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Luiz Francisco Cardoso, Daniella Vianna C Krokoscz, Edison Ferreira de Paiva, Ilka Spinola Furtado, Jorge Mattar Jr, Marcia Martiniano de Souza e Sá, Antonio Carlos Onofre de Lira Sírio Libanês Hospital, São Paulo, Brazil Introduction: Venous thromboembolism (VTE) is the leading cause of preventable death in hospitalized patients. However, existing prophylaxis guidelines are rarely followed. Objective: The aim of the study was to present and discuss implementation strategies and the results of a VTE prophylaxis program for medical and surgical patients admitted to a large general hospital. Patients and methods: This prospective observational study was conducted to describe the strategy used to implement a VTE prophylaxis program in hospitalized medical and surgical patients and to analyze the results in terms of the risk assessment rate within the first 24 hours after admission, adequacy of the prophylaxis prescription, and prevalence of  VTE in the discharge records before and after program implementation. We used the Mantel–Haenszel chi-square test for the linear trend of the data analysis and set the significance level to P

The study investigates the effect of organizational citizenship behavior (OCB) on well-being at work. The study further examines the moderating role of people and task-focused leadership styles between OCB on well-being at work. Individual-directed organizational citizenship behaviors (OCBI) and organizational-directed organizational citizenship behaviors (OCBO) will also be analyzed. A quantitative study was conducted and convenient sampling was adopted in selecting respondent workers ( n = 200) in different Portuguese organizations. The results show that OCBs positively and significantly influence well-being at work. The strength of individual-directed organizational citizenship behaviors (OCBI) on well-being at work is stronger than that of organization-directed organizational citizenship behaviors (OCBO). Contrary to expectations, the relationship between leadership styles and well-being was not statistically significant, offering possibilities for discussion regarding the central importance usually attributed to leadership in the organizational context. However, leadership styles have a moderating effect between OCB and well-being at work, except when the employee adopts OCBO and the leadership style is people-oriented. The present study is innovative because it positions OCB as an antecedent in the relationship with well-being at work and investigates the moderating role of leadership styles in the relationship between organizational citizenship behavior and well-being., Competing Interests: The authors declare no conflicts of interest.

Nowadays, macrophages are recognized as key cells involved in chronic inflammatory conditions, and play central roles in all inflammatory diseases and cancer. Due to their extensive involvement in the pathogenesis of inflammatory diseases, they are now considered a relevant therapeutic target in the development of new therapeutic strategies. 2-Iminothiazolidines are associated with important anti-inflammatory activity and represent a rich source for the development of new drugs and treatments. Our research focuses on evaluating the anti-inflammatory capacity of these compounds and their relationship with M1/M2 macrophage polarization. The results demonstrate that 2-iminothiazolidines have the capacity to decrease the levels of anti-inflammatory biomarkers, such as cytokines (IL-1β, TNF-α, and IL-6), nitric oxide synthase (with impact on NOx production), and COX-2, following a significant decline in NF-kB activation. We also observed an increase in levels of anti-inflammatory cytokines (IL-4 and IL-13) in the in vitro model of RAW 264.7 macrophages induced by LPS. Moreover, this is the first report, suggesting that the anti-inflammatory activity of 2-iminothiazolidines is associated with the ability to enhance phagocytosis, increase Arginase-1 and CD206 expression, and increase the secretion of IL-10. Furthermore, an in vivo study using the acute lung injury model induced by LPS proved the anti-inflammatory activity of a selected 2-iminothiazolidine, named methyl 2-(benzoylimino)-3-methyl-4-(4-nitrobenzyl)-1,3-thiazolidine-4-carboxylate. All these results, taken together, lead us to hypothesize that the mechanism of anti-inflammatory effect observed with this compound is closely related to the ability of this compound to produce macrophage repolarization, from the M1 to the M2 phenotype., (© 2022. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

The inflammatory process is a mammalian physiological reaction against infectious agents or injuries. Among the cells involved, the macrophages have a highlighted role during this process. Depending on the inflammatory context, they can polarize into pro- or anti-inflammatory profiles (M1 and M2). In this context, compounds derived from cinnamic acid have demonstrated strong evidence of anti-inflammatory activity; however, the mechanism responsible for this effect remains unclear. In this study, we investigated the anti-inflammatory activity of five cinnamate-derived dienes of synthetic origin. The compounds that did not demonstrate significant cytotoxicity were tested to assess anti-inflammatory activity (NO x ) in RAW 264.7 cells stimulated with LPS. Then, the selected compound (diene 1) was evaluated as to its ability to inhibit the secretion of pro-inflammatory cytokines (IL-1β, TNF-α, INF-γ, MCP-1, and IL-6) and increase the production of anti-inflammatory cytokines (IL-13, IL-4, and IL-10). Finally, diene 1 was able to reduce the expression of TLR4 and increase the phagocytic activity of the macrophages. Gathering these results together, we conclude that diene 1 showed an important anti-inflammatory effect, and this effect is linked to its immunomodulatory characteristic. Since the M1 markers were reduced at the same time, M2 markers were increased by the treatment of the macrophages with diene 1., (© 2022 Société Française de Pharmacologie et de Thérapeutique.)

