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During the period 2018-2020 in the experimental field of the Agricultural Institute, Shumen, on calcic chernozem soil type, a field experiment with triticale (x Triticosecale Wittmack) was conducted. The experiment was based on the block method, in four replications with a size of the experimental plot of 10 m2. Sowing was carried out in October with a sowing rate of 500 germinate able seeds/m2 after the predecessor sugar beet (Beta vulgaris L.). In the appropriate periods treatments were made in 4 variants: 1) Control-untreated variant. 2) Treatment with biodynamic preparations: Preparation 500 (5% solution) + Fladen preparation (1.5% solution) + preparation 501 (1.5 g for 300 l H2O/ha). 3) Treatment with biological preparations: Heliosulfur (500 ml/ha) + Free N (500 ml/ha). 4) Combined treatment with the same biodynamic and biological preparations. The following indicators were studied: plant height, number of spikelet's per spike, number of grains per spike, grain weight per spike. After the statistical analysis for the first year of the study, a proven positive difference was found in all indicators in the combined biodynamic + biological method of cultivation, as well as in the stand-alone biological. In the second year of the study, a proven positive difference was obtained in all studied indicators in the variants treated with biodynamic preparations and the combination of biodynamic + biological preparations, with statistical significance for p<0.001. A positive correlation was found between all variants of the observed indicators at p<0.05. [ABSTRACT FROM AUTHOR]

Determining the productive potential of flowering vegetation is crucial in obtaining bee products. The application of a remote sensing approach of terrestrial objects can provide accurate information for the preparation of maps of the potential bee pasture in a given region. The study is aimed at the creation of a novel algorithm to identify and distinguish white flowering honey plants, such as black locust (Robinia pseudo-acacia) and to determine the areas occupied by this forest species in mixed forest ecosystems using UAV-based RGB imaging. In our study, to determine the plant cover of black locust in mixed forest ecosystems we used a DJI (Da-Jiang Innovations, Shenzhen, China) Phantom 4 Multispectral drone with 6 multispectral cameras with 1600 × 1300 image resolution. The monitoring was conducted in the May 2023 growing season in the village of Yuper, Northeast Bulgaria. The geographical location of the experimental region is 43°32′4.02″ N and 25°45′14.10″ E at an altitude of 223 m. The UAV was used to make RGB and multispectral images of the investigated forest massifs, which were thereafter analyzed with the software product QGIS 3.0. The spectral images of the observed plants were evaluated using the newly created criteria for distinguishing white from non-white colors. The results obtained for the scanned area showed that approximately 14–15% of the area is categorized as white-flowered trees, and the remaining 86–85%—as non-white-flowered. The comparison of the developed algorithm with the Enhanced Bloom Index (EBI) approach and with supervised Support Vector Machine (SVM) classification showed that the suggested criterion is easy to understand for users with little technical experience, very accurate in identifying white blooming trees, and reduces the number of false positives and false negatives. The proposed approach of detecting and mapping the areas occupied by white flowering honey plants, such as black locust (Robinia pseudo-acacia) in mixed forest ecosystems is of great importance for beekeepers in determining the productive potential of the region and choosing a place for an apiary. [ABSTRACT FROM AUTHOR]

Several models on honeybee population dynamics have been considered in the past decades, which explain that the growth of bee colonies is highly dependent on the availability of food and social inhibition. The phenomenon of the Colony Collapse Disorder (CCD) and its exact causes remain unclear and here we are interested on the factor of social immunity. We work with the mathematical model in [1]. The core model, consisting of four nonlinear ordinary differential equations with unknown functions: brood and nurses B, iB, N and iN represent the number of healthy brood, infected brood, healthy nurses, and infected nurses, respectively. First, this model implements social segregation. Highrisk individuals such as foragers are limited to contact only nectar-receivers, but not other vulnerable individuals (nurses and brood) inside the nest. Secondly, it includes the hygienic behavior, by which healthy nurses actively remove infected workers and brood from the colony. We aim to study the dynamics and the long-term behavior of the proposed model, as well as to discuss the effects of crucial parameters associated with the model. In the first stage, we study the model equilibria stability in dependence of the reproduction number. In the second stage, we investigate the inverse problem of parameters identification in the model based on finite number time measurements of the population size. The conjugate gradient method with explicit Frechet derivative of the cost functional is proposed for the numerical solution of the inverse problem. Computational results with synthetic and realistic data are performed and discussed. [ABSTRACT FROM AUTHOR]

