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Fatty acid binding proteins (FABPs) govern intracellular lipid transport to cytosolic organelles and nuclear receptors. More recently, FABP5 has emerged as a key regulator of synaptic endocannabinoid signaling, suggesting that FABPs may broadly regulate the signaling of neuroactive lipids in the brain. Herein, we demonstrate that brain-expressed FABPs (FABP3, FABP5, and FABP7) interact with epoxyeicosatrienoic acids (EETs) and the peroxisome proliferator-activated receptor gamma agonist 15-deoxy-Δ 12,14 -Prostaglandin J2 (15d-PGJ 2 ). Among these lipids, EETs displayed highest affinities for FABP3 and FABP5, and 11,12-EET was identified as the preferred FABP ligand. Similarly, 15d-PGJ 2 interacted with FABP3 and FABP5 while binding to FABP7 was markedly lower. Molecular modeling revealed unique binding interactions of the ligands within the FABP binding pockets and highlighted major contributions of van der Waals clashes and acyl chain solvent exposure in dictating FABP affinity and specificity. Functional studies demonstrated that endogenous EETs gate the strength of CA1 hippocampal glutamate synapses and that this function was impaired following FABP inhibition. As such, the present study reveals that FABPs control EET-mediated synaptic gating, thereby expanding the functional roles of this protein family in regulating neuronal lipid signaling., (© 2023. Springer Nature Limited.)

Indigenous populations are disproportionately affected by type 2 diabetes (T2DM) compared to non-Indigenous people. Of importance, the prevalence of T2DM is greater amongst females than males in First Nations communities, in contrast to higher male prevalence reported in non-Indigenous Canadians. Therefore, in this study we extend our previously published work with respect to females, and the potential association between environmental exposures to organochlorine pesticides, such as dichlorodiphenyltrichloroethane (DDT), and dichlorodiphenyldichloroethylene (DDE) to explain the greater prevalence of T2DM among Indigenous females compared to males. Using data from the Multi-Community Environment-and-Health Study, Principal Component Analysis (PCA), examined 9-polychlorinated biphenyl congeners, 7-organic pesticides, and 4-metal/metalloids. Modified Poisson regression with robust error variance estimated adjusted prevalence ratios (PR) and corresponding 95% confidence intervals (95% CI), regressing prevalent T2DM on the newly derived principal components (PC), adjusting for a priori covariates, including parity. We further examined the relationship between high detection concentrations of DDT and tertials of categorized DDE exposures on T2DM among Indigenous Cree women. Among 419 female participants, 23% (n = 95) had physician-diagnosed T2DM. PCA analysis show that DDT and Lead (Pb) loaded highly on the second axis (PC-2), although in opposite directions, indicating the different exposure sources. As previously published, T2DM was significantly associated with PC-2 across adjusted models, however, after further adjusting for parity in this analysis, T2DM was no longer significantly associated with increasing PC-2 scores (PR = 0.88, 95% 0.76, 1.03). Furthermore, we found that the highest detectable levels of DDT, and tertiles of DDE were significantly associated with prevalent T2DM in the fully adjusted model (PR = 1.93, 1.17, 3.19), and (PR = 3.58, 1.10, 11.70), respectively. This cross-sectional analysis suggests organochlorines, specifically, detectable high exposure concentrations of DDT and DDE are associated with prevalent type 2 diabetes, signifying a possible important link between parity and environmental organochlorines pesticides among Indigenous Cree women. [ABSTRACT FROM AUTHOR]

Stressful conditions during development can have sub-lethal consequences on organisms aside from mortality. Using previously reported in-hive residues from commercial colonies, we examined how multi-pesticide exposure can influence honey bee (Apis mellifera) queen health. We reared queens in beeswax cups with or without a pesticide treatment within colonies exposed to treated or untreated pollen supplement. Following rearing, queens were open-mated and then placed into standard hive equipment in an "artificial swarm" to measure subsequent colony growth. Our treated wax had a pesticide Hazard Quotient comparable to the average in beeswax from commercial colonies, and it had no measurable effects on queen phenotype. Conversely, colonies exposed to pesticide-treated pollen had a reduced capacity for viable queen production, and among surviving queens from these colonies we observed lower sperm viability. We found no difference in queen mating number across treatments. Moreover, we measured lower brood viability in colonies later established by queens reared in treated-pollen colonies. Interestingly, royal jelly from colonies exposed to treated pollen contained negligible pesticide residues, suggesting the indirect social consequences of colony-level pesticide exposure on queen quality. These findings highlight how conditions during developmental can impact queens long into adulthood, and that colony-level pesticide exposure may do so indirectly.

