Semisynthetic bile acid derivatives as human receptor modulators

Bile acids (BAs) are considered signaling molecules able to interact with nuclear and membrane endogenous receptors, inducing several cellular networks that regulate lipids, glucose and bile acids homeostasis. Two well-known targets of BAs are the endogenous nuclear receptor FXR (farnesoid-x-receptor) and the membrane receptor GPBAR1 (G-protein coupled receptor 1) and since their activation is linked to the control of different metabolic and enterohepatic functions, they could be considered efficient targets in the treatment of several human diseases. In the last few years, medicinal chemistry modifications on bile acid scaffolds, afforded a large amount of exogenous derivatives with different pharmacological profiles, useful in the treatment of metabolic and enterohepatic disorders, ranging from metabolic syndrome, diabetes, cholestasis and non-alcoholic steatohepatiti

Peri-operative red blood cell transfusion in neonates and infants: NEonate and Children audiT of Anaesthesia pRactice IN Europe: A prospective European multicentre observational study

BACKGROUND: Little is known about current clinical practice concerning peri-operative red blood cell transfusion in neonates and small infants. Guidelines suggest transfusions based on haemoglobin thresholds ranging from 8.5 to 12 g dl-1, distinguishing between children from birth to day 7 (week 1), from day 8 to day 14 (week 2) or from day 15 (≥week 3) onwards. OBJECTIVE: To observe peri-operative red blood cell transfusion practice according to guidelines in relation to patient outcome. DESIGN: A multicentre observational study. SETTING: The NEonate-Children sTudy of Anaesthesia pRactice IN Europe (NECTARINE) trial recruited patients up to 60 weeks' postmenstrual age undergoing anaesthesia for surgical or diagnostic procedures from 165 centres in 31 European countries between March 2016 and January 2017. PATIENTS: The data included 5609 patients undergoing 6542 procedures. Inclusion criteria was a peri-operative red blood cell transfusion. MAIN OUTCOME MEASURES: The primary endpoint was the haemoglobin level triggering a transfusion for neonates in week 1, week 2 and week 3. Secondary endpoints were transfusion volumes, 'delta haemoglobin' (preprocedure - transfusion-triggering) and 30-day and 90-day morbidity and mortality. RESULTS: Peri-operative red blood cell transfusions were recorded during 447 procedures (6.9%). The median haemoglobin levels triggering a transfusion were 9.6 [IQR 8.7 to 10.9] g dl-1 for neonates in week 1, 9.6 [7.7 to 10.4] g dl-1 in week 2 and 8.0 [7.3 to 9.0] g dl-1 in week 3. The median transfusion volume was 17.1 [11.1 to 26.4] ml kg-1 with a median delta haemoglobin of 1.8 [0.0 to 3.6] g dl-1. Thirty-day morbidity was 47.8% with an overall mortality of 11.3%. CONCLUSIONS: Results indicate lower transfusion-triggering haemoglobin thresholds in clinical practice than suggested by current guidelines. The high morbidity and mortality of this NECTARINE sub-cohort calls for investigative action and evidence-based guidelines addressing peri-operative red blood cell transfusions strategies. TRIAL REGISTRATION: ClinicalTrials.gov, identifier: NCT02350348

Mulheres candidatas: relações entre gênero, mídia e discurso

http://dx.doi.org/10.1590/S0104-026X2006000200002 Tendo como pano de fundo a sobreposição das presenças da mulher e do político nas candidaturas a cargos públicos, neste artigo discutimos o peso da mídia na influência sobre a escolha dos eleitores e a posição destes como intérpretes dessas mensagens midiáticas. Assumindo um entendimento que relativiza o poder da mídia, indicamos como a idéia de discurso de (e sobre) gênero pode ser compreendido como mediador dessa influência. Embora pesquisas indiquem que a presença da mulher na mídia como candidata, transformada em um produto de marketing, tendem a desqualificá-la, esses efeitos apenas acompanham o estereótipo da mulher restrita à cena privada, alimentado por um discurso social que identifica o lugar da mulher como sendo o lar, longe, portanto, do espaço público. A mídia, assim, além de sua responsabilidade pela instalação desse lugar de mulher, atua pela sua manutenção. Concluímos que a participação política das mulheres se apresenta intimamente ligada a como elas são representadas no senso comum, indicando que uma mudança da participação política feminina passaria pela mudança nos discursos hegemônicos sobre as mulheres, discursos esses que atravessam os indivíduos e os grupos sociais

