indica cell wall modulates gene expression and metabolite profile in Linum album hairy roots.

MAIN CONCLUSION: Elicitation of Linum album hairy roots by Piriformospora indica cell wall induced the target genes and specific metabolites in phenylpropanoid pathway and shifted the amino acid metabolism toward the phenolic compound production. Plants have evolved complex mechanisms to defend themselves against various biotic stresses. One of these responses is the production of metabolites that act as defense compounds. Manipulation of plant cell cultures by biotic elicitors is a useful strategy for improving the production of valuable secondary metabolites. This study focused on hairy root culture of Linum album, an important source for lignans. The effects of cell wall elicitor extracted from Piriformospora indica on phenylpropanoid derivatives were evaluated to identify metabolic traits related to biotic stress tolerance. Significant increases in lignin, lignans; lariciresinol, podophyllotoxin, and 6-methoxy podophyllotoxin; phenolic acids: cinnamic acid, ferulic acid, and salicylic acid; flavonoids: myricetin, kaempferol, and diosmin were observed in response to the fungal elicitor. In addition, the gene expression levels of phenylalanine ammonia-lyase, cinnamyl alcohol dehydrogenase, cinnamoyl-CoA reductase, and pinoresinol-lariciresinol reductase significantly increased after elicitation. The composition of free amino acids was altered under the elicitation. Phenylalanine and tyrosine, as precursors of phenylpropanoid metabolites, were increased, but alanine, serine, and glutamic acid significantly decreased in response to the fungal elicitor, suggesting that the amino acid pathway may be shifted toward biosynthesis of aromatic amino acids and precursors of the phenylpropanoid pathway. These results provided evidence that up-regulation of genes involved in the phenylpropanoid pathway in response to the fungal elicitor resulted in enhanced metabolic responses associated with the protection in L. album. This approach can also be applied to improve lignan production.

Development of models for predicting Torsade de Pointes cardiac arrhythmias using perceptron neural networks.

BACKGROUND: Blockage of some ion channels and in particular, the hERG (human Ether-a'-go-go-Related Gene) cardiac potassium channel delays cardiac repolarization and can induce arrhythmia. In some cases it leads to a potentially life-threatening arrhythmia known as Torsade de Pointes (TdP). Therefore recognizing drugs with TdP risk is essential. Candidate drugs that are determined not to cause cardiac ion channel blockage are more likely to pass successfully through clinical phases II and III trials (and preclinical work) and not be withdrawn even later from the marketplace due to cardiotoxic effects. The objective of the present study is to develop an SAR (Structure-Activity Relationship) model that can be used as an early screen for torsadogenic (causing TdP arrhythmias) potential in drug candidates. The method is performed using descriptors comprised of atomic NMR chemical shifts (13C and 15N NMR) and corresponding interatomic distances which are combined into a 3D abstract space matrix. The method is called 3D-SDAR (3-dimensional spectral data-activity relationship) and can be interrogated to identify molecular features responsible for the activity, which can in turn yield simplified hERG toxicophores. A dataset of 55 hERG potassium channel inhibitors collected from Kramer et al. consisting of 32 drugs with TdP risk and 23 with no TdP risk was used for training the 3D-SDAR model. RESULTS: An artificial neural network (ANN) with multilayer perceptron was used to define collinearities among the independent 3D-SDAR features. A composite model from 200 random iterations with 25% of the molecules in each case yielded the following figures of merit: training, 99.2%; internal test sets, 66.7%; external (blind validation) test set, 68.4%. In the external test set, 70.3% of positive TdP drugs were correctly predicted. Moreover, toxicophores were generated from TdP drugs. CONCLUSION: A 3D-SDAR was successfully used to build a predictive model for drug-induced torsadogenic and non-torsadogenic drugs based on 55 compounds. The model was tested in 38 external drugs.

In vitro polyploidy induction: changes in morphology, podophyllotoxin biosynthesis, and expression of the related genes in Linum album (Linaceae).

