AimSerotonin is crucial for proper foetal development, and the placenta has been described as a ‘donor’ of serotonin for the embryo/foetus. However, in later stages of gestation the foetus produces its own serotonin from maternally‐derived tryptophan and placental supply is no longer needed. We propose a novel model of serotonin homeostasis in the term placenta with special focus on the protective role of organic cation transporter 3 (OCT3/SLC22A3).MethodsDually perfused rat term placenta was employed to quantify serotonin/tryptophan transport and metabolism. Placental membrane vesicles isolated from human term placenta were used to characterize serotonin transporters on both sides of the syncytiotrophoblast.ResultsWe obtained the first evidence that serotonin is massively taken up from the foetal circulation by OCT3. This uptake is concentration‐dependent and inhibitable by OCT3 blockers of endogenous (glucocorticoids) or exogenous (pharmaceuticals) origin. Population analyses in rat placenta revealed that foetal sex influences placental extraction of serotonin from foetal circulation. Negligible foetal serotonin levels were detected in maternal‐to‐foetal serotonin/tryptophan transport and metabolic studies.ConclusionWe demonstrate that OCT3, localized on the foetus‐facing membrane of syncytiotrophoblast, is an essential component of foeto‐placental homeostasis of serotonin. Together with serotonin degrading enzyme, monoamine oxidase‐A, this offers a protective mechanism against local vasoconstriction effects of serotonin in the placenta. However, this system may be compromised by OCT3 inhibitory molecules, such as glucocorticoids or antidepressants. Our findings open new avenues to explore previously unsuspected/unexplained complications during pregnancy including prenatal glucocorticoid excess and pharmacotherapeutic risks of treating pregnant women with OCT3 inhibitors.

Placental Tryptophan Metabolism During Gestation models are not suitable to study placental handling of tryptophan. Altogether, our data provide the first comprehensive evidence of changes in placental homeostasis of tryptophan and its metabolites as a function of gestational age, which is critical for proper placental function and fetal development.

Menstrual cycle effects on postprandial lipemia were investigated in 13 healthy women. They were monitored (dietary intake, basal body temperature) for a period of one cycle. Statistically significant follicular-luteal differences were neither observed between fasting triglyceride serum levels nor between areas under triglyceride response curves after a standardized oral fat load.

Placental homeostasis of tryptophan is essential for fetal development and programming. The two main metabolic pathways (serotonin and kynurenine) produce bioactive metabolites with immunosuppressive, neurotoxic, or neuroprotective properties and their concentrations in the fetoplacental unit must be tightly regulated throughout gestation. Here, we investigated the expression/function of key enzymes/transporters involved in tryptophan pathways during mid-to-late gestation in rat placenta and fetal organs. Quantitative PCR and heatmap analysis revealed the differential expression of several genes involved in serotonin and kynurenine pathways. To identify the flux of substrates through these pathways, Droplet Digital PCR, western blot, and functional analyses were carried out for the rate-limiting enzymes and transporters. Our findings show that placental tryptophan metabolism to serotonin is crucial in mid-gestation, with a subsequent switch to fetal serotonin synthesis. Concurrently, at term, the close interplay between transporters and metabolizing enzymes of both placenta and fetal organs orchestrates serotonin homeostasis and prevents hyper/hypo-serotonemia. On the other hand, the placental production of kynurenine increases during pregnancy, with a low contribution of fetal organs throughout gestation. Any external insult to this tightly regulated harmony of transporters and enzymes within the fetoplacental unit may affect optimal in utero conditions and have a negative impact on fetal programming.

Tuberculosis (TB) caused by Mycobacterium tuberculosis (Mtb) has become a frequently deadly infection due to increasing antimicrobial resistance. This serious issue has driven efforts worldwide to discover new drugs effective against Mtb. One research area is the synthesis and evaluation of pyrazinamide derivatives as potential anti-TB drugs. In this paper we report the synthesis and biological evaluations of a series of ureidopyrazines. Compounds were synthesized by reacting alkyl/aryl isocyanates with aminopyrazine or with propyl 5-aminopyrazine-2-carboxylate. Reactions were performed in pressurized vials using a CEM Discover microwave reactor with a focused field. Purity and chemical structures of products were assessed, and the final compounds were tested in vitro for their antimycobacterial, antibacterial, and antifungal activities. Propyl 5-(3-phenylureido)pyrazine-2-carboxylate (compound 4, MICMtb = 1.56 μg/mL, 5.19 μM) and propyl 5-(3-(4-methoxyphenyl)ureido)pyrazine-2-carboxylate (compound 6, MICMtb = 6.25 μg/mL, 18.91 μM) had high antimycobacterial activity against Mtb H37Rv with no in vitro cytotoxicity on HepG2 cell line. Therefore 4 and 6 are suitable for further structural modifications that might improve their biological activity and physicochemical properties. Based on the structural similarity to 1-(2-chloropyridin-4-yl)-3-phenylurea, a known plant growth regulator, two selected compounds were evaluated for similar activity as abiotic elicitors.

Commercially available antibacterial semisolid preparations intended for topical application provide only short-term drug release. A sustained kinetics is possible by exploitation of a biodegradable polymer carrier. The purpose of this work is to formulate a mucoadhesive system with aciclovir (ACV) based on a solid molecular dispersion of this drug in poly(lactic-co-glycolic acid) branched on tripenterythritol (PLGA/T). The ACV incorporation into PLGA/T was carried out either by solvent method, or melting method, or plasticization method using various plasticizers. The drug-polymer miscibility, plasticizer efficiency and content of residual solvent were found out employing DSC. Viscosity was measured at the shear rate range from 0.10 to 10.00 s(-1) at three temperatures and data were analyzed by Newtonian model. The mucoadhesive properties were ascertained in the tensile test on a mucin substrate. The amount of ACV released was carried out in a wash-off dissolution test. The DSC results indicate a transformation of crystalline form of ACV into an amorphous dissolved in branched polyester carrier, and absence of methyl formate residuals in formulation. All the tested plasticizers are efficient at Tg depression and viscosity decrease. The non-conventional ethyl pyruvate possessing supportive anti-inflammatory activity was evaluated as the most suitable plasticizer. The ACV release was strongly dependent on the ethyl pyruvate concentration and lasted from 1 to 10 days. The formulated PLGA/T system with ACV exhibits increased adhesion to mucosal hydrophilic surfaces and prolonged ACV release controllable by degradation process and viscosity parameters.

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