Removal of C-ring from the CD-ring skeleton of 1alpha,25-dihydroxyvitamin D3 does not alter its target tissue metabolism significantly

It is now well established that 1alpha,25(OH)2D3 is metabolized in its target tissues through the modifications of both side chain and A-ring. The C-24 oxidation pathway is the side chain modification pathway through which 1alpha,25(OH)2D3 is metabolized into calcitroic acid. The C-3 epimerization pathway is the A-ring modification pathway through which 1alpha,25(OH)2D3 is metabolized into 1alpha,25(OH)2-3-epi-D3. During the past two decades, a great number of vitamin D analogs were synthesized by altering the structure of both side chain and A-ring of 1alpha,25(OH)2D3 with the aim to generate novel vitamin D compounds that inhibit proliferation and induce differentiation of various types of normal and cancer cells without causing significant hypercalcemia. Previously, we used some of these analogs as molecular probes to examine how changes in 1alpha,25(OH)2D3 structure would affect its target tissue metabolism. Recently, several nonsteroidal analogs of 1alpha,25(OH)2D3 with unique biological activity profiles were synthesized. Two of the analogs, SL 117 and WU 515 lack the C-ring of the CD-ring skeleton of 1alpha,25(OH)2D3. SL 117 contains the same side chain as that of 1alpha,25(OH)2D3, while WU 515 contains an altered side chain with a 23-yne modification combined with hexafluorination at C-26 and C-27. Presently, it is unknown how the removal of C-ring from the CD-ring skeleton of 1alpha,25(OH)2D3 would affect its target tissue metabolism. In the present study, we compared the metabolic fate of SL 117 and WU 515 with that of 1alpha,25(OH)2D3 in both the isolated perfused rat kidney, which expresses only the C-24 oxidation pathway and rat osteosarcoma cells (UMR 106), which express both the C-24 oxidation and C-3 epimerization pathways. The results of our present study indicate that SL 117 is metabolized like 1alpha,25(OH)2D3, into polar metabolites via the C-24 oxidation pathway in both rat kidney and UMR 106 cells. As expected, WU 515 with altered side chain structure is not metabolized via the C-24 oxidation pathway. Unlike in rat kidney, both SL 117 and WU 515 are also metabolized into less polar metabolites in UMR 106 cells. These metabolites displayed GC and MS characteristics consistent with A-ring epimerization and were putatively assigned as C-3 epimers of SL 117 and WU 515. In summary, we report that removal of the C-ring from the CD-ring skeleton of 1alpha,25(OH)2D3 does not alter its target tissue metabolism significantly.     

Detection of anti-M. leprae antibodies in children in leprosy-endemic areas: A systematic review

BackgroundLeprosy elimination primarily targets transmission of Mycobacterium leprae which is not restricted to patients’ households. As interruption of transmission is imminent in many countries, a test to detect infected asymptomatic individuals who can perpetuate transmission is required. Antibodies directed against M. leprae antigens are indicative of M. leprae infection but cannot discriminate between active and past infection. Seroprevalence in young children, however, reflects recent M. leprae infection and may thus be used to monitor transmission in an area. Therefore, this literature review aimed to evaluate what has been reported on serological tests measuring anti-M. leprae antibodies in children without leprosy below the age of 15 in leprosy-endemic areas.Methods and findingsA literature search was performed in the databases Pubmed, Infolep, Web of Science and The Virtual Health Library. From the 724 articles identified through the search criteria, 28 full-text articles fulfilled all inclusion criteria. Two additional papers were identified through snowballing, resulting in a total of 30 articles reporting data from ten countries. All serological tests measured antibodies against phenolic glycolipid-I or synthetic derivatives thereof, either quantitatively (ELISA or UCP-LFA) or qualitatively (ML-flow or NDO-LID rapid test). The median seroprevalence in children in endemic areas was 14.9% and was stable over time if disease incidence remained unchanged. Importantly, seroprevalence decreased with age, indicating that children are a suitable group for sensitive assessment of recent M. leprae infection. However, direct comparison between areas, solely based on the data reported in these studies, was impeded by the use of different tests and variable cut-off levels.ConclusionsQuantitative anti-PGL-I serology in young children holds promise as a screening test to assess M. leprae infection and may be applied as a proxy for transmission and thereby as a means to monitor the effect of (prophylactic) interventions on the route to leprosy elimination.     