MAIN CONCLUSION: Induction of tetraploidy was performed and podophyllotoxin production increased by upregulating the expression level and enzyme activity of genes related to its biosynthesis in tetraploid compared to diploid Linum album. Linum album is a valuable medicinal plant that produces antiviral and anticancer compounds including podophyllotoxin (PTOX). To achieve homogeneous materials, in vitro diploid clones were established, and their nodal segments were exposed to different concentrations and durations of colchicine. This resulted in successful tetraploidy induction, confirmed by flow cytometry, and is being reported for the first time. The highest efficiency of tetraploid induction (22%) was achieved after 72 h exposure to 2.5-mM colchicine treatment. The stable tetraploids were produced after being subcultured three times, and their ploidy stability was confirmed after each subculture. The effects of autopolyploidy were measured on the morphological and phytochemical characteristics, as well as enzyme activity and the expression levels of some key genes involved in the PTOX biosynthetic pathway, including phenylalanine ammonia-lyase (PAL), cinnamoyl-Coa reductase (CCR), cinnamyl-alcohol dehydrogenase (CAD), and pinoresinol-lariciresinol reductase (PLR). The tetraploid plants had larger leaves and stomata (length and width) and lower density stomata. Increasing the ploidy level from diploid to tetraploid resulted in 1.39- and 1.23-fold enhancement of PTOX production, respectively, in the leaves and stem. The increase in PTOX content was associated with upregulated activities of some enzymes studied related to its biosynthetic pathway and the expression of the corresponding genes. The expression of the PAL gene and PLR enzymatic activity had the most positive correlation with the ploidy level in both leaf and stem tissues. Our results verified that autotetraploid induction is a useful breeding method, remarkably increasing the PTOX content in the leaves and stem of L. album.

Effect of OATP-binding on the prediction of biliary excretion.

1. Biliary excretion of compounds is dependant on several transporter proteins for the active uptake of compounds from the blood into the hepatocytes. Organic anion-transporting polypeptides (OATPs) are some of the most abundant transporter proteins in the sinusoidal membrane and have been shown to have substrate specificity similar to the structural characteristics of cholephilic compounds. 2. In this study, we sought to use measures of OATP binding as predictors of biliary excretion in conjunction with molecular descriptors in a quantitative structure-activity relationship (QSAR) study. Percentage inhibitions of three subtypes of OATPs were used as surrogate indicators of OATP substrates. Several statistical modelling techniques were incorporated including classification and regression trees, boosted trees, random forest and multivariate adaptive regression splines (MARS) in order to first develop QSARs for the prediction of OATP inhibition of compounds. The predicted OATP percentage inhibition using selected models were then used as features of the QSAR models for the prediction of biliary excretion of compounds in rat. 3. The results indicated that incorporation of predicted OATP inhibition improves accuracy of biliary excretion models. The best result was obtained from a simple regression tree that used predicted OATP1B1 percentage inhibition at the root node of the tree.

Favouring NO over H2O2 production will increase Pb tolerance in Prosopis farcta via altered primary metabolism.

Reactive oxygen species (ROS) and nitric oxide (NO) are known in triggering defense functions to detoxify heavy metal stresses. To investigate the relevance of ROS production, Pb treatment (400µM) alone and in combination with 400µM sodium ascorbate (Asc: as H2O2 scavenger) were given to hydroponically grown Prosopis farcta seedlings over a time course of 72h. Data presented here indicate that, the low extent of H2O2 due to scavenging by ascorbate, together with high level of NO improved Pb+Asc- treated Prosopis growth. Following the evoked potential of both the signals, significant increases in phenolic acids; caffeic, ferulic and salicylic acid were observed with Pb treatment; which are consistent with observed increase in lignin content and consequently with growth inhibition. In contrast, Pb+Asc treatment induced more flavonoids (quercetin, kaempferol, luteolin), diminished phenolic acids contents and also lignin. Elicited expression rate of phenylalanine ammonia-lyase gene (PAL) and also its enzymatic activity verified the induced phenylpropanoid metabolism by Pb and Pb+Asc treatments. In comparison with Pb stress, Asc+Pb application induced the high expression of arginine decarboxylase gene (ADC), in polyamines biosynthesis pathway, and conducted the N flow towards polyamines and γ-amino butyric acid (GABA). Examining the impact on enzyme activities, catalase, and guaiacol peroxidase; Pb+Asc reduced activity but this increased ascorbate peroxidase, and aconitase activity. Our observations are consistent with conditions favouring NO production and reduced H2O2 can improve Pb tolerance via wide-ranging effects on a primary metabolic network.