Inspection on bile acid scaffold in the discovery of the first example of LXRa/GPBAR1 dual agonists

L'acido iodeossicolico (HDCA), è un acido biliare secondario che si genera nell’intestino a partire dall’acido litocolico attraverso una C-6 idrossilazione batterica. Chimicamente, gli acidi biliari sono derivati del colesterolo provvisti di una catena laterale troncata. Oltre alla canonica funzione di emulsionamento dei lipidi, gli acidi biliari, interagiscono con almeno quattro tipi di recettori appartenenti alla super-famiglia dei recettori nucleari (NR): il recettore X dei farnesoidi (FXR), identificato come il sensore degli acidi biliari endogeni, il recettore costitutivo per l’androstano (CAR), il recettore X del pregnano (PXR), il recettore X del fegato (LXR) e il recettore della vitamina D (VDR). Inoltre, gli acidi biliari secondari attivano i recettori accoppiati a proteine G(GPCR), tra cui GPBAR1 (noto anche come M-BAR, TGR5, o BG37). Anche se l’acido iodesossicolico ha una serie di proprietà farmacologiche quale ad esempio la protezione contro la formazione delle placche aterosclerotiche, non è praticamente un attivatore di FXR ed è un debolissimo attivatore di GP-BAR1 e LXR. Durante questo studio è stato dimostrato che nonostante l’acido iodesossicolico HDCA non sia in grado di modulare efficacemente l’attività di questi recettori, piccole modifiche della sua catena laterale hanno portato all’ottenimento di composti in grado di transattivarli in modo selettivo e soprattutto in modo duale. Sfruttando proprio l'azione duale, i nuovi derivati semisintetici dell’HDCA potrebbero essere impiegati in diversi disturbi metabolici quali il diabete, stati infiammatori cronici e malattie neurodegenerative

Inspection on bile acid scaffold in the discovery of the first example of LXR/GPBAR1 dual agonists

Hyodeoxycholic acid (HDCA), also known as 3α,6α-dihydroxy-5β-cholan-24-oic acid, is a secondary hydrophilic bile acid formed in human small intestine by bacterial C-6 hydroxylation of lithocholic acid. BAs are signaling molecules that activate at least four members of the nuclear receptors (NRs) superfamily: the farnesoid X receptor (FXR, NR1H4), identified as the endogenous bile acid sensor, the constitutive androstane receptor (CAR, NR1I3), the pregnane X receptor (PXR, NR1I2), the liver X receptor and the vitamin D receptor (VDR, NR1I1). In addition, secondary BAs activate G protein-coupled receptors (GPCRs), including GPBAR1 (also known as M-BAR, TGR5 or BG37). Several studies affirmed the therapeutical potential of HDCA administration in various metabolic disorders. HDCA has been shown to prevent gallstone formation, to reduce the levels of cholesterol in the liver and in the plasma suggesting its beneficial effects in the treatment of increased plasma cholesterol levels and atherosclerosis. In this communication, we report a novel library of semisynthetic bile acid derivatives obtained by modifications on the HDCA scaffold. The pharmacological characterization of this library led to the discovery of the first examples of novel dual ligands for LXR and GP-BAR1 receptors that might hold utility in the treatment of several metabolic disorders such as obesity and atherosclerosi

