Synthesis of Ergosta-5,22,24(28)-trienol from Stigmasterol

https://openriver.winona.edu/urc2018/1127/thumbnail.jp

Antirheumatic drugs and reproduction in women and men with chronic arthritis.

The impact of rheumatic disease on fertility and reproduction can be remarkable. Many disease-related factors can influence patients' sexual functioning, perturb fertility and limit family planning. Antirheumatic pharmacological treatment can also have a crucial role in this field. Proper counselling, preferably provided by a multidisciplinary team of rheumatologists, obstetricians, gynaecologists and neonatologists, is recommended for patients taking antirheumatic drugs, not only at the beginning, but also during the course of treatment. Paternal exposure to antirheumatic drugs was not found to be specifically associated with congenital malformation and adverse pregnancy outcome, therefore discontinuation of these drugs while planning for conception should be weighed against the risk of disease flare. Drugs in Food and Drug Administration (FDA) category 'X' should be withdrawn in a timely manner in women who desire a pregnancy. Meanwhile, disease control can be achieved with anti-tumour necrosis factor (TNF)-α agents, which are not teratogenic drugs. If maternal disease control is permissive, they can be stopped as soon as the pregnancy test turns positive and be resumed during pregnancy in case of a flare

Emerging Direct Targeting β-Catenin Agents

Aberrant accumulation of β-catenin in the cell nucleus as a result of deregulation of the Wnt/β-catenin pathway is found in various types of cancer. Direct β-catenin targeting agents are being researched despite obstacles; however, specific β-catenin drugs for clinical treatments have not been approved so far. We focused on direct β-catenin targeting of potential therapeutic value as anticancer agents. This review provides recent advances on small molecule β-catenin agents. Structure-activity relationships and biological activities of reported inhibitors are discussed. This work provides useful knowledge in the discovery of β-catenin agents

Modeling Epac1 interactions with the allosteric inhibitor AM-001 by co-solvent molecular dynamics

The exchange proteins activated by cAMP (EPAC) are implicated in a large variety of physiological processes and they are considered as promising targets for a wide range of therapeutic applications. Several recent reports provided evidence for the therapeutic effectiveness of the inhibiting EPAC1 activity cardiac diseases. In that context, we recently characterized a selective EPAC1 antagonist named AM-001. This compound was featured by a non-competitive mechanism of action but the localization of its allosteric site to EPAC1 structure has yet to be investigated. Therefore, we performed cosolvent molecular dynamics with the aim to identify a suitable allosteric binding site. Then, the docking and molecular dynamics were used to determine the binding of the AM-001 to the regions highlighted by cosolvent molecular dynamics for EPAC1. These analyses led us to the identification of a suitable allosteric AM-001 binding pocket at EPAC1. As a model validation, we also evaluated the binding poses of the available AM-001 analogues, with a different biological potency. Finally, the complex EPAC1 with AM-001 bound at the putative allosteric site was further refined by molecular dynamics. The principal component analysis led us to identify the protein motion that resulted in an inactive like conformation upon the allosteric inhibitor binding

Drug design and synthesis of first in class PDZ1 targeting NHERF1 inhibitors as anticancer agents

Targeted approaches aiming at modulating NHERF1 activity, rather than its overall expression, would be preferred to preserve the normal functions of this versatile protein. We focused our attention on the NHERF1/PDZ1 domain that governs its membrane recruitment/displacement through a transient phosphorylation switch. We herein report the design and synthesis of novel NHERF1 PDZ1 domain inhibitors. These compounds have potential therapeutic value when used in combination with antagonists of β-catenin to augment apoptotic death of colorectal cancer cells refractory to currently available Wnt/β-catenin-targeted agents

Propagation of Radiosonde Pressure Sensor Errors to Ozonesonde Measurements

Several previous studies highlight pressure (or equivalently, pressure altitude) discrepancies between the radiosonde pressure sensor and that derived from a GPS flown with the radiosonde. The offsets vary during the ascent both in absolute and percent pressure differences. To investigate this problem further, a total of 731 radiosonde-ozonesonde launches from the Southern Hemisphere subtropics to Northern mid-latitudes are considered, with launches between 2005 - 2013 from both longer-term and campaign-based intensive stations. Five series of radiosondes from two manufacturers (International Met Systems: iMet, iMet-P, iMet-S, and Vaisala: RS80-15N and RS92-SGP) are analyzed to determine the magnitude of the pressure offset. Additionally, electrochemical concentration cell (ECC) ozonesondes from three manufacturers (Science Pump Corporation; SPC and ENSCI-Droplet Measurement Technologies; DMT) are analyzed to quantify the effects these offsets have on the calculation of ECC ozone (O3) mixing ratio profiles (O3MR) from the ozonesonde-measured partial pressure. Approximately half of all offsets are 0.6 hPa in the free troposphere, with nearly a third 1.0 hPa at 26 km, where the 1.0 hPa error represents 5 persent of the total atmospheric pressure. Pressure offsets have negligible effects on O3MR below 20 km (96 percent of launches lie within 5 percent O3MR error at 20 km). Ozone mixing ratio errors above 10 hPa (30 km), can approach greater than 10 percent ( 25 percent of launches that reach 30 km exceed this threshold). These errors cause disagreement between the integrated ozonesonde-only column O3 from the GPS and radiosonde pressure profile by an average of +6.5 DU. Comparisons of total column O3 between the GPS and radiosonde pressure profiles yield average differences of +1.1 DU when the O3 is integrated to burst with addition of the McPeters and Labow (2012) above-burst O3 column climatology. Total column differences are reduced to an average of -0.5 DU when the O3 profile is integrated to 10 hPa with subsequent addition of the O3 climatology above 10 hPa. The RS92 radiosondes are superior in performance compared to other radiosondes, with average 26 km errors of -0.12 hPa or +0.61 percent O3MR error. iMet-P radiosondes had average 26 km errors of -1.95 hPa or +8.75 percent O3MR error. Based on our analysis, we suggest that ozonesondes always be coupled with a GPS-enabled radiosonde and that pressure-dependent variables, such as O3MR, be recalculated-reprocessed using the GPS-measured altitude, especially when 26 km pressure offsets exceed 1.0 hPa 5 percent