Transpeptidation and reverse proteolysis and their consequences for immunity

Reverse proteolysis and transpeptidation lead to the generation of polypeptide sequences that cannot be inferred directly from genome sequences as they are post-translational phenomena. These phenomena have so far received little attention although the physiological consequences may reach far. The protease-mediated synthesis of several immunodominant MHC class I antigens was recently reported, underscoring its importance to immunity. Reverse proteolytic and transpeptidation mechanisms as well as conditions that favor successful protease-catalyzed synthetic events are discussed here.     

Low Atmospheric Nitrogen Loads Lead to Grass Encroachment in Coastal Dunes,but Only on Acid Soils

The impact of atmospheric N-deposition on succession from open sand to dry, lichen-rich, short grassland, and tall grass vegetation dominated by Carex arenaria was surveyed in 19 coastal dune sites along the Baltic Sea. Coastal dunes with acid or slightly calcareous sand reacted differently to atmospheric wet deposition of 5–8 kg N ha⁻¹ y⁻¹. Accelerated acidification, as well as increased growth of Carex and accumulation of organic matter, was observed only at acid sites with pH_NaCl of the parent material below 6.0. At sites with slightly calcareous parent material, increased N-deposition had no effect. A trigger for grass encroachment seems to be high acidification in early successional stages to below pH_NaCl 4.0. Metals like Al or Fe become freely available and may hamper intolerant species. At acid sites, N-mineralization increases with elevated N-deposition, which may further stimulate Carex arenaria. Due to high growth plasticity, efficient resource allocation and tolerance of high metal concentrations, C. arenaria is a superior competitor under these conditions and can start to dominate the dune system. Carex-dominated vegetation is species-poor. Even at the moderate N-loads in this study, foliose lichens, forbs and grasses were reduced in short grass vegetation at acid sites. Species indicating these first effects of atmospheric deposition on dry, lichen-rich, short grasslands are identified and recommendations for restoration of grass-encroached sites given.     

Novel A-ring homodimeric C-3-carbamate analogues of 1alpha,25-dihydroxyvitamin D3: synthesis and preliminary biological evaluation

The synthesis of a new class of vitamin D3 analogues in which two units of 1alpha,25-dihydroxyvitamin D3 are linked at the C-3 position by a dicarbamate functionality of variable length is described. The analogues demonstrated no affinity for the vitamin D receptor and possessed no antiproliferative or transactivating properties.     

Natural Selection of Human Embryos: Decidualizing Endometrial Stromal Cells Serve as Sensors of Embryo Quality upon Implantation

Background

Pregnancy is widely viewed as dependent upon an intimate dialogue, mediated by locally secreted factors between a developmentally competent embryo and a receptive endometrium. Reproductive success in humans is however limited, largely because of the high prevalence of chromosomally abnormal preimplantation embryos. Moreover, the transient period of endometrial receptivity in humans uniquely coincides with differentiation of endometrial stromal cells (ESCs) into highly specialized decidual cells, which in the absence of pregnancy invariably triggers menstruation. The role of cyclic decidualization of the endometrium in the implantation process and the nature of the decidual cytokines and growth factors that mediate the crosstalk with the embryo are unknown.

Methodology/Principal Findings

We employed a human co-culture model, consisting of decidualizing ESCs and single hatched blastocysts, to identify the soluble factors involved in implantation. Over the 3-day co-culture period, approximately 75% of embryos arrested whereas the remainder showed normal development. The levels of 14 implantation factors secreted by the stromal cells were determined by multiplex immunoassay. Surprisingly, the presence of a developing embryo had no significant effect on decidual secretions, apart from a modest reduction in IL-5 levels. In contrast, arresting embryos triggered a strong response, characterized by selective inhibition of IL-1β, -6, -10, -17, -18, eotaxin, and HB-EGF secretion. Co-cultures were repeated with undifferentiated ESCs but none of the secreted cytokines were affected by the presence of a developing or arresting embryo.

Conclusions

Human ESCs become biosensors of embryo quality upon differentiation into decidual cells. In view of the high incidence of gross chromosomal errors in human preimplantation embryos, cyclic decidualization followed by menstrual shedding may represent a mechanism of natural embryo selection that limits maternal investment in developmentally impaired pregnancies.