Profiling of acidic (amino and phenolic acids) and phenylpropanoids production in response to methyl jasmonate-induced oxidative stress in Scrophularia striata suspension cells.

MAIN CONCLUSION: A metabolic profiling including calculation of energy cost of amino acids biosynthesis in cultured cells of Scrophularia striata showed that methyl jasmonate-inducible oxidative stress elicited secondary metabolites formation derived from phenylalanine and tyrosine and increased energy cost for these amino acids biosynthesis. Understanding of the metabolic pathways in cell culture of Scrophularia striata, an aromatic plant species, facilitates means of production of pharmaceutical metabolites under oxidative stress. In this study, we evaluated the effects of MeJA on the S. striata metabolic pathway and the responses to oxidative stress. Exposure to methyl jasmonate (MeJA) affects plant growth, effectively induces production of reactive oxygen species (ROS) and inserts oxidative stress at the cellular level which results in alteration of primary metabolites and production of phenylepropanoid compounds. Cells treated with MeJA indicated increase in the activities of three antioxidant enzymes including superoxide dismutase (SOD), catalase (CAT), guaiacol peroxidase (GPx) as well as intracellular H2O2 and MDA contents compared with mock-treated cells. High performance liquid chromatography (HPLC)-based metabolome analysis revealed dynamic metabolic changes in oxidatively stressed S. striata cells, e.g., general phenylpropanoid pathway, phenylethanoid-glycosides, lignans, and increased energy cost of biosynthesis and accumulation of amino acids. Furthermore, principal component analysis (PCA)-derived score plots demonstrated that MeJA affects cellular metabolism in S. striata cells and significantly alters metabolite composition under MeJA-inducible oxidative stress. These observations suggest that MeJA-elicited cell suspension cultures of S. striata balanced the production of primary and secondary metabolites in coordination with ROS-scavenging system.

Pulseless electrical activity in pulmonary embolism treated with thrombolysis (from the "PEAPETT" study).

OBJECTIVE: Pulseless electrical activity (PEA) during cardiac arrest portends a poor prognosis. There is a paucity of data in the use of thrombolytic therapy in PEA and cardiopulmonary arrest due to confirmed pulmonary embolism (PE). We evaluated the outcome of low-dose systemic thrombolysis with tissue plasminogen activator (tPA) in patients presenting with PEA due to PE. METHODS: During a 34-month period, we treated 23 patients with PEA and cardiopulmonary arrest due to confirmed massive PE. All patients received 50 mg of tPA as intravenous push in 1 minute while cardiopulmonary resuscitation was ongoing. The time from initiation of cardiopulmonary resuscitation to administration of tPA was 6.5 ± 2.1 minutes. RESULTS: Return of spontaneous circulation occurred in 2 to 15 minutes after tPA administration in all but 1 patient. There was no minor or major bleeding despite chest compression. Of the 23 patients, 2 died in the hospital, and at 22 ± 3 months of follow-up, 20 patients (87%) were still alive. The right ventricular/left ventricular ratio and pulmonary artery systolic pressure dropped from 1.79 ± 0.27 and 58.10 ± 7.99 mm Hg on admission to 1.16 ± 0.13 and 40.25 ± 4.33 mm Hg within 48 hours, respectively (P< .001 for both comparisons). There was no recurrent venous thromboembolism or bleeding during hospitalization or at follow-up. CONCLUSION: Rapid administration of 50 mg of tPA is safe and effective in restoration of spontaneous circulation in PEA due to massive PE leading to enhanced survival and significant reduction in pulmonary artery pressures.