We analyze a mathematical model of the effects of soil contamination by heavy metals, which is expressed as systems of nonlinear ordinary differential equations (ODEs). The model is based on the symmetry dynamics of heavy metals soil–plant interactions. We aim to study this symmetric process and its long-term behavior, as well as to discuss the role of two crucial parameters, namely the flux of the hydrogen protons to the soil in rainfall events W (t) , and the available water for roots p (t) . We study the boundedness and positivity of the solution. Further, a parameter identification analysis of the model is presented. Numerical experiments with synthetic and realistic data of honeybee population are discussed. [ABSTRACT FROM AUTHOR]

We consider an inverse problem of recovering the mortality rate in the honey bee difference equation model, that tracks a forage honeybee leaving and entering the hive each day. We concentrate our analysis to the model without pesticide contamination in the symmetric spatial environment. Thus, the mathematical problem is formulated as a symmetric inverse problem for reaction coefficient at final time constraint. We use the overspecified information to transform the inverse coefficient problem to the forward problem with non-local terms in the differential operator and the initial condition. First, we apply semidiscretization in space to the new nonsymmetric differential operator. Then, the resulting non-local nonsymmetric system of ordinary differential equations (ODEs) is discretized by three iterative numerical schemes using different time stepping. Results of numerical experiments which compare the efficiency of the numerical schemes are discussed. Results from numerical tests with synthetic and real data are presented and discussed, as well. [ABSTRACT FROM AUTHOR]

BACKGROUND. The registration of the nasal cycle by separate measurement of breathing through the left and the right nostril appears a non-invasive method, in which the passability of the nostrils is assessed by the respiratory amplitudes of the air. OBJECTIVE. To present the dynamics and periods of the nasal cycle during night sleep using the Interface 2-Channel System Method. MATERIAL AND METHODS. The recordings demonstrate the dynamics and periods of the nasal cycle during the night sleep of a healthy volunteer. RESULTS. The patient respiratory and nasal cycle through the left and right nostril was measured separately for 10 hours. The entire record consisted of 3 large nasal cycles lasting 4.0h, 3.5h and 2.5h, separated by short awakenings, getting out of bed lasting no longer than 10 minutes. Each part was composed of smaller cycles that structure separate stages of the nasal and sleep cycles. The smallest period recorded in the nasal cycle was about 4 minutes long. Records show that the duration of the REM stage must be longer than 20 minutes to perform the nasal cycle reversal. In the presented records, the nasal cycle reversals were performed after a 30-minute duration of the REM stages. It has been found that nasal cycles can change fast (impulse change) and gradually (gradual change). The impulse change implies that the passability of only one nostril lasts for about 12 seconds, while the other nostril retains its passability. The slow gradual changes of the nasal cycle involve both nostrils and continue for about 4 minutes. Waking up and getting up of persons for about 10 minutes restarts the nasal cycle with potential for a new nasal cycle reversal. CONCLUSION. The method provides an objective assessment of nasal resistance, which can be used in the diagnosis of patients with breathing disorders during sleep. [ABSTRACT FROM AUTHOR]

Honeybee losses are an extensive global problem. In this study, a new compartment model of honeybee population that mainly concerns honey production is developed. The model describes the interaction of the food stock with the brood (immature bees), adult bees and produced honey. In the present paper, the issue of an adequate model recovery is addressed and the parameter identification inverse problem is solved. An adjoint equation procedure to obtain the unknown parameter values by minimizing the functional error during a period of time is proposed. Numerical simulations with realistic data are discussed. [ABSTRACT FROM AUTHOR]

Circulating uncarboxylated matrix Gla protein (ucMGP) is possibly related to coronary arterial calcification (CAC) in cardiovascular disease (CVD) patients. We aimed to evaluate the relationships between circulating ucMGP, CVD pathology and CAC and its interplay with CVD risk factors. ucMGP was measured in 99 CVD-patients. CAC score was determined by multislice computed tomography. Circulating ucMGP, uncarboxylated (ucOC) and carboxylated osteocalcin (cOC) were assayed by ELISA kits. Vitamin-K status was evaluated by ucOC/cOC ratio. A tendency for decreased ucMGP was observed for CAC ≥ 100 AU vs. CAC = 1-99 AU after exclusion of the patients on vitamin K-antagonist anticoagulants. Significant inverse correlations between ucMGP and vitamin-K status were indicated for the entire cohort and according to CAC score. Significant associations were found between ucMGP and risk factors for CVD. Circulating ucMGP may reflect certain stages of CVD and CAC. Future studies are needed to clarify its role as potential biomarker. [ABSTRACT FROM AUTHOR]

