rss_2.0Acta Pharmaceutica FeedSciendo RSS Feed for Acta Pharmaceutica Pharmaceutica 's Cover and development of novel 1,2,3-triazole chalcone derivatives as potential anti-osteosarcoma agents inhibition of PI3K/Akt/mTOR signalling pathway<abstract> <title style='display:none'>Abstract</title> <p>Osteosarcoma (OS) is an uncommon tumour that mainly affects bone in children and adolescents. The current treatment options of OS are of limited significance due to their immense side effects. In the present manuscript, we have developed a novel series of 1,2,3-triazole chalcone derivatives as potential agents against OS. The compounds were synthesized and evaluated for their PI3K and mTOR inhibitory activity using luminescent kinase assay, and Lance ultra assay, resp. The entire set of compounds showed significant to moderate inhibition of both kinases in the nanomolar range. The three most active compounds: <bold>4e</bold> (<italic>N</italic>-(4-(3-(1-(4-bromophenyl)-1<italic>H</italic>-1,2,3-triazol-4-yl)acryloyl)phenyl)-4-nitrobenzamide), <bold>4f</bold> (<italic>N</italic>-(4-(3-(1-(4-bromophenyl)-1<italic>H</italic>-1,2,3-triazol-4-yl)acryloyl)phenyl)-4-chlorobenzamide) and <bold>4g</bold> (4-bromo-<italic>N</italic>-(4-(3-(1-(4-bromophenyl)-1<italic>H-</italic>1,2,3-triazol-4-yl)acryloyl)phenyl)benzamide), were evaluated for anticancer activity against human OS cancer cell line (MG-63), liver cancer cell line (HepG2), lung cancer cell line (A549) and cervical cancer (HeLa), using MTT assay. Among the tested series, compound <bold>4e</bold> showed a better inhibitory profile than gedatolisib against PI3K and was approximately comparable to that of gedatolisib against mTOR. The most significant inhibitory activity was observed for compound <bold>4e</bold> against all cell lines (MG-63, HepG2, A549 and HeLa), still somewhat lower to comparable to that of gedatolisib, but with the highest potency against MG-63 cells. Compound <bold>4e</bold> was further tested for anti-cancer activity against other OS cells and showed to be equipo-tent to gedatolisib against U2OS and Saos-2 cells. Moreover, it was also found non-toxic to normal cells (BEAS-2B and MCF 10A). The effect of compound <bold>4e</bold> was further determined on apoptosis of Saos-2 cells by Annexin-PI assay, where it significantly amplified the percentage of apoptotic cells. Novel 1,2,3-triazole chalcone derivatives are potential agents against OS.</p> </abstract>ARTICLE2022-04-13T00:00:00.000+00:00Polyphenol content and antioxidant activity of phytoestrogen containing food and dietary supplements: DPPH free radical scavenging activity by HPLC<abstract> <title style='display:none'>Abstract</title> <p>Soy, red clover, chaste tree, hop and flax have all been found to contain a wide range of phytoestrogenic compounds, and a large number of dietary supplements contain their extracts as principal ingredients. This study is aimed to evaluate the total polyphenolic content and antioxidant activity of phytoestrogen-containing food and formulated dietary supplements. The HPLC-DPPH method was applied for DPPH free radical scavenging activity testing of various phytoestrogen-containing samples. Polyphenol content and antioxidant activity in dietary supplements were higher than in functional food samples; multiple-botanical-source preparations showed higher polyphenol content and antioxidant activity than the mono-botanical counterparts. Furthermore, the correlation between polyphenol content and anti-oxidant activity was strongly statistically significant, so it might be concluded that antioxidant activity is proportional to the content of these secondary metabolites. The most striking batch-to-batch deviations were represented by one chaste berry-based product (RSD 41.3 %) and one red clover derived product (RSD 57.9 %). The results of this study contribute to a better understanding of the phenolic profile and antioxidant properties of phytoestrogen containing food and dietary supplements.