Lignan enhancement in hairy root cultures of Linum album using coniferaldehyde and methylenedioxycinnamic acid.

Feeding experiments with hairy root cultures of Linum album have established that the extracellular coniferaldehyde is a good precursor for production of two lignans: lariciresinol (LARI) and pinoresinol (PINO). The accumulation of the LARI, PINO, and podophyllotoxin (PTOX) in hairy roots were enhanced about 14.8-, 8.7-, and 1.5-fold (107.61, 8.7 and 6.42 µg g(-1) Fresh Wight), respectively, by the addition of coniferaldehyde (2 mM) to the culture media (after 24 hr). This result was correlated with an increase pinoresinol/lariciresinol reductase (PLR) expression gene and cinnamyl alcohol dehydrogenase (CAD) activity in the fed hairy roots. Adding 3,4-(methylendioxy)cinnamic acid (MDCA) precursor did not influence on the lignans accumulation, but the lignin content of the hairy roots was increased. Moreover, the expression genes of phenylalanine ammonialyase (PAL), CAD, and cinnamoyl-CoA reductase (CCR) were influenced after feeding hairy roots with MDCA.

Low incidence of post-thrombotic syndrome in patients treated with new oral anticoagulants and percutaneous endovenous intervention for lower extremity deep venous thrombosis.

Post-thrombotic syndrome (PTS) is a common complication of deep venous thrombosis (DVT) of the iliofemoral venous system leading to significant morbidity and high health care costs. It has been recently shown that percutaneous endovenous intervention (PEVI) can effectively reduce the incidence of PTS. The role of new oral anticoagulants (NOACs) in combination with PEVI in the reduction of PTS has not been previously studied. This report sought to evaluate the role of PEVI plus NOACs in the reduction of PTS in acute symptomatic femoropopliteal and iliac DVT. We studied 127 patients with acute lower extremity DVT who had undergone PEVI plus administration of NOACs. All had received a minimum of 3 months of anticoagulation with a NOAC following PEVI. The mean follow-up was 22±5 months. The patients were evaluated for development of PTS, bleeding, recurrent venous thromboembolism (VTE), duration of hospitalization and mortality. There was no in-hospital bleeding. The mean duration of hospitalization was 46±9 hours. DVT occurred in two patients who had been later switched to warfarin. There were four non-VTE-related deaths. PTS developed in five patients (3%), two of whom were those who had been switched to warfarin. Their mean Villalta score was 6.2±0.9. We conclude that the combination of PEVI plus NOAC and low dose aspirin is associated with a very low rate of PTS with the severity being only mild. This approach leads to very low rates of bleeding and recurrent VTE and promotes early discharge.

Transforming and simplifying the treatment of pulmonary embolism: "safe dose" thrombolysis plus new oral anticoagulants.

BACKGROUND: Administration of systemic thrombolysis in pulmonary embolism (PE) has been limited to severe forms due to the risk of intracerebral hemorrhage (ICH). There is growing evidence from small studies that low-dose systemic thrombolysis has equal efficacy to standard dose, while eliminating the risk of ICH. Little data exists on the combined use of low-dose systemic thrombolysis and new oral anticoagulants (NOAC). We evaluated the clinical and echocardiographic outcome of patients treated with low or "safe dose" thrombolysis (SDT) and NOAC at intermediate term. METHODS: We retrospectively identified 159 patients with massive and submassive PE who were treated with SDT and NOAC over a 2-year period by our group. They were followed prospectively for PE-related mortality, recurrent PE, bleeding, change in right/left ventricle (RV/LV) size, pulmonary artery systolic pressure (PASP), and clinical improvement at a mean follow-up of 18 ± 3 months. RESULTS: At 6 months, the RV/LV size was reduced from 1.29 ± 0.28 to 0.89 ± 0.03 (p < 0.001). The PASP dropped from 53.12 ± 3.85 mmHg to 30.39 ± 3.93 mmHg (p < 0.001). There was no ICH or in-hospital major or minor bleeding. At 18 months, three patients died of cancer. Recurrent PE developed in one patient who had been later switched to warfarin. The duration of hospitalization was 1.8 ± 0.3 days. CONCLUSION: With combination of SDT and NOAC, treatment of massive and submassive PE becomes identical and is transformed from an "anticoagulation first" to a "thrombolysis first" approach, thereby making treatment streamlined, simple, safe and effective, accessible and inexpensive.