The search of a new chemical substances influencing platelet aggregation is a very important endeavor for medical practice. Among the compounds that have antiaggregating activity are some peptides, tannins, etc. Here we present antiaggregation activity of Arg-Gly-Asp (RGD) peptide derivatives. Synthetic procedures of new peptide-galantamine derivatives including also glucose moiety designed to possess such activity are included. The in vitro effect of water extract from 20 tannins-containing plants from Bulgarian flora on aggregation of modified rat platelet-rich plasma was investigated and seven of them (Corylus avellana L, Cydonia oblonga Mill, Dryopteris filix-mas (L.) Schott, Ephedra distachya L., Geum urbanum L., Primula officinalis (L.) Hill and Punica granatum L.)were able to inhibit platelet aggregation. [ABSTRACT FROM AUTHOR]

An approach to modeling herbicide installation for the treatment of peach plantations is proposed. The height of the stem was determined for 4 varieties of peaches. Considering this parameter, the maximum height of the herbicide system and the nozzles on it are indicated. Simulated modelling of the sprayed fluid along the working width of each nozzle was performed. The irregularity of spraying was determined depending on the distance between the nozzles. On the basis of the analysis, the optimal parameters of the spreader system were determined: height - 0.35 m, distance between the spreaders - 0.40 m. [ABSTRACT FROM AUTHOR]

BACKGROUND: Aerobic organisms are equipped with enzymatic defence against oxidative stress. However, protection might be also provided by nonenzymatic antioxidant compounds. Ruminants can make polyphenols bioavailable because of the unique properties of their digestive system. OBJECTIVE: It was assumed that chokeberry pomace may be considered as additive rich in plant antioxidants, able to be deposited in small ruminants muscle tissue. METHODS: The study was conducted, using native breeds of lamb - Polish Merino and Wrzosówka. The experimental animals received chokeberry pomace as an addition in amount 150 or 300 grams per each kg of basic feed. Muscles obtained from lambs were assayed for antioxidative properties of enzymatic systems (superoxide dismutase, glutathione peroxidase) and nonenzymatic compounds or their equivalents (total nonenzymatic antioxidant capacity, potential to scavenge the free DPPH radical, total polyphenols content) contained in tissues. RESULTS: Obtained results provide novel information about bioactivity, bioretention and potential applications of dietary polyphenols in livestock feeding. One of the important findings concerns activity of glutathione peroxidase in the saddle of Polish Merino's animals (control group had activity of 376 nmol/min/mL, the group which received 150 g of chokeberry pomace had 468 nmol/min/mL, and 300 g of supplementation resulted in activity of 738 nmol/min/mL). The decreased peroxidation process related with malondialdehyde levels in saddle and leg (respectively) of the Polish Merino (control group - 7.50μM, 7.75μM, group with 150 g of chokeberry pomace 5.25μM, 6.70μM, and with 300 g of pomace- 3.63μM, 3.83μM) and Wrzosówka animals (control group - 5.5μM, 11.5μM, group with 150 g of chokeberry pomace addition - 4.25μM, 10.4μM, and with 300 g of pomace - 3.48μM, 5.80μM) is crucial in the context of animal health and meat quality. CONCLUSION: Since examined parameters related to oxidative status (malondialdehyde level, chemicals and physicochemical parameters) respond to chokeberry pomace addition, the later may bring many benefits connected with antioxidative cellular protection. [ABSTRACT FROM AUTHOR]

Graphical abstract Highlights • Management of cancers in advanced stages is a major challenge in daily practice of oncologists. • Anticancer drugs from natural sources such as trabectedin showed promising activities in randomized and controlled clinical trials. • Cancer biomarkers were recently developed for optimizing the use of these therapeutic agents and predicting their response. Abstract Intrinsic or acquired drug resistance, adverse drug reactions and tumor heterogeneity between and within cancer patients limit the efficacy of clinical management of advanced cancers. To overcome these barriers, predictive biomarkers have recently emerged to guide medical oncologists in the selection of cancer patients who will respond to various anticancer treatments and to improve the toxicity to benefit ratio. Notably, targeted therapy has significantly benefited from these advances, but the application of predictive biomarkers have been a bit slower with some drugs derived from natural sources such as trabectedin, cabazitaxel and alvocidib. In this paper, we discuss some recent advances regarding the use of cancer biomarkers to predict efficacy of some selected natural compounds with a focus on human clinical studies. [ABSTRACT FROM AUTHOR]