Maternal nicotine exposure causes several consequences in offspring phenotype, such as obesity and thyroid dysfunctions. Nicotine exposure can increase oxidative stress levels, which could lead to thyroid dysfunction. However, the mechanism by which nicotine exposure during breastfeeding leads to thyroid gland dysfunction remains elusive. We aimed to investigate the long-term effects of maternal nicotine exposure on redox homeostasis in thyroid gland, besides other essential steps for thyroid hormone synthesis in rats from both sexes. Lactating Wistar rats were implanted with osmotic minipumps releasing nicotine (NIC, 6 mg/kg/day) or saline (control) from postnatal day 2 to 16. Offspring were analyzed at 180-day-old. NIC males showed lower plasma TSH, T 3 and T 4 while NIC females had higher T 3 and T 4 . In thyroid, NIC males had higher sodium-iodide symporter protein expression, whereas NIC females had higher thyroid-stimulating hormone receptor (TSHr) and thyroperoxidase (TPO) protein expression. TPO activity was lower in NIC males. Hydrogen peroxide generation was decreased in NIC males. Activities of superoxide dismutase, catalase and glutathione peroxidase were compromised in NIC animals from both sexes. 4-Hydroxynonenal was higher only in NIC females, while thiol was not affected in NIC animals from both sexes. NIC offspring also had altered expression of sex steroid receptors in thyroid gland. Both sexes showed similar thyroid morphology, with lower follicle and colloid size. Thyroid from female offspring exposed to nicotine during breastfeeding developed oxidative stress, while the male gland seemed to be protected from redox damage. Thyroid dysfunctions seem to be associated with redox imbalance in a sex-dependent manner.

Phosphorylation of Munc18-1 (Stxbp1), a presynaptic organizer of synaptic vesicle fusion, is a powerful mechanism to regulate synaptic strength. Munc18-1 is a proposed substrate for the Down Syndrome-related kinase dual-specificity tyrosine phosphorylation-regulate kinase 1a (Dyrk1a) and mutations in both genes cause intellectual disability. However, the functional consequences of Dyrk1a-dependent phosphorylation of Munc18-1 for synapse function are unknown. Here, we show that the proposed Munc18-1 phosphorylation site, T479, is among the highly constrained phosphorylation sites in the coding regions of the gene and is also located within a larger constrained coding region. We confirm that Dyrk1a phosphorylates Munc18-1 at T479. Patch-clamp physiology in conditional null mutant hippocampal neurons expressing Cre and either wildtype, or mutants mimicking or preventing phosphorylation, revealed that synaptic transmission is similar among the three groups: frequency/amplitude of mEPSCs, evoked EPSCs, paired pulse plasticity, rundown kinetics upon intense activity and the readily releasable pool. However, synapses expressing the phosphomimic mutant responded to intense activity with more pronounced facilitation. These data indicate that Dyrk1a-dependent Munc18-1 phosphorylation has a minor impact on synaptic transmission, only after intense activity, and that the role of genetic variation in both genes in intellectual disability may be through different mechanisms.

Recently developed genomics-based tools are allowing repositioning of Food and Drug Administration (FDA)-approved drugs as cancer treatments, which were employed to identify drugs that target cancer stem cells (CSCs) of breast cancer. Gene expression datasets of CSCs from six studies were subjected to connectivity map to identify drugs that may ameliorate gene expression patterns unique to CSCs. All-trans retinoic acid (ATRA) was negatively connected with gene expression in CSCs. ATRA reduced mammosphere-forming ability of a subset of breast cancer cells, which correlated with induction of apoptosis, reduced expression of SOX2 but elevated expression of its antagonist CDX2. SOX2/CDX2 ratio had prognostic relevance in CSC-enriched breast cancers. K-ras mutant breast cancer cell line enriched for CSCs was resistant to ATRA, which was reversed by MAP kinase inhibitors. Thus, ATRA alone or in combination can be tested for efficacy using SOX2, CDX2, and K-ras mutation/MAPK activation status as biomarkers of response. [ABSTRACT FROM AUTHOR]