Subpopulations of anti-β2glycoprotein I antibodies with different pathogenic potential: fine specificity against the domains of β2glycoprotein I

Objective: Anti-β2glycoprotein I antibodies (a-β2GPI) are a laboratory criterion for the antiphospholipid syndrome (APS) and were demonstrated to be involved in the pathogenesis of APS. However, they can also be detected in asymptomatic subjects. It has been suggested that a-β2GPI against Domain1 (D1) associate with thrombosis, while those recognizing Domain4/5 (D4/5) have been identified in non-thrombotic conditions. We evaluate the specificity of a- β2GPI in different clinical situations. Methods: We studied 39 one-year-old healthy children born to mothers with systemic autoimmune diseases (SAD) (15 (38.4%) were born to mothers who were a-β2GPI positive), 33 children with atopic dermatitis (AD) and 55 patients with APS (50 adults and 5 paediatrics). All subjects were IgG a-β2GPI positive. IgG a-β2GPI were performed by homemade ELISA, while IgG a-β2GPI D1 and D4/5 were tested on research ELISAs containing recombinant β2GPI domains antigens. Results: One-year-old children and AD children displayed preferential reactivity for D4/5; patients with APS recognized preferentially D1. We also found a good correlation between a-β2GPI and D4/5 in one-year-old (r=0.853) and AD children (r=0.879) and between a-β2GPI and D1 in the APS group (r=0.575). No thrombotic events were recorded in both groups of children. Conclusions: A-β2GPI found in non-thrombotic conditions (healthy children born to mothers with SAD and AD children) mostly recognize D4/5, in contrast to the prevalent specificity for D1 in the APS group. The different specificity could at least partially explain the "innocent" profile of a-β2GPI in children

Targeting PDZ domains as potential treatment for viral infections, neurodegeneration and cancer

The interaction between proteins is a fundamental event for cellular life that is generally mediated by specialized protein domains or modules. PDZ domains are the largest class of protein–protein interaction modules, involved in several cellular pathways such as signal transduction, cell–cell junctions, cell polarity and adhesion, and protein trafficking. Because of that, dysregulation of PDZ domain function often causes the onset of pathologies, thus making this family of domains an interesting pharmaceutical target. In this review article we provide an overview of the structural and functional features of PDZ domains and their involvement in the cellular and molecular pathways at the basis of different human pathologies. We also discuss some of the strategies that have been developed with the final goal to hijack or inhibit the interaction of PDZ domains with their ligands. Because of the generally low binding selectivity of PDZ domain and the scarce efficiency of small molecules in inhibiting PDZ binding, this task resulted particularly difficult to pursue and still demands increasing experimental efforts in order to become completely feasible and successful in vivo

Graft preservation in heart transplantation: current approaches

Heart transplantation (HTx) represents the current best surgical treatment for patients affected by end-stage heart failure. However, with the improvement of medical and interventional therapies, the population of HTx candidates is increasingly old and at high-risk for mortality and complications. Moreover, the use of “extended donor criteria” to deal with the shortage of donors could increase the risk of worse outcomes after HTx. In this setting, the strategy of donor organ preservation could significantly affect HTx results. The most widely used technique for donor organ preservation is static cold storage in ice. New techniques that are clinically being used for donor heart preservation include static controlled hypothermia and machine perfusion (MP) systems. Controlled hypothermia allows for a monitored cold storage between 4°C and 8°C. This simple technique seems to better preserve the donor heart when compared to ice, probably avoiding tissue injury due to sub-zero °C temperatures. MP platforms are divided in normothermic and hypothermic, and continuously perfuse the donor heart, reducing ischemic time, a well-known independent risk factor for mortality after HTx. Also, normothermic MP permits to evaluate marginal donor grafts, and could represent a safe and effective technique to expand the available donor pool. However, despite the increasing number of donor hearts preserved with these new approaches, whether these techniques could be considered superior to traditional CS still represents a matter of debate. The aim of this review is to summarize and critically assess the available clinical data on donor heart preservation strategies employed for HTx