Inhibition of human platelet aggregation in vitro by standardized extract of Wendtia calycina

Wendtia calycina (Griseb.) Griseb., Vivianiaceae, is a Paraguayan herbaceous plant commonly known as burrito. Our previous study indicated that burrito leaves are a very good source of phenylpropanoid glycosides, principally verbascoside. From W. calycina leaves, a standardized, water-soluble extract rich in phenylpropanoid glycosides (WSE) has been developed on an industrial scale to be used as a food supplement, cosmetic, phytomedicine, and ingredient of different formulations. In this study, we investigated the effect of the WSE on human platelet aggregation in vitro induced by adenosine diphosphate (ADP), epinephrine (EPN), collagen (COL) or arachidonic acid (AA). WSE, concentration-dependently, inhibited ADP and EP-induced human platelet aggregation (IC50 were 0.82±0.15 mg/mL and 0.41±0.02 mg/mL, respectively). It did not inhibit collagen-induced platelet aggregation, thus suggesting a selectivity for the ADP-induced platelet activation pathways

Structural basis of the pleiotropic and specific phenotypic consequences of missense mutations in the multifunctional NAD(P)H:quinone oxidoreductase 1 and their pharmacological rescue

JLP-G and ALP were supported by the ERDF/Spanish Ministry of Science, Innovation and Universities-State Research Agency (Grant RTI2018-096246-B-I00) and Consejeria de Economia, Conocimiento, Empresas y Universidad, Junta de Andalucia (Grants P11-CTS-7187 and P18-RT-2413) . NM-T was supported by Aula FUNCANIS-UGR. ES was supported by the ERDF/Spanish Ministry of Science, Innovation and Universities-State Research Agency (Grant SAF2015-69796) . Access to an EU_FT-ICR_MS network installation was funded by the EU Horizon 2020 grant 731077. EA-C and MM were supported by the Spanish Ministry of Science and Innovation-State Research Agency (Grant PID2019-103901 GB-I00) and Gobierno de Aragon-FEDER (Grant E35_20R) . Support of the BioCeV center (CZ.1.05/1.1.00/02.0109) and the CMS/CIISB facility (MEYS CZ-LM2018127) is also gratefully acknowledged. ANN was supported by grants BT/PR26099/BID/7/811/2017 from Department of Biotechnology (DBT, India) and MTR/2019/000392 from Science, Engineering and Research Board (SERB, India) .The multifunctional nature of human flavoproteins is critically linked to their ability to populate multiple conformational states. Ligand binding, post-translational modifications and disease-associated mutations can reshape this functional landscape, although the structure-function relationships of these effects are not well understood. Herein, we characterized the structural and functional consequences of two mutations (the cancer associated P187S and the phosphomimetic S82D) on different ligation states which are relevant to flavin binding, intracellular stability and catalysis of the disease-associated NQO1 flavoprotein. We found that these mutations affected the stability locally and their effects propagated differently through the protein structure depending both on the nature of the mutation and the ligand bound, showing directional preference from the mutated site and leading to specific phenotypic manifestations in different functional traits (FAD binding, catalysis and inhibition, intracellular stability and pharmacological response to ligands). Our study thus supports that pleitropic effects of disease-causing mutations and phosphorylation events on human flavoproteins may be caused by longrange structural propagation of stability effects to different functional sites that depend on the ligation-state and site-specific perturbations. Our approach can be of general application to investigate these pleiotropic effects at the flavoproteome scale in the absence of high-resolution structural models.ERDF/Spanish Ministry of Science, Innovation and Universities-State Research Agency RTI2018-096246-B-I00- SAF2015-69796Junta de Andalucia P11-CTS-7187- P18-RT-2413Aula FUNCANIS-UGREuropean Commission 731077Spanish Ministry of Science and Innovation-State Research Agency PID2019-103901 GB-I00Gobierno de Aragon-FEDER E35_20RBioCeV center CZ.1.05/1.1.00/02.0109CMS/CIISB facility MEYS CZ-LM2018127Department of Biotechnology (DBT) India BT/PR26099/BID/7/811/2017Science, Engineering and Research Board (SERB, India) MTR/2019/00039

