Prenatal Cannabis Use and Infant Birth Outcomes in the Pregnancy Risk Assessment Monitoring System.

OBJECTIVES: To examine the association of prenatal cannabis use and adverse infant outcomes in a nationally representative cohort and consider the impact of concurrent cigarette exposure. STUDY DESIGN: We conducted a retrospective cohort study on 32 583 new mothers from the 2017-2019 Pregnancy Risk Assessment Monitoring System. Cannabis use was evaluated as a binary variable (use or no use) as well as ordinal categories (no, light, moderate, heavy use). We used multivariable logistic regression to examine the relationship between prenatal cannabis exposure and low birthweight (LBW), preterm birth, and small for gestational age. RESULTS: Prenatal cannabis use was associated with significantly greater odds of LBW (aOR, 1.27; 95% CI, 1.05-1.54) and small for gestational age (aOR, 1.35; 95% CI, 1.09-1.68) but not preterm birth. Compared with nonusers, heavy users (weekly or more) were twice as likely to deliver a LBW infant (aOR, 2.07; 95% CI, 1.46-2.94) or small for gestational age infant (aOR, 2.14; 95% CI, 1.38-3.30). When examining combined cannabis and cigarette use, prenatal exposure to both substances increased the likelihood of LBW (aOR, 2.27; 95% CI, 1.71-3.01), preterm birth (aOR, 1.61; 95% CI, 1.12-2.31), and small for gestational age (aOR, 3.29; 95% CI, 2.39-4.55) compared with no use, and the increased odds were greater than for either substance alone. CONCLUSIONS: Our results suggest that cannabis use during pregnancy may harm fetal development, and recommendations to improve birth outcomes should address co-use of cannabis and tobacco.

Calcitonin receptors are ancient modulators for rhythms of preferential temperature in insects and body temperature in mammals.

Daily body temperature rhythm (BTR) is essential for maintaining homeostasis. BTR is regulated separately from locomotor activity rhythms, but its molecular basis is largely unknown. While mammals internally regulate BTR, ectotherms, including Drosophila, exhibit temperature preference rhythm (TPR) behavior to regulate BTR. Here, we demonstrate that the diuretic hormone 31 receptor (DH31R) mediates TPR during the active phase in Drosophila DH31R is expressed in clock cells, and its ligand, DH31, acts on clock cells to regulate TPR during the active phase. Surprisingly, the mouse homolog of DH31R, calcitonin receptor (Calcr), is expressed in the suprachiasmatic nucleus (SCN) and mediates body temperature fluctuations during the active phase in mice. Importantly, DH31R and Calcr are not required for coordinating locomotor activity rhythms. Our results represent the first molecular evidence that BTR is regulated distinctly from locomotor activity rhythms and show that DH31R/Calcr is an ancient specific mediator of BTR during the active phase in organisms ranging from ectotherms to endotherms.

Insights into the phosphatidylcholine and phosphatidylethanolamine biosynthetic pathways in Leishmania parasites and characterization of a choline kinase from Leishmania infantum.

The protozoan parasite Leishmania infantum is a causative agent of the disease visceral leishmaniasis, which can be fatal if not properly treated. Phosphatidylcholine (PC) and phosphatidylethanolamine (PE) biosynthesis pathways are attractive targets for new antileishmanial compounds since these Leishmania cell membrane phospholipids are important for parasite morphology and physiology. In this work we observed Leishmania synthesize PC and PE from extracellular choline and ethanolamine, respectively, suggesting the presence of CDP-choline and CDP-ethanolamine pathways. In addition, Leishmania converted PE to PC, indicating the parasite possesses phosphatidylethanolamine N-methyltransferase (PEMT) activity. The first step in the biosynthesis of PC or PE requires the phosphorylation of choline or ethanolamine by a kinase. We cloned the gene encoding a putative choline/ethanolamine kinase from Leishmania infantum and expressed and purified the encoded recombinant protein. The enzyme possesses choline kinase activity with a Vmax of 3.52µmol/min/mg and an apparent Km value of 0.089mM with respect to choline. The enzyme can also phosphorylate ethanolamine in vitro, but the apparent Km for ethanolamine is 850-fold greater than for choline. In an effort to probe requirements for small molecule inhibition of Leishmania choline kinase, the recombinant enzyme was evaluated for the ability to be inhibited by novel quaternary ammonium salts. The most effective inhibitor was N-iodomethyl-N,N,-dimethyl-N-(6,6-diphenyl hex-5-en-1-yle) ammonium iodide, denoted compound C6. In the presence of 4mM compound C6, the Vmax/Km decreased to approximately 1% of the wild-type catalytic efficiency. In addition, in Leishmania cells treated with compound C6 choline transport was inhibited.

Inhibitory effects of decavanadate on several enzymes and Leishmania tarentolae in vitro.

Multiple studies report apparent effects of vanadium on various systems in vivo and in vitro. Vanadium species may be possible deterrents for the growth of the Leishmania parasite, which causes the sometimes deadly diseases known as leishmaniasis. The current studies focus specifically on decavanadate V(10)O(28)(6-) (V10), which has a potential to be a potent effector for disease treatment. The X-ray structure of a new solvate salt of V10, namely (NH(4))(6)V(10)O(28)·5H(2)O, is also reported. Other vanadium complexes with imidazole carboxylate, anthranilate, or picolinate were also evaluated. The yellow-orange oxoanion, used as the (NH(4))(6)V(10)O(28)·6H(2)O salt, was tested (at 1-100 µM) directly with two strains of Leishmania tarentolae promastigotes in culture to evaluate the effect on cell viability. Vanadium coordination complexes are known effective inhibitors of phosphatases. Using the artificial phosphatase substrate para-nitrophenylphosphate in the presence of a bovine calf intestine alkaline phosphatase enzyme, V10 (from 5 to 100 µM) was shown to be a mixed inhibitor for this enzyme and decreased the activity of the other two phosphatases tested. The effect of V10 and the other vanadium complexes on the activity of phosphoglycerate mutase B (PGAM), an important enzyme in glycolysis and gluconeogenesis, was also evaluated. At 10 µM, V10 was the most potent inhibitor of PGAM, with an apparent reduction of about 50%. Taken together, we speculate that V10 could have a role in treating Leishmania diseases.

New application for expanded porphyrins: sapphyrin and heterosapphyrins as inhibitors of Leishmania parasites.

Sapphyrins and a series of related porphyrinoid macrocycles have been investigated as potential agents for the treatment of leishmaniasis. The effectiveness of the compounds was evaluated in vitro upon incubation with Leishmania tarentolae or L. panamensis amastigotes and promastigotes. Their effectiveness was also assessed against intracellular L. panamensis. The cytotoxicity of the compounds was evaluated in vitro using the U937 human promonocyte cell line. Effectiveness and cytotoxicity were assessed in the presence and absence of visible light to assess the photodynamic activity of the compounds. Sapphyrin and two related heterosapphyrins were shown to be particularly effective as inhibitors of Leishmania. A photodynamic effect was observed, which may be attributed to the formation of reactive oxygen species. Yields of singlet oxygen ((1)O(2)) produced were determined in ethanol solutions by direct measurement of (1)O(2) phosphorescence. Confocal microscopy demonstrated that sapphyrin and related macrocycles were taken up by the Leishmania cells and that their presence induces the formation of mitochondrial superoxide. Sapphyrins have been widely investigated as anticancer agents and we here show activity against the Leishmania parasites.