</p> </abstract>ARTICLE2022-04-13T00:00:00.000+00:00Potential anti-ageing effects of probiotic-derived conditioned media on human skin cells<abstract> <title style='display:none'>Abstract</title> <p>In this study, the protective functions of bacteria-free conditioned media from <italic>Bifidobacterium</italic> and <italic>Lactobacillus</italic> species against ultraviolet radiation-induced skin ageing and associated cellular damage were investigated. The effects of ultraviolet radiation-induced reactive oxygen species production were suppressed by all conditioned media; particularly, the loss of cell viability and downregulation of collagen gene expression were significantly reversed by the conditioned media from <italic>B. longum</italic> and <italic>B. lactis</italic>. Further exa mination of potential anti-pigmentation effects revealed that the <italic>B. lactis</italic>-derived conditioned media significantly inhibited tyrosinase activity and alpha-melanocyte-stimulating hormone-induced melanin production in human epidermal melanocytes. Further, the conditioned media suppressed the phosphorylation of extracellular signal- related kinase, which functions as an upstream regulator of melanogenesis. Therefore, <italic>B. lactis</italic>-derived conditioned media can potentially protect against cellular damage involved in skin-ageing processes.</p> </abstract>ARTICLE2022-04-13T00:00:00.000+00:00Fingolimod exerts anticancer activity against hepatocellular carcinoma cell lines YAP/TAZ suppression<abstract> <title style='display:none'>Abstract</title> <p>Hepatocellular carcinoma (HCC) remains a notably global health challenge with high mortality rates and poor prognosis. The deregulation of the Hippo signalling pathway, especially the overexpression and activation of downstream effector Yes-associated protein (YAP), has been demonstrated to result in the rapid malignant evolution of HCC. In this context, multiple efforts have been dedicated to targeting YAP for HCC therapy, but effective YAP inhibitors are still lacking. In this study, through a YAP-TEAD (8×GTIIC) luciferase reporter assay, we identified fingolimod, an immunomodulatory drug approved for the treatment of multiple sclerosis, as a novel YAP inhibitor. Fingolimod suppressed the proliferation of HCC cell lines by downregulating the protein levels as well as the trans-activating function of YAP. Overall, our current study not only identifies fingolimod as a novel YAP-targeting in hibitor, but also indicates that this clinically-approved drug could be utilized as a potential and feasible therapeutic drug for HCC.</p> </abstract>ARTICLE2022-04-13T00:00:00.000+00:00Metabolomics reveal the mechanism for anti-renal fibrosis effects of an -butanol extract from<abstract> <title style='display:none'>Abstract</title> <p>To reveal the mechanism of anti-renal fibrosis effects of an <italic>n</italic>-butanol extract from <italic>Amygdalus mongolica,</italic> renal fibrosis was induced with unilateral ureteral obstruction (UUO) and then treated with an <italic>n</italic>-butanol extract (BUT) from <italic>Amygdalus mongolica</italic> (Rosaceae). Sixty male Sprague-Dawley rats were randomly divided into the sham-operated, renal fibrosis (RF) model, benazepril hydrochloride-treated model (1.5 mg kg<sup>−1</sup>) and BUT-treated (1.75, 1.5 and 1.25 g kg<sup>−1</sup>) groups and the respective drugs were administered intragastrically for 21 days. Related biochemical indices in rat serum were determined and histopathological morphology observed. Serum metabolomics was assessed with HPLC-Q-TOF-MS. The BUT reduced levels of blood urea nitrogen, serum creatinine and albumin and lowered the content of malondialdehyde and hydroxyproline in tissues. The activity of superoxide dismutase in tissues was increased and an improvement in the severity of RF was observed. Sixteen possible biomarkers were identified by metabolomic analysis and six key metabolic pathways, including the TCA cycle and tyrosine metabolism, were analyzed. After treatment with the extract, 8, 12 and 9 possible biomarkers could be detected in the high-, medium- and low-dose groups, respectively. Key biomarkers of RF, identified using metabolomics, were most affected by the medium dose. <italic>A. mongolica</italic> BUT extract displays a protective effect on RF in rats and should be investigated as a candidate drug for the treatment of the disease.