Contribution of ceramides metabolism in psychiatric disorders.

Psychiatric disorders affect 970 million people worldwide, representing a significant source of disability. Although the underlying neurobiological traits for these disorders are not fully understood, a complex interplay between psychological, environmental, and biological factors contributes to their outcomes. Recent advances in lipidomic analysis and artificial intelligence algorithms have improved the identification of selective lipid species modulating the susceptibility to mental disorders. Sphingolipids (SLs) and ceramides-related SLs are among the most abundant lipids species in the brain that support major key pathways during neurodevelopment and brain plasticity. High levels of ceramides in plasma and brain contribute to psychiatric illness susceptibility in humans and animal models. However, the neuropathological mechanism regarding the involvement of ceramides in these disorders remain inconclusive. The brain is highly susceptible to nutritional insults, which could lead to functional impairment and influence the development and progression of psychiatric disorders. While the brain relies on glucose metabolism to support its physiological needs, a selective nutrient formula appears to have greater effects on brain health than others. For instance, consumption of high-energy diets is associated with brain anatomical, physiological, and metabolic changes, including ceramides metabolism. Herein, we will address the contribution of ceramides metabolism as a modulator of major psychiatric disorders such as depression, anxiety, bipolar disorder, schizophrenia, and attention deficit-hyperactivity disorder. We will also describe molecular and cellular targets of ceramides metabolism assisting the maintenance and progression of psychiatric disorders and their modulation by dietary formulas as non-pharmacologic treatments.

Mobile Source Benzene Regulations and Risk of Childhood and Young Adult Hematologic Cancers in Alaska: A Quasi-experimental Study.

BACKGROUND: We aimed to evaluate the impact of the EPA's Mobile Source Air Toxics rules (MSAT), which targeted benzene emissions, on childhood and young adult leukemia and lymphoma incidence in Alaska. METHODS: MSAT was implemented in 2011 and produced a dramatic decline in ambient benzene in Alaska. Due to previous benzene-related regulations enacted in the continental United States, MSAT had relatively modest impacts in other states. This created quasi-experimental conditions leveraged in this study. Using 2-year state-level incidence rates of childhood and young adult leukemia and lymphoma for each US state 2001-2018, we examined MSAT-attributable changes in incidence by applying a difference-in-differences approach. RESULTS: We found evidence of a substantial reduction associated with MSAT in incidence of childhood and young adult lymphoma (-1.23 [-1.84, -0.62] cases per 100,000), but not in leukemia (-0.13 [-0.77, 0.51] cases per 100,000). CONCLUSIONS: Our findings are consistent with the hypothesis that MSAT, which reduced benzene levels in Alaska, led to a decline in lymphoma incidence in children and young adults.

Consequences of the exposome to gestational diabetes mellitus.

The exposome is the cumulative measure of environmental influences and associated biological responses throughout the lifespan, including those from the environment, diet, behaviour, and endogenous processes. The exposome concept and the 2030 Agenda for the Sustainable Development Goals (SDGs) from the United Nations are the basis for understanding the aetiology and consequences of non-communicable diseases, including gestational diabetes mellitus (GDM). Pregnancy may be developed in an environment with adverse factors part of the immediate internal medium for fetus development and the external medium to which the pregnant woman is exposed. The placenta is the interface between maternal and fetal compartments and acts as a protective barrier or easing agent to transfer exposome from mother to fetus. Under and over-nutrition in utero, exposure to adverse environmental pollutants such as heavy metals, endocrine-disrupting chemicals, pesticides, drugs, pharmaceuticals, lifestyle, air pollutants, and tobacco smoke plays a determinant role in the development of GDM. This phenomenon is worsened by metabolic stress postnatally, such as obesity which increases the risk of GDM and other diseases. Clinical risk factors for GDM development include its aetiology. It is proposed that knowledge-based interventions to change the potential interdependent ecto-exposome and endo-exposome could avoid the occurrence and consequences of GDM.

Maternal care of the whole litter improves the success rate of diabetes in pregnancy in rats.

Induction of diabetes mellitus by streptozotocin (STZ) in rats at birth is of high mortality and low success rate when male puppies are separated from females, prioritizing females breastfeeding. Cross-parental care of the entire litter and SZT-induced diabetes up to 12 h post-birth become with high success rate, low animal death, and females with glycaemia >140 mg/dL on the 90 postnatal day. Cross-parental care is more effective in STZ-induction of diabetes, which is maintained during pregnancy (diabetes in pregnancy), than the conventional protocol of male separation at birth.