Karanjin interferes with ABCB1, ABCC1, and ABCG2.

PURPOSE: The prominent ATP-binding cassette (ABC) transporters ABCB1, ABCC1, and ABCG2 are involved in substance transport across physiological barriers and therefore in drug absorption, distribution, and elimination. They also mediate multi-drug resistance in cancer cells. Different flavonoids are known to interfere with different ABC transporters. Here, the effect of the furanoflavonol karanjin, a potential drug with antiglycaemic, gastroprotective, antifungal, and antibacterial effects, was investigated on ABCB1, ABCC1, and ABCG2-mediated drug transport in comparison to the flavonoids apigenin, genistein, and naringenin. METHODS: Cells expressing the relevant transporters (ABCB1: UKF-NB-3(ABCB1), UKF-NB-3(r)VCR¹°; ABCC1: G62, PC-3(r)VCR²°; ABCG2: UKF-NB-3(ABCG2)) were used in combination with specific fluorescent and cytotoxic ABC transporter substrates and ABC transporter inhibitors to study ABC transporter function. Moreover, the effects of the investigated flavonoids were determined on the ABC transporter ATPase activities. RESULTS: Karanjin interfered with drug efflux mediated by ABCB1, ABCC1, and ABCG2 and enhanced the ATPase activity of all three transporters. Moreover, karanjin exerted more pronounced effects than the control flavonoids apigenin, genistein, and naringenin on all three transporters. Most notably, karanjin interfered with ABCB1 at low concentrations being about 1 µM. CONCLUSIONS: Taken together, these findings should be taken into account during further consideration of karanjin as a potential drug for different therapeutic indications. The effects on ABCB1, ABCC1, and ABCG2 may affect the pharmacokinetics of co-administered drugs.

Differential effects of the oncogenic BRAF inhibitor PLX4032 (vemurafenib) and its progenitor PLX4720 on ABCB1 function.

PURPOSE: The clinically approved oncogenic BRAF inhibitor PLX4032 (vemurafenib) was shown to be a substrate of the ATP-binding cassette (ABC) transporter ABCB1. Here, we compared PLX4032 and its structurally closely related precursor compound PLX4720 for their interference with ABCB1 and the ABCB1-mediated compound transport using docking and cell culture experiments. METHODS: For the docking study of PLX4032 and PLX4720 with ABCB1, we analysed binding of both compounds to mouse Abcb1a and to human ABCB1 using a homology model of human ABCB1 based on the 3D structure of Abcb1a. Naturally ABCB1 expressing cells including V600E BRAF-mutated and BRAF wild-type melanoma cells and cells transduced with a lentiviral vector encoding for ABCB1 were used as cell culture models. ABCB1 expression and function were studied by the use of fluorescent and cytotoxic ABCB1 substrates in combination with ABCB1 inhibitors. RESULTS: Docking experiments predicted PLX4032 to interact stronger with ABCB1 than PLX4720. Experimental studies using different cellular models and structurally different ABCB1 substrates confirmed that PLX4032 interfered stronger with ABCB1 function than PLX4720. For example, PLX4032 (20 µM) induced a 4-fold enhanced rhodamine 123 accumulation compared to PLX4720 (20 µM) in ABCB1-transduced UKF-NB-3 cells and reduced the IC50 for the cytotoxic ABCB1 substrate vincristine in this model by 21-fold in contrast to a 9-fold decrease induced by PLX4720. CONCLUSIONS: PLX4032 exerted stronger effects on ABCB1-mediated drug transport than PLX4720. This indicates that small changes in a molecule can substantially modify its interaction with ABCB1, a promiscuous transporter that transports structurally different compounds.