</p> </abstract>ARTICLE2022-04-13T00:00:00.000+00:00Evaluation and molecular modelling of bis-Schiff base derivatives as potential leads for management of diabetes mellitus<abstract> <title style='display:none'>Abstract</title> <p>Developing a medication to cure and manage diabetes mellitus complications is of interest in medicinal chemistry. Toward this end, six bis-biphenyl-salicylaldehyde Schiff base derivatives have been evaluated for their α-glucosidase inhibition, antiglycation and anti-inflammation potentials. Four compounds (compounds <bold>2</bold>–<bold>5</bold>) showed an excellent α-glucosidase inhibitory effect superior to that produced by acarbose. Additionally, the docking study revealed that these compounds are anchored within the binding pocket of α-glucosidase <italic>via</italic> hydrogen bonding, π-stacking and hydrophobic interactions, comparable to a high number of hydrogen bonding involved in anchoring acarbose. Interestingly, all tested compounds showed varying degrees of antiglycation activity with superior activity for two of them (compound <bold>1</bold> and compound <bold>6</bold>) compared to the standard rutin. Moreover, the results indicated an outstanding anti-inflammatory activity for two compounds (compounds <bold>1</bold> and <bold>6</bold>) compared to ibuprofen.</p> </abstract>ARTICLE2022-04-13T00:00:00.000+00:00Dasatinib enhances curcumin-induced cytotoxicity, apoptosis and protective autophagy in human schwannoma cells HEI-193: The role of Akt/mTOR/p70S6K signalling pathway<abstract> <title style='display:none'>Abstract</title> <p>The present study was carried out in human schwannoma cells (HEI-193) to determine the combined anti-cancer effect of curcumin and dasatinib. Cells were treated with curcumin only, dasatinib only, or the combination of curcumin and dasatinib for 24 hours. Cellular toxicity, cell proliferation, and cell death were determined by LDH, MTT, and trypan blue dye assays, respectively. ELISA based kit was used to determine apoptotic cell death. Western blotting was used to determine the expression of apoptotic and autophagy-associated protein markers. Similarly, expression levels of Akt/mTOR/p70S6K signalling pathway-related proteins were studied using Western blotting. Cell death and apoptosis were significantly higher in HEI-193 cells treated with curcumin and dasatinib combination compared to individual controls. The combination of curcumin and dasatinib significantly enhances autophagy markers compared to individual controls. Furthermore, the combination of curcumin and dasatinib significantly activates Akt/mTOR/p70S6K signalling pathway compared to individual controls. In conclusion, our results suggest that the combination of curcumin and dasatinib significantly enhances cytotoxicity, apoptosis, and protective autophagy in HEI-193 cells through Akt/mTOR/p70S6K signalling pathway.</p> </abstract>ARTICLE2022-04-13T00:00:00.000+00:00AXL inhibitors selected by molecular docking: Option for reducing SARS-CoV-2 entry into cells<abstract> <title style='display:none'>Abstract</title> <p>The COVID-19 pandemic is ongoing and the benefit from vaccines is still insufficient since COVID-19 continues to be dia g-nosed in vaccinated individuals. It is, therefore, necessary to propose specific pharmacological treatments against COVID-19. A new therapeutic target on the human cellular membrane is AXL (<italic>anexelekto</italic>), proposed as an independent pathway by which interaction with the S protein of SARS-CoV-2 allows the virus to enter the cell, without the participation of ACE2. AXL serves as another gate through which SARS-CoV-2 can enter cells. Therefore, any stage of COVID-19 could be ameliorated by hindering the interaction between AXL and SARS-CoV-2. This study proposes ten compounds (<bold>1–10</bold>), selected by mole-cu lar docking and using a library of nearly 500,000 compounds, to develop a new drug that will decrease the interaction of AXL with the S protein of SARS-CoV-2. These compounds have a specific potential site of interaction with AXL, between Glu59, His61, Glu70 and Ser74 amino acids. This site is necessary for the interaction of AXL with the S protein. With this, we propose to develop a new adjuvant treatment against COVID-19.</p> </abstract>ARTICLE2022-04-13T00:00:00.000+00:00Bivalirudin exerts antiviral activity against respiratory syncytial virus-induced lung infections in neonatal mice<abstract> <title style='display:none'>Abstract</title> <p>Respiratory syncytial virus (RSV) is the most common cause of small airways inflammation in the lungs (bronchiolitis) in neonates and immunocompromised adults. The deregulation of cellular and plasma components leads to increased morbidity and mortality. The activation of the clotting cascade plays a key role in the progression of disease severity during viral infection. The current investigation studied the effect of bivalirudin (BR) on the progression and cellular effects of RSV-induced infection in the neonatal mice model. Mice (5–7 days old) were inoculated intranasally with RSV with or without BR administration (2 mg kg<sup>−1</sup> day<sup>−1</sup>, <italic>i.v.