In recent years, there has been a great deal of attention toward the molecular machinery relevant to age-related progression controlled through the external intervention of polyphenols- an epigenetic-modulating diet. Natural products modulate cellular longevity through histone post-translational modification and can also induce the upregulation of autophagy, thus reducing the level of acetyl coenzyme A (AcCoA). In addition, the effect of caloric restriction (CR) on cancer-related chronic inflammation is of great significance in aging. In line with this, SIRT1 protein levels are expanded in response to calorie restriction mimetics (CRM), in this way acting as autophagy inducers relevant to cancer prevention. [ABSTRACT FROM AUTHOR]

Meat and meat products are a good source of bioactive compounds with positive effect on human health such as vitamins, minerals, peptides or fatty acids. Growing food consumer awareness and intensified global meat producers competition puts pressure on creating new healthier meat products. In order to meet these expectations, producers use supplements with functional properties for animal diet and as direct additives for meat products. In the presented work seven groups of key functional constituents were chosen: (i) fatty acids; (ii) minerals; (iii) vitamins; (iv) plant antioxidants; (v) dietary fibers; (vi) probiotics and (vii) bioactive peptides. Each of them is discussed in term of their impact on human health as well as some quality attributes of the final products. [ABSTRACT FROM AUTHOR]

Background Food choices represent a highly significant approach to combat human obesity. Dietary intake of lipids, especially polyunsaturated and monounsaturated fatty acids, is gaining popularity in the effort to reduce or eliminate the occurrence of obesity. Pecan ( Carya illinoinensis ) nuts are an abundant source of these dietary fatty acids. Moreover, they are a rich source of epigallocatechin-3-gallate (EGCG), a polyphenol with a variety of health-beneficial properties. Scope and approach In this review, we summarize the literature reports examining physiological effects associated with pecan nuts consumption and described effects of their bioactive constituents. Key findings and conclusions The growing body of evidence suggests including pecan nuts into obesity management strategies. The consumption of pecan nuts can mitigate inflammation by reducing the extent of the synthesis of inflammatory mediator molecules. Pecan nuts can also counteract the pro-inflammatory effects of a diet rich in commonly overconsumed saturated fatty acids, characteristic of the Western diet. Additionally, consumption of pecans and other nuts has been linked to reduced risk of physiological parameters associated with cardiovascular disease or metabolic disorders. Diets enriched with tree nuts and peanuts can modulate the blood level of cholesterol, adiposity, and insulin resistance. Almonds and walnuts have been so far the most studied nuts, and studies with them have led to a greater understanding of the protective effects of diverse tree nuts on human physiology. In this review, we summarize the available data indicating that pecan nuts exert similar health-promoting benefits. [ABSTRACT FROM AUTHOR]

The 46th EuroCongress on Drug Synthesis and Analysis (ECDSA-2017) was arranged within the celebration of the 65th Anniversary of the Faculty of Pharmacy at Comenius University in Bratislava, Slovakia from 5-8 September 2017 to get together specialists in medicinal chemistry, organic synthesis, pharmaceutical analysis, screening of bioactive compounds, pharmacology and drug formulations; promote the exchange of scientific results, methods and ideas; and encourage cooperation between researchers from all over the world. The topic of the conference, "Drug Synthesis and Analysis," meant that the symposium welcomed all pharmacists and/or researchers (chemists, analysts, biologists) and students interested in scientific work dealing with investigations of biologically active compounds as potential drugs. The authors of this manuscript were plenary speakers and other participants of the symposium and members of their research teams. The following summary highlights the major points/topics of the meeting. [ABSTRACT FROM AUTHOR]