Women candidates: the relationships between gender, media and discourse

On this paper we discuss, within the cross over of two representations - woman and politic function - the media’s power to influence voters’ choices and their roles as interpreters of media messages. Under a position that understands the relativity of the media’s power, we set the idea of gender discourse as a mediator of its influence. Whereas literature shows how a candidate suffers an important effect of media exposition, transformed in a marketing product, we suggest that women in politics suffer from the stereotype that states "women’s place is at home". We conclude that women politic participation is strongly linked to the way in which they are represented in the common sense and a change in the hegemonic discourses about women that cross individuals and social groups becomes necessary as to have this situation modified

Biological Profile of Two Gentiana lutea L. Metabolites Using Computational Approaches and In Vitro Tests

Natural products have been the main source of bioactive molecules for centuries. We tested the biological profile of two metabolites extracted from Gentiana lutea L. by means of computational techniques and in vitro assays. The two molecules (loganic acid and entiopicroside) were tested in silico using an innovative technique, named Inverse Virtual Screening (IVS), to highlight putative partners among a panel of proteins involved in inflammation and cancer events. A positive binding with cyclooxygenase-2 (COX-2), alpha-1-antichymotrypsin, and alpha-1-acid glycoprotein emerged from the computational experiments and the outcomes from the promising interaction with COX-2 were confirmed by Western blot, highlighting the reliability of IVS in the field of the natural products

Towards FXR selectivity: manipulation of 6-ethylcholane scaffold

Bile acids, the end-products of cholesterol catabolism, are signaling molecules activating several cellular networks through the recognition of nuclear and membrane receptors, such as the farnesoid-x-receptor (FXR) and a G-proteins coupled receptor (GP-BAR1). BAs are generated in the liver as primary bile acids, cholic acid (CA) and chenodeoxycholic acid (CDCA), conjugated with glycine and taurine, and then secreted in the small intestine and transformed by the intestinal microbiota into secondary bile acids, deoxycholic acid (DCA) and lithocholic acid (LCA). CDCA is the endogenous agonist of FXR while LCA and its corresponding tauro- and glyco-conjugates (GLCA and TLCA) are the most potent natural agonists for GP-BAR1. The main physiological role of FXR is the regulation of bile acids absorption, synthesis and secretion in the intestine, liver and kidney and it is considered a promising target in cholestasis. Although, GP-BAR1 agonists represent a novel opportunity in the treatment of entero-hepatic and metabolic disorders, a recent study has provided evidence that this receptor is the physiologic mediator of pruritus, a common symptom observed in cholestasis. In this contest, we have manipulated the scaffold of 6-ethylcholane acid (6-ECDCA), a semi-synthetic bile acid, to obtain potent and selective FXR agonist

Towards FXR selectivity: manipulation of 6-ethylcholane scaffold

Bile acids, the end-products of cholesterol catabolism, are signaling molecules activating several cellular networks through the recognition of nuclear and membrane receptors, such as the farnesoid-x-receptor (FXR) and a G-proteins coupled receptor (GP-BAR1). BAs are generated in the liver as primary bile acids, cholic acid (CA) and chenodeoxycholic acid (CDCA), conjugated with glycine and taurine, and then secreted in the small intestine and transformed by the intestinal microbiota into secondary bile acids, deoxycholic acid (DCA) and lithocholic acid (LCA). CDCA is the endogenous agonist of FXR while LCA and its corresponding tauro- and glyco-conjugates (GLCA and TLCA) are the most potent natural agonists for GP-BAR1. The main physiological role of FXR is the regulation of bile acids absorption, synthesis and secretion in the intestine, liver and kidney and it is considered a promising target in cholestasis. Although, GP-BAR1 agonists represent a novel opportunity in the treatment of entero-hepatic and metabolic disorders, a recent study has provided evidence that this receptor is the physiologic mediator of pruritus, a common symptom observed in cholestasis. In this contest, we have manipulated the bile acids scaffolds to obtain potent and selective FXR agonist