</italic>) for 2 weeks. Tissue histopathology, inflammatory signalling genes such as TLR, and cytokines were analyzed. The results showed pneumocytes exhibiting nuclear pyknosis, cellular infiltration in lung tissue and increased lung titers in RSV-infected mice compared to the control. Furthermore, RSV-infected mice demonstrated altered clotting parameters such as D-dimer, soluble thrombomodulin, and increased inflammatory cytokines IL-5, 6, IFN-γ, IL-13, and CXCL1. Additionally, the mRNA expression analysis displayed increased levels of IL-33, TLR3, and TLR7 genes in RSV-infected lung tissue. Further, to delineate the role of micro RNAs, the qRT-PCR analysis was done, and the results displayed an increase in miR-136, miR-30b, and let-7i. At the same time, the down-regulated expression of miR-221 in RSV-infected mice compared to the control. BR treatment reduced the cellular infiltration with reduced inflammatory cytokines and normalized clotting indices. Thus, the study shows that RSV infection induces specific changes in lung tissue and the clotting related signalling mechanism. Additionally, BR treatment significantly reduces bronchiolitis and prevents the severity of the infections suggesting that BR can possibly be used to reduce the viral-mediated infections in neonates.</p> </abstract>ARTICLE2022-04-13T00:00:00.000+00:00The effectiveness of dexamethasone as a combination therapy for COVID-19<abstract> <title style='display:none'>Abstract</title> <p>Coronavirus disease 2019 (COVID-19) was reported as a global pandemic in March 2020 after invading many countries and leaving behind tens of thousands of infected patients in a brief time span. Approval of a few vaccines has been obtained and their efficacy of varying degrees established. Still, there is no effective pharmaceutical agent for the treatment of COVID-19 though several drugs are undergoing clinical trials. Recent studies have shown that dexamethasone, a corticosteroid, can reduce the rate of COVID-19-related mortality in the intensive care unit by 35 % for patients who are on mechanical ventilation. Although variable efficacy of other combination therapies has been reported for treating COVID-19 associated with acute respiratory distress syndrome (ARDS), dexamethasone is an extensively used drug in many treatment regimens against COVID-19. The current review aims to explore the role of dexamethasone as an efficient combination treatment for COVID-19.</p> </abstract>ARTICLE2022-04-13T00:00:00.000+00:00Antithrombotic activity of flavonoids and polyphenols rich plant species<abstract><title style='display:none'>Abstract</title><p>Cardiovascular diseases represent one of the most notable health problems of the modern civilization. Stroke and heart attack often lead to lethal outcome; essential problem underneath being thrombus formation. Prophylactic approaches include acetylsalicylic acid and clopidogrel therapy on the level of primary hemostasis, <italic>i.e</italic>., primary clot formation. In the last five years, in the USA, health care expenses related to cardiovascular diseases have increased 50 %, to over 350 billion dollars. Thus, application of plant species and medicinal plants rich in polyphenols in prevention of thrombus formation are of interest. This is supported by the fact that the number of publications on antiaggregatory effect of polyphenols has doubled in the last decade. In this review we focus on antiaggregatory effect of most abundant polyphenols – flavonoids, the effect of plant extracts rich in polyphenols (propolis, species <italic>Salvia</italic> sp., <italic>Calamintha nepeta</italic> L., <italic>Lavandula angustifolia</italic> Mill., <italic>Melissa officinalis</italic> L, <italic>Mentha x piperita</italic> L., <italic>Ocimum basilicum</italic> L., <italic>Origanum vulgare</italic> L., <italic>Rosmarinus officinalis</italic> L.) on platelet aggregation, association of chemical composition and antioxidant properties with the observed biological effect, and possible clinical significance of the published results.