The role of damage associated molecular pattern molecules (DAMPs) and permeability of the blood-brain barrier in depression and neuroinflammation.

Depression is a heterogeneous mental disorder characterized by feelings of sadness and loss of interest that render the subject unable to handle basic daily activities such as sleeping, eating, or working. Neurobiological traits leading to depression include genetic background, early life abuse, life stressors, and systemic and central inflammatory profiles. Several clinical and preclinical reports documented that depression shows an increase in pro-inflammatory markers such as interleukin (IL-)1ß, IL-6, IL-12, tumor necrosis factor (TNF), and interferon (IFN)-γ; and a decrease in anti-inflammatory IL-4, IL-10, and transforming growth factor (TGF)-ß species. Inflammatory activation may trigger and maintain depression. Dynamic crosstalk between the peripheral immune system and the central nervous system (CNS) such as activated endothelial cells, monocytes, monocyte-derived dendritic cells, macrophages, T cells, and microglia has been proposed as a leading cause of neuroinflammation. Notably, pro-inflammatory cytokines disrupt the hypothalamic-pituitary-adrenal (HPA) axis and serotonergic, noradrenergic, dopaminergic, and glutamatergic neurotransmission. While still under investigation, peripheral cytokines can engage brain pathways and affect the central synthesis of HPA hormones and neurotransmitters through several mechanisms such as activation of the vagus nerve, increasing the permeability of the blood-brain barrier (BBB), altered cytokines transport systems, and engaging toll-like receptors (TLRs) by pathogen-associated molecular patterns (PAMPs) or damage-associated molecular patterns (DAMPs). However, physiological mechanisms that favor time-dependent central inflammation before or during illness are not totally understood. This review will provide preclinical and clinical evidence of DAMPs and the BBB permeability as contributors to depression and neuroinflammation. We will also discuss pharmacologic approaches that could potentially modulate DAMPs and BBB permeability for future interventions against major depression.

Maternal high-dense diet programs interferon type I signaling and microglia complexity in the nucleus accumbens shell of rats showing food addiction-like behavior.

OBJECTIVE: This study aimed to characterize the molecular immune networks and microglia reactivity in the nucleus accumbens (NAc) shell affected by fetal nutritional programming leading to addiction-like behavior in the offspring of Wistar rats. Fetal nutritional programming by energy-dense foods leads to addiction-like behavior in the offspring. Exposure to energy-dense foods also activates systemic and central inflammation in the offspring. METHODS: Females Wistar rats were exposed to cafeteria (CAF) diet or control diet for 9 weeks (prepregnancy, pregnancy and lactation), and male offspring at 2 months of age were diagnosed with food addiction-like behavior using operant conditioning. Global microarray analysis, RTqPCR, proinflammatory plasma profile and microglia immunostaining were performed in the NAc shell of male rats. SIM-A9 microglia cells were stimulated with IFN-α and palmitic acid, and microglia activation and phagocytosis were determined by RTqPCR and incubation of green-fluorescent latex beads, respectively. RESULTS: Microarray analysis in the NAc shell of the male offspring exposed to CAF during development and diagnosed with addiction-like behavior showed increasing in the type I interferon-inducible gene, Ift1 , gene network. Genomic and cellular characterization also confirmed microglia hyperreactivity and upregulation of the Ifit1 in the NAc shell of animals with addiction-like behavior. In-vitro models demonstrated that microglia do respond to IFN-α promoting a time-dependent genomic expression of Ift1, IL-1ß and IL-6 followed by increased phagocytosis. CONCLUSION: Prenatal exposure to energy-dense foods primes the IFN type I signaling and microglia complexity in the NAc shell of rats diagnosed with food addiction-like behavior.

Glycaemia dynamics in gestational diabetes mellitus.

Pregnant women may develop gestational diabetes mellitus (GDM), a disease of pregnancy characterised by maternal and fetal hyperglycaemia with hazardous consequences to the mother, the fetus, and the newborn. Maternal hyperglycaemia in GDM results in fetoplacental endothelial dysfunction. GDM-harmful effects result from chronic and short periods of hyperglycaemia. Thus, it is determinant to keep glycaemia within physiological ranges avoiding short but repetitive periods of hyper or hypoglycaemia. The variation of glycaemia over time is defined as 'glycaemia dynamics'. The latter concept regards with a variety of mechanisms and environmental conditions leading to blood glucose handling. In this review we summarized the different metrics for glycaemia dynamics derived from quantitative, plane distribution, amplitude, score values, variability estimation, and time series analysis. The potential application of the derived metrics from self-monitoring of blood glucose (SMBG) and continuous glucose monitoring (CGM) in the potential alterations of pregnancy outcome in GDM are discussed.