L-asparaginase (ASNase) from Escherichia coli (EcAII) is used in the treatment of acute lymphoblastic leukaemia (ALL). EcAII activity in vivo has been described to be influenced by the human lysosomal proteases asparaginyl endopeptidase (AEP) and cathepsin B (CTSB); these hydrolases cleave and could expose epitopes associated with the immune response against EcAII. In this work, we show that ASNase resistance to CTSB and/or AEP influences the formation of anti-ASNase antibodies, one of the main causes of hypersensitivity reactions in patients. Error-prone polymerase chain reaction was used to produce variants of EcAII more resistant to proteolytic cleavage by AEP and CTSB. The variants with enzymatic activity and cytotoxicity levels equivalent to or better than EcAII WT were submitted to in vivo assays. Only one of the mutants presented increased serum half-life, so resistance to these proteases is not the only feature involved in EcAII stability in vivo. Our results showed alteration of the phenotypic profile of B cells isolated after animal treatment with different protease-resistant proteoforms. Furthermore, mice that were exposed to the protease-resistant proteoforms presented lower anti-asparaginase antibodies production in vivo. Our data suggest that modulating resistance to lysosomal proteases can result in less immunogenic protein drugs., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Diazo compounds are versatile reagents in chemical synthesis and biology due to the tunable reactivity of the diazo functionality and its compatibility with living systems. Much effort has been made in recent years to explore their accessibility and synthetic potential; however, their preparation through stereoselective enzymatic asymmetric synthesis has been scarcely reported in the literature. Alcohol dehydrogenases (ADHs, also called ketoreductases, KREDs) are powerful redox enzymes able to reduce carbonyl compounds in a highly stereoselective manner. Herein, we have developed the synthesis and subsequent bioreduction of nine α-diazo-β-keto esters to give optically active α-diazo-β-hydroxy esters with potential applications as chiral building blocks in chemical synthesis. Therefore, the syntheses of prochiral α-diazo-β-keto esters bearing different substitution patterns at the adjacent position of the ketone group (N 3 CH 2 , ClCH 2 , BrCH 2 , CH 3 OCH 2 , NCSCH 2 , CH 3 , and Ph) and in the alkoxy portion of the ester functionality (Me, Et, and Bn), were carried out through the diazo transfer reaction to the corresponding β-keto esters in good to excellent yields (81-96%). After performing the chemical reduction of α-diazo-β-keto esters with sodium borohydride and developing robust analytical conditions to monitor the biotransformations, their bioreductions were exhaustively studied using in-house made Escherichia coli overexpressed and commercially available KREDs. Remarkably, the corresponding α-diazo-β-hydroxy esters were obtained in moderate to excellent conversions (60 to >99%) and high selectivities (85 to >99% ee ) after 24 h at 30 °C. The best biotransformations in terms of conversion and enantiomeric excess were successfully scaled up to give the expected chiral alcohols with almost the same activity and selectivity values observed in the enzyme screening experiments.

