Activity

As a result of the search, 42 publications were included into this systematic review, of which 30 publications reported preclinical and 12 manuscripts presented clinical data. In addition to a critical analysis of the present data, gaps in knowledge were highlighted in order to foster further research.

Evidence suggests that vitamin D suppresses the production of pro-inflammatory cytokines and induces the production of anti-inflammatory cytokines during pregnancy.

To assess, through a systematic literature review, the relationship between maternal or cord blood concentrations of 25-hydroxycholecalciferol (25-OH-D) or vitamin D supplementation during pregnancy and the cytokines profile in the umbilical cord.

The following databases were searched PUBMED, CENTRAL, Web of Science, LILACS, and gray literature, up to July 2020. The search strategy included terms related to the exposure (25-OH-D) and the primary outcome (cytokines). Observational studies and randomized clinical trials were included, measuring cytokines in the umbilical cord blood, or in ex vivo bioassays, and blood concentrations of 25-OH-D, either throughout pregnancy or in the umbilical cord blood. Studies with twin pregnancies, with placental or autoimmune diseases, were excluded. The protocol is registered in PROSPERO (number CRD42019136643).

From 14,605 unique articles identified in the databases, 28 were read in full, and of these, eight met the eligibility criteria, being three randomized clinical trials, and five observational studies. Divarasib clinical trial The eight studies showed adequate methodological quality. IL-10 was the most studied cytokine, being reported in seven studies. There were higher concentrations of IL-10 in the umbilical cord of women with 25-OH-D sufficiency in the observational studies. Clinical trials showed mixed results with the use of ex vivo bioassays with several stimulants. Associations with other cytokines were less consistent or absent.

25-OH-D status is positively associated with the IL-10 levels of the umbilical cord, in observational studies.

25-OH-D status is positively associated with the IL-10 levels of the umbilical cord, in observational studies.Behavioral phenotyping is an essential part of neuro-active drug discovery and predictive neurotoxicology. Due to limitations of conventional rodent in vivo models, chemobehavioral phenotypic analysis utilizing innovative small model organisms; such as nematodes, planarians and zebrafish are emerging as distinctively advantageous for high-throughput phenotypic discovery of neuroceuticals and evaluating deleterious effects of industrial pollutants on the central nervous system. Digital film recording with subsequent analysis of video sequences using specialised animal tracking software has become a standard in obtaining behavioral biometric data. At present animal tracking algorithms are largely capable of detecting and tracking small number of animals and extracting quantitative endpoints associated with specific behavioral traits based on reconstruction of movement trajectories and occupancy heatmaps. However, despite recent and significant progress in development of diverse proxy biological models, the software algorithms still lack the ability to track multiple organisms on a large scale, automatically generate behavioral fingerprints and utilize intensive computational approaches to mine rich biometric data. This creates a significant bottleneck for effective high-throughput chemobehavioral screening in drug discovery and neurotoxicology. This review outlines recent advances as well as limitations of high-throughput animal tracking and provides an outlook on future developments in rapidly evolving field of neurobehavioral phenomics.Bestatin and bacitracin are inhibitors of metallo aminopeptidases and bacterial proteases. However, their effects on other human peptidases, like dipeptidyl peptidase IV (DPP-IV, EC 3.4.14.5) are not established. Inhibitors of DPP-IV activity are used for treating type 2 diabetes mellitus, cancers and immune system diseases. Bacitracin and bestatin inhibited porcine membrane-bound DPP-IV (pDPP-IV) activity. Mechanisms were different, i.e. non-competitive with α > 1 (α = 3.9) and Ki value of 75 μM for bestatin, and competitive with Ki value of 630 μM for bacitracin. The binding mode in the tertiary complex enzymesubstratebestatin suggested the structural basis of the inhibitory effect and that bestatin is potentially selective for DPP-IV, ineffective vs. S9 family members dipeptidyl peptidase 8/9 and fibroblast activation protein. In the human melanoma MeWo cell line, bestatin and bacitracin inhibited aminopeptidase N (APN) and DPP-IV activities, reduced cell viability and increased DNA fragmentation, suggesting induction of apoptosis. Since bacitracin and bestatin are already marketed drugs, studying in depth the molecular mechanisms underlying their effects on melanoma cells is warranted. Additionally, bestatin emerges as a new lead compound for the development of DPP-IV inhibitors, and a promising dual APN/DPP-IV inhibitor for the treatment of pathologies in which both enzymes are upregulated.Naja atra cobrotoxin and cardiotoxin 3 (CTX3) exhibit neurotoxicity and cytotoxicity, respectively. In the present study, we aimed to investigate whether the carboxyl groups of cobrotoxin play a role in structural constraints, thereby preventing cobrotoxin from exhibiting cytotoxic activity. Six of the seven carboxyl groups in cobrotoxin were conjugated with semicarbazide. Measurement of circular dichroism spectra and Trp fluorescence quenching showed that the gross conformation of semicarbazide-modified cobrotoxin (SEM-cobrotoxin) and cobrotoxin differed. In sharp contrast to cobrotoxin, SEM-cobrotoxin demonstrated membrane-damaging activity and cytotoxicity, which are feature more characteristic of CTX3. Furthermore, both SEM-cobrotoxin and CTX3 induced cell death through AMPK activation. Analyses of the interaction between polydiacetylene/lipid vesicles and fluorescence-labeled lipids revealed that SEM-cobrotoxin and cobrotoxin adopted different membrane-bound states. The structural characteristics of SEM-cobrotoxin were similar to those of CTX3, including trifluoroethanol (TFE)-induced structural transformation and membrane binding-induced conformational change.