Exposome and foetoplacental vascular dysfunction in gestational diabetes mellitus.

A balanced communication between the mother, placenta and foetus is crucial to reach a successful pregnancy. Several windows of exposure to environmental toxins are present during pregnancy. When the women metabolic status is affected by a disease or environmental toxin, the foetus is impacted and may result in altered development and growth. Gestational diabetes mellitus (GDM) is a disease of pregnancy characterised by abnormal glucose metabolism affecting the mother and foetus. This disease of pregnancy associates with postnatal consequences for the child and the mother. The whole endogenous and exogenous environmental factors is defined as the exposome. Endogenous insults conform to the endo-exposome, and disruptors contained in the immediate environment are the ecto-exposome. Some components of the endo-exposome, such as Selenium, vitamins D and B12, adenosine, and a high-fat diet, and ecto-exposome, such as the heavy metals Arsenic, Mercury, Lead and Copper, and per- and polyfluoroakyl substances, result in adverse pregnancies, including an elevated risk of GDM or gestational diabesity. The impact of the exposome on the human placenta's vascular physiology and function in GDM and gestational diabesity is reviewed.

Pro-angiogenic approach for skeletal muscle regeneration.

The angiogenesis process is a phenomenon in which numerous molecules participate in the stimulation of the new vessels' formation from pre-existing vessels. Angiogenesis is a crucial step in tissue regeneration and recovery of organ and tissue function. Muscle diseases affect millions of people worldwide overcome the ability of skeletal muscle to self-repair. Pro-angiogenic therapies are key in skeletal muscle regeneration where both myogenesis and angiogenesis occur. These therapies have been based on mesenchymal stem cells (MSCs), exosomes, microRNAs (miRs) and delivery of biological factors. The use of different calls of biomaterials is another approach, including ceramics, composites, and polymers. Natural polymers are use due its bioactivity and biocompatibility in addition to its use as scaffolds and in drug delivery systems. One of these polymers is the natural rubber latex (NRL) which is biocompatible, bioactive, versatile, low-costing, and capable of promoting tissue regeneration and angiogenesis. In this review, the advances in the field of pro-angiogenic therapies are discussed.

Gestational diabesity and foetoplacental vascular dysfunction.

Gestational diabetes mellitus (GDM) shows a deficiency in the metabolism of D-glucose and other nutrients, thereby negatively affecting the foetoplacental vascular endothelium. Maternal hyperglycaemia and hyperinsulinemia play an important role in the aetiology of GDM. A combination of these and other factors predisposes women to developing GDM with pre-pregnancy normal weight, viz. classic GDM. However, women with GDM and prepregnancy obesity (gestational diabesity, GDty) or overweight (GDMow) show a different metabolic status than women with classic GDM. GDty and GDMow are associated with altered l-arginine/nitric oxide and insulin/adenosine axis signalling in the human foetoplacental microvascular and macrovascular endothelium. These alterations differ from those observed in classic GDM. Here, we have reviewed the consequences of GDty and GDMow in the modulation of foetoplacental endothelial cell function, highlighting studies describing the modulation of intracellular pH homeostasis and the potential implications of NO generation and adenosine signalling in GDty-associated foetal vascular insulin resistance. Moreover, with an increase in the rate of obesity in women of childbearing age worldwide, the prevalence of GDty is expected to increase in the next decades. Therefore, we emphasize that women with GDty and GDMow should be characterized with a different metabolic state from that of women with classic GDM to develop a more specific therapeutic approach for protecting the mother and foetus.

Mitochondrial dysfunction in the fetoplacental unit in gestational diabetes mellitus.

Gestational diabetes mellitus (GDM) is a disease of pregnancy that is associated with d-glucose intolerance and foeto-placental vascular dysfunction. GMD causes mitochondrial dysfunction in the placental endothelium and trophoblast. Additionally, GDM is associated with reduced placental oxidative phosphorylation due to diminished activity of the mitochondrial F0F1-ATP synthase (complex V). This phenomenon may result from a higher generation of reactive superoxide anion and nitric oxide. Placental mitochondrial biogenesis and mitophagy work in concert to maintain cell homeostasis and are vital mechanisms securing the efficient generation of ATP, whose demand is higher in pregnancy, ensuring foetal growth and development. Additional factors disturbing placental ATP synthase activity in GDM include pre-gestational maternal obesity or overweight, intracellular pH, miRNAs, fatty acid oxidation, and foetal (and 'placental') sex. GDM is also associated with maternal and foetal hyperinsulinaemia, altered circulating levels of adiponectin and leptin, and the accumulation of extracellular adenosine. Here, we reviewed the potential interplay between these molecules or metabolic conditions on the mechanisms of mitochondrial dysfunction in the foeto-placental unit in GDM pregnancies.