</p></abstract>ARTICLE2019-10-21T00:00:00.000+00:00Evaluation of stability and wound healing potential of melatonin loaded (lipid enriched) chitosan based microspheres<abstract><title style='display:none'>Abstract</title><p>The aim of this study was to evaluate long-term stability and assess the wound healing potential of the innovative melatonin-loaded lipid-enriched hybrid system compared to conventional melatonin-loaded chitosan microspheres. The hybrid system contained nanostructured lipid carrier incorporated in the chitosan matrix, in order to modify melatonin release and alter physicochemical characteristics of the delivery system. Stability testing was performed during a six-month period under two conditions: refrigerated (5 ± 3 °C) and at room temperature (25 ± 2 °C/60 ± 5 % RH). Samples stored at both conditions were analyzed in terms of particle size, zeta potential, moisture content and thermal properties. At the end of testing, drug content was determined in all samples. Dressings wound healing potential was assessed by <italic>in vitro</italic> scratch test using human skin fibroblast cell line. Although both systems showed good stability characteristics, the addition of lipids in the system has improved its wound healing potential.</p></abstract>ARTICLE2019-10-21T00:00:00.000+00:00Phenolic compounds of and their antimycobacterial effects<abstract><title style='display:none'>Abstract</title><p>Little is known about the pharmacological activities of <italic>Iris adriatica</italic> (Iridaceae), a plant endemic to Dalmatia (Croatia). We therefore performed a bioassay-guided fractionation including high-performance counter current chromatography (HPCCC) and antibacterial tests using <italic>Mycobacterium smegmatis</italic> mc<sup>2</sup> 155. One obtained fraction was found to be antimycobacterially active with a MIC of 64 mg L<sup>−1</sup>. Furthermore, fractions were tested for resistance modulatory effects using ethidium bromide as substrate. We were able to identify the pure isoflavonic compounds irigenin and irilone and a fraction containing mainly benzophenone 2,4,6-trihydroxy-4-methoxy-benzophenone, responsible for the resistance-modulatory activity of this plant.</p></abstract>ARTICLE2019-10-21T00:00:00.000+00:00Application of medicinal plants in several dermatovenerological entities<abstract><title style='display:none'>Abstract</title><p>Treatment of skin conditions with medicinal plants has been an ongoing human activity lasting over thousands of years. The use of specific plant species developed regionally, based on local flora. Commonly used medicinal plants for dermatological complaints are: <italic>Phlebodium aureum</italic> (L.) J. Sm., <italic>Ginkgo biloba</italic> L., <italic>Rosmarinus officinalis</italic> L., <italic>Panax ginseng</italic> C.A.Mey., <italic>Allium cepa</italic> L., <italic>Aloe vera</italic> (L.) Burm.f., <italic>Capsicum annuum</italic> L., <italic>Berbe ris aquifolium</italic> Pursh, <italic>Camellia sinensis</italic> (L.) Kuntze, and <italic>Podophyllum peltatum</italic> L.</p><p>The demand for complementary therapeutics is an emerging trend due to the awareness of potential side effects that synthetic drugs might cause. More scientific evidence and better documentation are needed before advising dermatologic patients on herbal medicinal treatment. Standardised extracts and formulations with proven clinical efficacy should be developed for this cause. Here provided review entails the use of herbal medicinal products in the treatment of frequent chronic skin diseases, such as vitiligo, alopecia, psoriasis and genital warts.</p></abstract>ARTICLE2019-10-21T00:00:00.000+00:00Actualities in the phytochemical research on selected terpenes<abstract><title style='display:none'>Abstract</title><p>A short review of our recent research on the essential oil phytochemical composition of <italic>Petasites albus</italic> (L.) Gaertn. and <italic>Petasites hybridus</italic> (L.) G. Gaertn., B. Mey. &amp; Scherb. (Asteraceae) as well as on the oils of <italic>Globularia cordifolia</italic> L., <italic>Globularia meridionalis</italic> (Podp.) O. Schwarz and <italic>Globularia punctata</italic> Lapeyr. (Plantaginaceae) is presented. All essential oils contained a variety of oxygenated sesquiterpenes among their major constituents, including a bakkane type sesquiterpene fukinanolid (bakkenolide A). The paper is focused on: <italic>i</italic>) a short overview of the abundance of major terpenes in the essential oils of <italic>Petasites</italic> and <italic>Globularia</italic> species from Croatia; <italic>ii</italic>) possible biosynthetic pathways of major identified sesquiterpenes; and <italic>iii</italic>) biological activities (literature data) of major sesquiterpenes from <italic>Petasites</italic> and <italic>Globularia</italic> species.