Portal vein thrombosis in a patient with severe hemophilia B: A challenging balanced management

Key Clinical Message The increased life expectancy in patients with hemophilia (PwH) over the last years has raised the incidence of comorbidities, including thromboembolic events. Thromboembolic events are rare in PwH and most of them occur in the presence of exogenous risk factors. There is still scarce scientific evidence on the optimal antithrombotic treatment and management approach in this population. Abstract In the hemophilic population thromboembolic events are rare. Most of them are often multifactorial and occur in the presence of both exogenous (orthopedic surgery, intensive replacement therapy, use of central venous catheters…) and endogenous (cardiovascular diseases) risk factors. We describe the case of a 43‐year‐old patient with severe hemophilia B (sHB) receiving prophylaxis with eftrenonacog alfa (rFIXFc) and antithrombotic treatment due to portal vein thrombosis. The patient was treated with extended half‐ life factor IX (EHL‐FIX) prophylaxis maintaining higher trough levels to avoid new bleeding episodes associated to the underlying disease and the use of antithrombotic therapy with low molecular weight heparin. EHL‐FIX concentrates allow prolonged intervals between intravenous infusions and higher hemostatic protection thanks to increased factor trough levels. This current case report provides clinical evidence in antithrombotic management in a patient with severe hemophilia B

HPLC-PDA-MS and NMR characterization of a hydroalcoholic extract of Citrus aurantium L. var. amara peel with antiedematogenic activity

The phytochemical profile of a hydroalcoholic extract of Citrus aurantium var. amara L. peel, used as herbal medicine, was characterized by HPLC-PDA-MS. Two di-C-glycosyl flavones (vincenin II and diosmetin 6,8-di-C-glucoside), a series of flavones (luteolin 7-O-neohesperidoside, rhoifolin, and neodiosmin), and flavanone (neoeriocitrin, naringin, and neohesperidin) 7-O-neohesperidosides and two methoxyflavones (nobiletin and tangeretin), commonly present in Citrus, were identified. Furthermore, brutieridin and melitidin, two 3-hydroxy-3-methylglutaryl flavanone glycosides, were also characterized along with rhoifolin 4′-glucoside and three coumarins (8,3′-β-d-glucopyranosyloxy-2′-hydroxy-3′-methylbutyl-7-methoxycoumarin, merazin hydrate, and isomerazin). A preparative isolation procedure followed by NMR spectroscopy confirmed the proposed structures of the major flavonoids and identified the coumarins. The phenolic content was found to be 14.8 mg mL–1, and naringin and neohesperidin were the compounds present in the highest concentration (3.6 and 2.6 mg mL–1). The extract of C. aurantium peel inhibited significantly (p < 0.05) both histamine- and dextran-induced edema in rats in a concentration-dependent manner (IC50 = 119.6 and 118.3 mg kg–1, respectively), providing evidence for the therapeutic use of C. aurantium var. amara peel

The major genetic determinants of HIV-1 control affect HLA class I peptide presentation.

Infectious and inflammatory diseases have repeatedly shown strong genetic associations within the major histocompatibility complex (MHC); however, the basis for these associations remains elusive. To define host genetic effects on the outcome of a chronic viral infection, we performed genome-wide association analysis in a multiethnic cohort of HIV-1 controllers and progressors, and we analyzed the effects of individual amino acids within the classical human leukocyte antigen (HLA) proteins. We identified &gt;300 genome-wide significant single-nucleotide polymorphisms (SNPs) within the MHC and none elsewhere. Specific amino acids in the HLA-B peptide binding groove, as well as an independent HLA-C effect, explain the SNP associations and reconcile both protective and risk HLA alleles. These results implicate the nature of the HLA-viral peptide interaction as the major factor modulating durable control of HIV infection