Despite being a plant by-product, chokeberry pomace is believed to exert some therapeutic effects because it is one of the richest sources of highly bioavailable non-enzymatic antioxidants. The aim of this study was to determine the functionality of bioactive compounds present in the Aronia melanocarpa pomace (chokeberry) based on enzymatic and non-enzymatic parameters related to the active defence of liver and blood against the effects of oxidative stress. The experiment was conducted with 48 lambs of two breeds--Polish Merino and Wrzosówka. Experimental groups were administered the basic feed with the addition of 150 g or 300 g of black chokeberry pomace per each kg of the complete feed. The activities of antioxidative enzymes (superoxide dismutase, glutathione peroxidase), peptides (glutathione, glutathione disulfide), and a lipid peroxidation indicator (malondialdehyde), as well as the capacity of non-enzymatic antioxidants were investigated. The results proved a strong effect of bioactive compounds contained in the black chokeberry pomace on the estimated parameters. The inclusion of chokeberry pomace in feed mixtures brought many benefits linked with the antioxidative protection. Parameters responsible for the oxidative status were significantly modified despite the commonly-held view about a limited possibility of transferring phenolic compounds to the organs. [ABSTRACT FROM AUTHOR]

The Eighth Central European Conference “Chemistry towards Biology” was held in Brno, Czech Republic, on 28 August–1 September 2016 to bring together experts in biology, chemistry and design of bioactive compounds; promote the exchange of scientific results, methods and ideas; and encourage cooperation between researchers from all over the world. The topics of the conference covered “Chemistry towards Biology”, meaning that the event welcomed chemists working on biology-related problems, biologists using chemical methods, and students and other researchers of the respective areas that fall within the common scope of chemistry and biology. The authors of this manuscript are plenary speakers and other participants of the symposium and members of their research teams. The following summary highlights the major points/topics of the meeting. [ABSTRACT FROM AUTHOR]

Chlorogenic acid (CA), also known as 5- O -caffeoylquinic acid, is a dietary phenolic acid produced by various plant species. CA, is the most ubiquitous compound among the phenolic acid group, is also present in tea and green coffee extracts. Its consumption reduces the risk of numerous diseases as validated by preclinical and clinical studies. CA possesses a wide range of pharmacological properties, such as hepatoprotective, antimicrobial, immunomodulatory, antioxidant, antidiabetic, and anticancer activities. It has been extensively used in the food, chemical, medicine, and health care industries. Available reports revealed that CA can exert anticancer activity by inhibiting the cell cycle, triggering apoptosis, and suppressing the proliferation of cancer cells. It upregulates the expression of nuclear factor of activated T cells 2 (NFATC2) and NFATC3 genes involved in immune pathway and downregulates B cell-specific moloney murine leukemia virus integration site 1 protein and SRY-box transcription factor 2 gene expression to facilitate tumor cell destruction. It promotes intracellular DNA impairment and topoisomerase I- and topoisomerase-II-DNA complex formation that perform a key function in apoptosis. In addition, CA has been documented to be an effective natural anticancer drug and was approved by the China Food and Drug Administration. Several previously published reports have provided fragmented summary of various anticancer activities of CA. Therefore, this review aims to deliver up-to-date and comprehensive assessment about the natural sources of CA, its bioavailability, metabolism, and anticancer property with an emphasis on the molecular mechanisms associated with several signaling pathways in tumor cells. [Display omitted] [ABSTRACT FROM AUTHOR]

Medicinal plants have historically proven their value as a source of molecules with therapeutic potential, and nowadays still represent an important pool for the identification of novel drug leads. In the past decades, pharmaceutical industry focused mainly on libraries of synthetic compounds as drug discovery source. They are comparably easy to produce and resupply, and demonstrate good compatibility with established high throughput screening (HTS) platforms. However, at the same time there has been a declining trend in the number of new drugs reaching the market, raising renewed scientific interest in drug discovery from natural sources, despite of its known challenges. In this survey, a brief outline of historical development is provided together with a comprehensive overview of used approaches and recent developments relevant to plant-derived natural product drug discovery. Associated challenges and major strengths of natural product-based drug discovery are critically discussed. A snapshot of the advanced plant-derived natural products that are currently in actively recruiting clinical trials is also presented. Importantly, the transition of a natural compound from a “screening hit” through a “drug lead” to a “marketed drug” is associated with increasingly challenging demands for compound amount, which often cannot be met by re-isolation from the respective plant sources. In this regard, existing alternatives for resupply are also discussed, including different biotechnology approaches and total organic synthesis. While the intrinsic complexity of natural product-based drug discovery necessitates highly integrated interdisciplinary approaches, the reviewed scientific developments, recent technological advances, and research trends clearly indicate that natural products will be among the most important sources of new drugs also in the future. [ABSTRACT FROM AUTHOR]