</p></abstract>ARTICLE2019-10-21T00:00:00.000+00:00Screening of flavonoid aglycons’ metabolism mediated by the human liver cytochromes P450<abstract><title style='display:none'>Abstract</title><p>Biological effects of flavonoids have been extensively studied in the last 80 years. As flavonoids represent a rather large group of compounds, data on metabolic biotransformations of these compounds is relatively limited to those well studied. The objective of this study was to screen the metabolism of 30 selected flavonoid aglycons mediated by the most relevant metabolic enzymes, human liver cytochromes P450. For this purpose, <italic>in vitro</italic> experiments with human liver microsomes and recombinant enzymes were conducted. To evaluate flavonoid’s metabolism and structure of the products, high-performance liquid chromatography coupled with high-resolution mass spectrometry was used. Out of 30 flavonoids, 15 were susceptible to oxidative metabolism mediated by cytochromes P450. Dominant reactions were aromatic hydroxylation and <italic>O</italic>-demethylation, or a combination of these reactions. The dominant enzyme responsible for the observed metabolic reactions is CYP1A2, whereas other human liver cytochromes P450, namely, CYP2C19, CYP2D6, CYP2E1 and CYP3A4, contribute to flavonoid metabolism to a lesser degree. These results, to some extent, contribute to the understanding of the metabolism of constituents found in antioxidant dietary supplements and their possible interactions with other xenobiotics, <italic>i.e</italic>., medicinal products.</p></abstract>ARTICLE2019-10-21T00:00:00.000+00:00Anticancer effects of olive oil polyphenols and their combinations with anticancer drugs<abstract><title style='display:none'>Abstract</title><p>Cancer presents one of the leading causes of death in the world. Current treatment includes the administration of one or more anticancer drugs, commonly known as chemotherapy. The biggest issue concerning the chemotherapeutics is their toxicity on normal cells and persisting side effects. One approach to the issue is chemoprevention and the other one is the discovery of more effective drugs or drug combinations, including combinations with polyphenols. Olive oil polyphenols (OOPs), especially hydroxytyrosol (HTyr), tyrosol (Tyr) and their derivatives oleuropein (Ole), oleacein and oleocanthal (Oc) express anticancer activity on different cancer models. Recent studies report that phenolic extract of virgin olive oil may be more effective than the individual phenolic compounds. Also, there is a growing body of evidence about the combined treatment of OOPs with various anticancer drugs, such as cisplatin, tamoxifen, doxorubicin and others. These novel approaches may present an advanced strategy in the prevention and treatment of cancer.</p></abstract>ARTICLE2019-10-21T00:00:00.000+00:00Efficacy and safety of local lysozyme treatment in patients with oral mucositis after chemotherapy and radiotherapy<abstract><title style='display:none'>Abstract</title><p>This observational clinical study was composed of two substudies: a non-comparative one (<italic>n</italic> = 166), testing only lysozyme-based compounds (LBCs), and a comparative substudy (<italic>n</italic> = 275), testing both LBCs and bicarbonate-based local compounds (BBCs) on the healing of oral mucositis during radio- or chemotherapy. The density of ulcerations has decreased significantly after the treatment with lysozyme in both substudies. The density of ulcerations in the radiotherapy group was lower in patients treated with LBCs compared to patients treated with BBCs (<italic>p</italic> &lt; 0.001). In the chemotherapy group, reduction of ulceration density was similar with both LBCs and BBCs. The LBCs reduced pain intensity during the intake of solid food and speech more than BBCs in both patient cohorts (<italic>p</italic> &lt; 0.05). In the radiotherapy cohort, pain intensity when consuming liquid foods was reduced more with LBCs than with BBCs (<italic>p</italic> &lt; 0.05). No adverse events were recorded. This study demonstrates the advantages of treating oral mucositis during radiotherapy or chemo-therapy with LBCs.