In a previous study, we described a series of 28 aryl- and alkyl-substituted isothiouronium salts with antitumor activity and selectivity toward a leukemia cell line. Among the synthesized compounds, methyl (Z)-2-(isothioureidomethyl)-2-pentenoate hydrobromide (IS-MF08) showed conspicuous activity. In the present study, we investigated the mechanism of action of IS-MF08. Our results showed that its mechanism most likely is related with the membrane receptor Fas and subsequent activation of the extrinsic cell death pathway, triggered by a decrease in the levels of the anti-apoptotic protein Bcl-2 and caspase-8 and -3 cascade activation, causing DNA damage and mitotic arrest. IS-MF08 also caused an increase in intracellular ROS, endoplasmic reticulum (ER) stress, and mitochondrial membrane permeabilization, resulting in organelle degradation as an attempt to reestablish cell homeostasis. Furthermore, cells exposed to IS-MF08 combined to an autophagy inhibitor were less susceptible to compound's cytotoxicity, suggesting that autophagy makes part of its mechanism of action. These data support the hypothesis that IS-MF08 acts by the apoptosis extrinsic pathway and possibly by autophagy as mechanisms of cell death., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Dermatophytes are the etiological agents of cutaneous mycoses, including the prevalent nail infections and athlete's foot. Candida spp. are opportunistic and emerging pathogens, causing superficial to deeper infections related to high mortality rates. As a consequence of prolonged application of antifungal drugs, the treatment failures combined with multidrug-resistance have become a serious problem in clinical practice. Therefore, novel alternative antifungals are required urgently. δ-Lactones have attracted great interest owing to their wide range of biological activity. This article describes the antifungal activity of synthetic δ-lactones against yeasts of the genus Candida spp. and dermatophytes (through the broth microdilution method), discusses the pathways by which the compounds exert this action (toward the fungal cell wall and/or membrane), and evaluates the toxicity to human leukocytes and chorioallantoic membrane (by the hen's egg test-chorioallantoic membrane). Two of the compounds in the series presented broader spectrum of antifungal activity, including against resistant fungal species. The mechanism of action was related to damage in the fungal cell wall and membrane, with specific target action dependent on the type of substituent present in the δ-lactone structure. The damage in the fungal cell was corroborated by electron microscopy images, which evidenced lysed and completely altered cells after in vitro treatment with δ-lactones. Toxicity was dose dependent for the viability of human leukocytes, but none of the compounds was mutagenic, genotoxic, or membrane irritant when evaluated at higher concentrations than MIC. In this way, δ-lactones constitute a class with excellent perspectives regarding their potential applications as antifungals.

Although inflammation is a biological phenomenon that exists to protect the host against infections and/or related problems, its unceasing activation results in the aggravation of several medical conditions. Imidazoles, whether natural or synthetic, are molecules related to a broad spectrum of biological effects, including anti-inflammatory properties. In this study, we screened eight novel small molecules of the imidazole class synthesized by our research group for their in vitro anti-inflammatory activity. The effect of the selected molecules was confirmed in an in vivo inflammatory model. We also analyzed whether the effects were caused by inhibition of nuclear factor kappa B (NF-κB) transcription factor transmigration. Of the eight imidazoles tested, methyl 1-allyl-2-(4-fluorophenyl)-5-phenyl-1H-imidazole-4-acetate (8) inhibited nitric oxide metabolites and pro-inflammatory cytokine (TNF-α, IL-6, and IL-1β) secretion in J774 macrophages stimulated with LPS. It also attenuated leukocyte migration and exudate formation in the pleural cavity of mice challenged with carrageenan. Furthermore, imidazole 8 reverted the oxidative stress pattern triggered by carrageenan in the pleural cavity by diminishing myeloperoxidase, superoxide dismutase, catalase, and glutathione S-transferase activities and reducing the production of nitric oxide metabolites and thiobarbituric acid-reactive substances. Finally, these effects can be attributed, at least in part, to the ability of this compound to prevent NF-κB transmigration. In this context, our results demonstrate that imidazole 8 has promising potential as a prototype for the development of a new anti-inflammatory drug to treat inflammatory conditions in which NF-κB and oxidative stress play a prominent role. Graphical Abstract ᅟ.

An efficient three-step protocol was developed to produce 2-(azidomethyl)oxazoles from vinyl azides in a continuous-flow process. The general synthetic strategy involves a thermolysis of vinyl azides to generate azirines, which react with bromoacetyl bromide to provide 2-(bromomethyl)oxazoles. The latter compounds are versatile building blocks for nucleophilic displacement reactions as demonstrated by their subsequent treatment with NaN 3 in aqueous medium to give azido oxazoles in good selectivity. Process integration enabled the synthesis of this useful moiety in short overall residence times (7 to 9 min) and in good overall yields.

A series of 28 aryl- and alkyl-substituted isothiouronium salts were readily synthesized in high yields through the reaction of allylic bromides with thiourea, N-monosubstituted thioureas or thiosemicarbazide. The S-allylic isothiouronium salts substituted with aliphatic groups were found to be the most effective against leukemia cells. These compounds combine high antitumor activity and low toxicity toward non-tumoral cells, with selectivity index higher than 20 in some cases. Furthermore, the selected isothiouronium salts induced G2/M cell cycle arrest and cell death, possibly by apoptosis. Therefore, these compounds can be considered as a promising class of antitumor agents due to the potent cytostatic activity associated with high selectivity., (Copyright © 2017 Elsevier Masson SAS. All rights reserved.)