Abstract: Ethnopharmacological relevance: The root bark of Lycium chinense Miller, Lycii Radicis Cortex, has been used in traditional Chinese medicine (TCM) to treat different inflammation-related symptoms, such as diabetes mellitus. The pro-inflammatory transcription factor nuclear factor kappa B (NF-?B) is a key regulator of inflammation, while the transcription factor peroxisome proliferator-activated receptor gamma (PPAR?) is a key modulator of genes involved in diabetes development. To identify putative active compound(s) from Lycii Radicis Cortex inhibiting NF-?B or activating PPAR?. Material and methods: Using activity-guided fractionation, six extracts with different polarity, isolated fractions, and purified compounds from Lycii Radicis Cortex were tested for NF-?B inhibition and PPAR? activation in vitro. The structure of the purified compounds was elucidated by NMR and MS techniques. Results: The ethyl acetate extract and the methanol extract of Lycii Radicis Cortex suppressed tumor necrosis factor alpha (TNF-?)-induced activation of NF-?B, while the dichloromethane extract activated PPAR?. Nine phenolic amide analogues, including trans-N-(p-coumaroyl)tyramine (1), trans-N-feruloyltyramine (2), trans-N-caffeoyltyramine (3), dihydro-N-caffeoyltyramine (4), three neolignanamides (5–7), and two lignanamide (8, 9), were isolated and their inhibitory potential on NF-?B was determined (1–4 were also contained in water decoction). Two of the nine isolated phenolic amides inhibited TNF-?-induced NF-?B activation. Trans-N-caffeoyltyramine was verified as the key component responsible for the NF-?B inhibition with an IC50 of 18.4?M in our cell-based test system. Activation of PPAR? was attributed to a palmitic-acid enriched fraction which displayed concentration-dependent effect ablated upon co-treatment with the PPAR? antagonist T0070907. Conclusions: Phenolic amides were confirmed as main components from Lycii Radicis Cortex responsible for NF-?B inhibition. Fatty acids were identified as the major plant constituent responsible for the PPAR? activation. Structure-activity relationship analysis suggests that the NF-?B inhibitory activity of trans-N-caffeoyltyramine may be attributed to its Michael acceptor-type structure (?,?-unsaturated carbonyl group). The data of this study contribute to a better understanding of the molecular mechanism of action of Lycii Radicis Cortex extracts in the context of inflammation. [Copyright &y& Elsevier]

Abstract: Background: Peroxisome proliferator-activated receptor gamma (PPARγ) agonists are clinically used to counteract hyperglycemia. However, so far experienced unwanted side effects, such as weight gain, promote the search for new PPARγ activators. Methods: We used a combination of in silico, in vitro, cell-based and in vivo models to identify and validate natural products as promising leads for partial novel PPARγ agonists. Results: The natural product honokiol from the traditional Chinese herbal drug Magnolia bark was in silico predicted to bind into the PPARγ ligand binding pocket as dimer. Honokiol indeed directly bound to purified PPARγ ligand-binding domain (LBD) and acted as partial agonist in a PPARγ-mediated luciferase reporter assay. Honokiol was then directly compared to the clinically used full agonist pioglitazone with regard to stimulation of glucose uptake in adipocytes as well as adipogenic differentiation in 3T3-L1 pre-adipocytes and mouse embryonic fibroblasts. While honokiol stimulated basal glucose uptake to a similar extent as pioglitazone, it did not induce adipogenesis in contrast to pioglitazone. In diabetic KKAy mice oral application of honokiol prevented hyperglycemia and suppressed weight gain. Conclusion: We identified honokiol as a partial non-adipogenic PPARγ agonist in vitro which prevented hyperglycemia and weight gain in vivo. General significance: This observed activity profile suggests honokiol as promising new pharmaceutical lead or dietary supplement to combat metabolic disease, and provides a molecular explanation for the use of Magnolia in traditional medicine. [Copyright &y& Elsevier]