Fetal Programming by Methyl Donors Modulates Central Inflammation and Prevents Food Addiction-Like Behavior in Rats.

Fetal programming by hypercaloric intake leads to food addiction-like behavior and brain pro-inflammatory gene expression in offspring. The role of methylome modulation during programming on central immune activation and addiction-like behavior has not been characterized. We employed a nutritional programming model exposing female Wistar rats to chow diet, cafeteria (CAF), or CAF-methyl donor's diet from pre-pregnancy to weaning. Addiction-like behavior in offspring was characterized by the operant training response using Skinner boxes. Food intake in offspring was determined after fasting-refeeding schedule and subcutaneous injection of ghrelin. Genome-wide DNA methylation in the nucleus accumbens (NAc) shell was performed by fluorescence polarization, and brain immune activation was evaluated using real-time PCR for pro-inflammatory cytokines (IL-1ß, TNF-1α, and IL-6). Molecular effects of methyl modulators [S-adenosylmethionine (SAM) or 5-azatidine (5-AZA)] on pro-inflammatory cytokine expression and phagocytosis were identified in the cultures of immortalized SIM-A9 microglia cells following palmitic acid (100 µM) or LPS (100 nM) stimulation for 6 or 24 h. Our results show that fetal programming by CAF exposure increases the number of offspring subjects and reinforcers under the operant training response schedule, which correlates with an increase in the NAc shell global methylation. Notably, methyl donor's diet selectively decreases lever-pressing responses for reinforcers and unexpectedly decreases the NAc shell global methylation. Also, programmed offspring by CAF diet shows a selective IL-6 gene expression in the NAc shell, which is reverted to control values by methyl diet exposure. In vitro analysis identified that LPS and palmitic acid activate IL-1ß, TNF-1α, and IL-6 gene expression, which is repressed by the methyl donor SAM. Finally, methylation actively represses phagocytosis activity of SIM-A9 microglia cells induced by LPS and palmitic acid stimulation. Our in vivo and in vitro data suggest that fetal programming by methyl donors actively decreases addiction-like behavior to palatable food in the offspring, which correlates with a decrease in NAc shell methylome, expression of pro-inflammatory cytokine genes, and activity of phagocytic microglia. These results support the role of fetal programming in brain methylome on immune activation and food addiction-like behavior in the offspring.

Characterization of type "B" esterases and hepatic CYP450 isoenzimes in Senegalese sole for their further application in monitoring studies.

In fish, the role that cholinesterases (ChEs) play in tissues other than those implicated in neural activity, as well as the involvement of carboxylesterases (CbEs) and cytochrome P450 isoenzymes (CYPs) in drug metabolism needs investigation. For that, Senegalese sole (Solea senegalensis) specimens were selected for characterization of several type B esterases and hepatic CYPs in order to further use this fish as sentinel. ChEs (acetylcholinesterase (AChE) and pseudocholinesterases (butyrylcholinesterase-BuChE and propionilcholinesterase-PrChE)) and CbEs were measured in brain, plasma, kidney, liver, gonad, muscle and gills. Moreover, seven fluorimetric substrates were selected to study CYP related activities in fish liver. The results showed that AChE was the dominant ChE form in brain whereas pseudocholinesterases were absent in most tissues, as demonstrated by low enzymatic activities using specific substrates and the lack of inhibition by iso-OMPA. Plasma exhibited trace activities of all the esterases assayed and no BuChE activity. CbEs were dominant in liver, but they were also present in kidney and brain. For CbE determination, α-naphtyl acetate (αNA) was seen as the most adequate substrate as it displayed higher enzymatic activities and showed more in vitro sensitivity to the carbamate eserine and the organophosphate pesticide dichlorvos. Alkoxyresorufin-O-dealkylase (EROD and BFCOD) activities, indicative in mammals of CYP1A and CYP3A subfamilies, respectively, were the highest microsomal CYP-related activities in liver. The results of this preliminary work allow us to select the most adequate esterase substrate, tissue and hepatic CYP substrate for further monitoring studies.