</p></abstract>ARTICLE2019-10-21T00:00:00.000+00:00Evaluation of phenylethylamine type entactogens and their metabolites relevant to ecotoxicology – a QSAR study<abstract><title style='display:none'>Abstract</title><p>The impact of the selected entactogens and their <italic>o</italic>-quinone metabolites on the environment was explored in QSAR studies by the use of predicted molecular descriptors, ADMET properties and environmental toxicity parameters, <italic>i.e.</italic>, acute toxicity in <italic>Tetrahymena pyriformis</italic> (TOX_ATTP) expressed as <italic>Th_pyr_pIGC</italic><sub>50</sub>/mmol L<sup>−1</sup>, acute toxicity in <italic>Pimephales promelas</italic>, the fathead minnow (TOX_FHM) expressed as <italic>Minnow LC</italic><sub>50</sub>/mg L<sup>−1</sup>, the acute toxicity in <italic>Daphnia magna</italic> (TOX_DM) expressed as <italic>Daphnia LC</italic><sub>50</sub>/mg L<sup>−1</sup> and bioconcentration factor (BCF).</p><p>The formation of corresponding <italic>o</italic>-quinones <italic>via</italic> benzo-dioxo-lone ring, <italic>O</italic>-demethylenation was predicted as the main metabolic pathway for all entactogens except for 1-(2,2-difluorobenzo[<italic>d</italic>][1,3]dioxol-5-yl)propan-2-amine (DiFMDA). The least favourable ADMET profile was revealed for <italic>N</italic>-(1-(benzo[<italic>d</italic>][1,3]dioxol-5-yl)propan-2-yl)-<italic>O-</italic>methylhydroxylamine (MDMEO).</p><p>QSAR studies revealed significant linear correlations between <italic>MlogP</italic> of entactogens and <italic>MlogP</italic> of <italic>o</italic>-quinone metabolites (<italic>R</italic> = 0.99), and <italic>Th_pyr_pIGC</italic><sub>50</sub>/mmol L<sup>−1</sup> (<italic>R</italic> = 0.94), also their <italic>MlogP</italic>s with <italic>Minnow_LC</italic><sub>50</sub>/mg L<sup>−1</sup> (<italic>R</italic> = 0.80 and <italic>R</italic> = 0.78), BCF (<italic>R</italic> = 0.86 and <italic>R</italic> = 0.82) and percentage of <italic>o</italic>-quinones’ yields (<italic>R</italic> = 0.73 and <italic>R</italic> = 0.80). Entactogens were predicted as non-biodegradable molecules, whereas the majority of their <italic>o</italic>-quinones were biodegradable.</p></abstract>ARTICLE2019-10-21T00:00:00.000+00:00Influence of flavonoids’ lipophilicity on platelet aggregation<abstract><title style='display:none'>Abstract</title><p>Flavonoids are natural polyphenolic compounds present in a wide spectrum of plants that have a beneficial effect on human health. In the context of cardiovascular diseases related to plaque and thrombus formation, flavonoids exhibit an anti-aggregatory effect. Previously, it has been reported that all tested flavonoids exhibit an antiaggregatory effect on platelet aggregation when measured by impedance aggregometry on whole blood, in the test of aggregation induced by adenosine diphosphate (ADP). As not all flavonoids have the same targets within signaling pathways, an assumption of a common non-specific mechanism related to lipophilicity is to be considered. To test this hypothesis, reverse-phase thin layer chromatography was used to assess the lipophilicity of flavonoids; impedance aggregometry was used for testing of platelet aggregation and flow cytometry to monitor the influence of flavonoids on platelet activation. Lipophilicity analysis showed a highly negative correlation of log<italic>P</italic> and <italic>MINaAC</italic> for groups of flavones and flavanones. As determined by flow cytometry, the exposition of receptors necessary for the promotion of platelet activation and primary clot formation was diminished, <italic>i.e</italic>., lowered expression of the activated form of integrin αIIbβ3 was observed in the presence of flavanone. Platelet membrane stabilization by flavonoids as a mechanism of antiaggregatory effect has been supported by impedance aggregometry experiments when specific inhibitors of platelet aggregation signaling pathways (U73122, indomethacin, verapamil) were used in the presence of a weak (ADP) and a strong (TRAP-6) agonist of aggregation. While individual flavonoids can have specific targets within aggregation signaling pathways, all flavonoids share a common non-specific mechanism of platelet aggregation inhibition related to their lipophilicity and membrane stabilization that, to some extent, contributes to their antiaggregatory effect.</p></abstract>ARTICLE2019-10-21T00:00:00.000+00:00en-us-1