Peroxisome proliferator-activated receptor gamma (PPARγ) is a key regulator of glucose and lipid metabolism and therefore an important pharmacological target to combat metabolic diseases. Since the currently used full PPARγ agonists display serious side effects, identification of novel ligands, particularly partial agonists, is highly relevant. Searching for new active compounds, we investigated extracts of the underground parts of Notopterygium incisum, a medicinal plant used in traditional Chinese medicine, and observed significant PPARγ activation using a PPARγ-driven luciferase reporter model. Activity-guided fractionation of the dichloromethane extract led to the isolation of six polyacetylenes, which displayed properties of selective partial PPARγ agonists in the luciferase reporter model. Since PPARγ activation by this class of compounds has so far not been reported, we have chosen the prototypical polyacetylene falcarindiol for further investigation. The effect of falcarindiol (10 µM) in the luciferase reporter model was blocked upon co-treatment with the PPARγ antagonist T0070907 (1 µM). Falcarindiol bound to the purified human PPARγ receptor with a Ki of 3.07 µM. In silico docking studies suggested a binding mode within the ligand binding site, where hydrogen bonds to Cys285 and Glu295 are predicted to be formed in addition to extensive hydrophobic interactions. Furthermore, falcarindiol further induced 3T3-L1 preadipocyte differentiation and enhanced the insulin-induced glucose uptake in differentiated 3T3-L1 adipocytes confirming effectiveness in cell models with endogenous PPARγ expression. In conclusion, we identified falcarindiol-type polyacetylenes as a novel class of natural partial PPARγ agonists, having potential to be further explored as pharmaceutical leads or dietary supplements. [ABSTRACT FROM AUTHOR]

17β-Hydroxysteroid dehydrogenase type 1 (17β-HSD1) catalyzes the conversion of estrone to the potent estrogen estradiol. 17β- HSD1 is highly expressed in breast and ovary tissues and represents a prognostic marker for the tumor progression and survival of patients with breast cancer and other estrogen-dependent tumors. Therefore, the enzyme is considered a promising drug target against estrogen-dependent cancers. For the development of novel inhibitors, an improved understanding of the structure-function relationships is essential. In the present study, we examined the role of a cysteine residue, Cys10, in the Rossmann-fold NADPH binding region, for 17β-HSD1 function and tested the sensitivity towards sulfhydryl modifying chemicals. 3D structure modeling revealed important interactions of Cys10 with residues involved in the stabilization of amino acids of the NADPH binding pocket. Analysis of enzyme activity revealed that 17β-HSD1was irreversibly inhibited by the sulfhydryl modifying agents N-ethylmaleimide (NEM) and dithiocarbamates. Preincubation with increasing concentrations of NADPH protected 17β-HSD1 from inhibition by these chemicals. Cys10 Ser mutant 17β-HSD1 was partially protected from inhibition by NEM and dithiocarbamates, emphasizing the importance of Cys10 in the cofactor binding region. Substitution of Cys10 with serine resulted in a decreased protein half-life, without significantly altering kinetic properties. Despite the fact that Cys10 on 17β-HSD1 seems to have limited potential as a target for new enzyme inhibitors, the present study provides new insight into the structure-function relationships of this enzyme. [ABSTRACT FROM AUTHOR]

Abstract: Endothelial nitric oxide synthase (eNOS) mediates important vaso-protective and immunomodulatory effects. Aim of this study was to examine whether lignan derivatives isolated from the roots of the anti-inflammatory medicinal plant Krameria lappacea influence eNOS activity and endothelial nitric oxide (NO) release. The study was performed using cultured human umbilical vein endothelial cells (HUVECs) and HUVEC-derived EA.hy926 cells. Among the eleven isolated compounds only 2-(2,4-dihydroxyphenyl)-5-(E)-propenylbenzofuran (DPPB) was able to increase eNOS enzyme activity. DPPB (1–10μM) treatment for 24h induced a significant and dose-dependent increase in eNOS activity as determined by the [14C]l-arginine/[14C]l-citrulline conversion assay. Immunoblotting studies further revealed a time-dependent DPPB-induced increase in eNOS-Ser1177 and decrease in eNOS-Thr495 phosphorylation, as well as increased AMPK phosphorylation at Thr172, whereas Akt phosphorylation at Ser473 was not affected. Si-RNA-mediated knockdown of AMPK and inhibition of CaMKKβ by STO 609, as well as intracellular Ca2+ chelation by Bapta AM abolished the stimulating effect of DPPB on eNOS-Ser1177 and AMPK-Thr172 phosphorylation. Furthermore, we could show that DPPB increases intracellular Ca2+ concentrations assessed with the fluorescent dye Fluo-3-AM. DPPB enhances eNOS activity and endothelial NO release by raising intracellular Ca2+ levels and increases signaling through a CaMKKβ–AMPK dependent pathway. [Copyright &y& Elsevier]