In the title compound, C 15 H 16 O 6 , obtained from the acyl-ation reaction between 2,3- O -iso-propyl-idene-d-ribono-1,4-lactone and benzoyl chloride, the known absolute configuration for the lactone moiety of the ester substituent has been confirmed. The five-membered rings of the bicyclic lactone-dioxolane moiety both show envelope conformations and form a dihedral angle of 19.82 (7)° between the lactone ring and the benzene ring. In the crystal, mol-ecules of the acyl-ated sugar are linked by very weak inter-molecular C-H⋯O inter-actions, forming a three-dimensional network.

The dopamine hypothesis states that decreased dopaminergic neurotransmission reduces schizophrenia symptoms. Neurokinin-3 receptor (NK3) antagonists reduce dopamine release and have shown positive effects in pre-clinical and clinical trials. We employed 2D and 3D-QSAR analysis on a series of 40 non-peptide NK3 antagonists. Multivariate statistical analysis, PCA and HCA, were performed to rational training/test set splitting and PLS regression was employed to construct all QSAR models. We constructed one highly predictive CoMFA model (q(2)= 0.810 and r(2)= 0.929) and acceptable HQSAR and CoMSIA models (HQSAR q(2)= 0.644 and r(2)= 0.910; CoMSIA q(2)= 0.691, r(2)= 0.911). The three different techniques provided convergent physicochemical results. All models indicate cyclopropane, piperidine and di-chloro-phenyl ring attached to cyclopropane ring and also the amide group attached to the piperidine ring could play an important role in ligand-receptor interactions. These findings may contribute to develop potential NK3 receptor antagonists for schizophrenia.

Coarse-grained molecular dynamics simulations are used to calculate the free energies of transfer of miltefosine, an alkylphosphocholine anticancer agent, from water to lipid bilayers to study its mechanism of interaction with biological membranes. We consider bilayers containing lipids with different degrees of unsaturation: dipalmitoylphosphatidylcholine (DPPC, saturated, containing 0%, 10%, and 30% cholesterol), dioleoylphosphatidylcholine (DOPC, diunsaturated), palmitoyloleoylphosphatidylcholine (POPC, monounsaturated), diarachidonoylphosphatidylcholine (DAPC, polyunsaturated), and dilinoleylphosphatidylcholine (DUPC, polyunsaturated). These free energies, calculated using umbrella sampling, were used to compute the partition coefficients (K) of miltefosine between water and the lipid bilayers. The K values for the bilayers relative to that of pure DPPC were found to be 5.3 (DOPC), 7.0 (POPC), 1.0 (DAPC), 2.2 (DUPC), 14.9 (10% cholesterol), and 76.2 (30% cholesterol). Additionally, we calculated the free energy of formation of miltefosine-cholesterol complexes by pulling the surfactant laterally in the DPPC + 30% cholesterol system. The free energy profile that we obtained provides further evidence that miltefosine tends to associate with cholesterol and has a propensity to partition into lipid rafts. We also quantified the kinetics of the transport of miltefosine through the various bilayers by computing permeance values. The highest permeance was observed in DUPC bilayers (2.28 × 10(-2) m/s) and the lowest permeance in the DPPC bilayer with 30% cholesterol (1.10 × 10(-7) m/s). Our simulation results show that miltefosine does indeed interact with lipid rafts, has a higher permeability in polyunsaturated, loosely organized bilayers, and has higher flip-flop rates in specific regions of cellular membranes.

Alkylphosphocholines (APCs) and alkyl-lysophosphocholines (ALPs) are antineoplastic agents that interfere with cellular membranes and signaling proteins. Protein kinase Cα (PKCα) is a signaling protein composed by catalytic (C3, C4) and regulatory domains (C1, C2). The C2 needs calcium (Ca(2+) ) and phosphatidylserine (PS) for activation. Miltefosine inhibits PKCα competitively with regard to PS and non-competitively with regard to Ca(2+) , however, the mechanism of action is unknown. We employed molecular docking, molecular dynamics and chemometric methods to verify how 7 APCs and ALPs derivatives and PS interact with the C2 domain. All ligands except PS were grouped in 2 clusters according to their interactions inside the enzyme. The findings showed that PS's phosphoryl oxygens interact with Ca(2+) , the serine moiety interacts with Asn189, and the carbonyl oxygen of the alkylic chain interacts with Arg249 and Thr251. On the other hand, ligands' phosphoryl oxygens interact with Asn189, Arg249, Thr250, and one water molecule instead of Ca(2+) . Because of the different binding mode, we hypothesize that the ligands cause conformational changes in the calcium binding region. Moreover, the packing mismatch between bilayer-forming lipids and ALP/APC chain impedes the C2 domain from docking to the internal leaflet of cellular membranes, interrupting PKCα activation., (© 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)