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Paternal environmental factors before conception and during sperm development may influence the offspring's health later in life. This study aimed to investigate whether paternal exposure to anabolic-androgenic steroids (AAS) before conception predisposes mouse offspring to autism spectrum disorder (ASD)-like behavior. For this purpose, male Swiss mice were randomly divided into two groups: the control group received peanut oil, while the treated group was administered testosterone propionate (7.5 mg/kg, s.c.) twice a week for five weeks. After this period, these males were mated, and their offspring underwent a behavioral test battery at 70 days of age, including the open field test, object recognition task, three-chamber social approach test, and light-dark box test. At the end of the experiment, the hippocampus was dissected for RNA analysis. Our results indicate that paternal AAS treatment induces long-lasting behavioral alterations in both female and male offspring, including increased anxiety-like behavior, impaired memory, and deficits in social interaction. Additionally, a strong effect of paternal AAS treatment during preconception period was verified in Gad1, Gabra2 and Bdnf expression. These findings suggest that paternal AAS exposure may program neurodevelopmental vulnerabilities in offspring, contributing to ASD-like phenotypes. Show less

The present study investigated the effect of perinatal programming combined with exposure to a western diet on gene expression related to inflammation, neurodegeneration, and synaptic plasticity in the hippocampus of adult rats. Male rats from mothers fed either a standard diet or a western diet during gestation and lactation were used. All pups received only the standard chow diet from the 25th postnatal day (PND), and their body weight was analysed. Rats from the two groups fed the maternal diet were then divided on the 195 Adult rats submitted to a western diet during pregnancy and lactation showed signs of metabolic programming. In addition, glucose and total protein were found to have increased in the serum. The effect of acute exposure to a western diet is increased cholesterol. The western diet decreased gene expression of inflammatory factors ( Acute exposure to a western diet in adulthood alters pre-translational pathways ( Show less

Alzheimer's disease (AD) is a progressive neurodegenerative disorder affecting millions of people worldwide, with its prevalence expected to rise in the coming years. Due to the complexity of AD and the intricate interplay among its pathological mechanisms, the development of multitarget-directed ligands (MTDLs) has emerged as a promising therapeutic strategy. These compounds could simultaneously modulate multiple pathogenic pathways. Specifically, cholinergic and amyloid mechanisms, implicated in the onset of the disease, are regulated by AChE and BACE1, respectively. Therefore, targeting both pathways offers substantial therapeutic potential for AD. Computational tools can be useful in the identification of potential MTDL for these enzymes, reducing both costs and time in the drug discovery process. This review explores the relevance of this approach in the research and development for novel AD therapies, highlighting ongoing efforts focused on the identification and development of MTDLs for AChE and BACE1 inhibition through in silico methods. Virtual screening was the most frequently applied technique for a fast selection of ligands based on their affinity for the enzymes of interest. The in silico ADMET prediction also appears with a technique that allows the screening of compounds with drug-likeness. Moreover, evidence suggests that combining multiple computational methods can effectively identify drug candidates with optimized properties for target modulation and brain bioavailability. Show less

Complex diseases arise from the interplay of genetic and environmental factors. We present a case where complex diseases seem to coexist. A 12-month-old girl was referred for short stature and hypotonia. Initial evaluation revealed central hypothyroidism, growth hormone deficiency and a small pituitary gland with ectopic neurohypophysis. Replacement therapy improved growth, but developmental delay and strabismus ensued. At age 10, she experienced a first seizure treated with levetiracetam. At age 12, she presented diabetic ketoacidosis and functional insulin therapy was started; positive autoantibodies confirmed autoimmune etiology. Initial genetic testing performed by microarray analysis retrieved normal results, but exome sequencing revealed a heterozygous pathogenic variant in KANSL1 gene, allowing for the diagnosis of Koolen-de Vries syndrome. In this patient, Koolen-de Vries syndrome presented initially as hypopituitarism and only later epilepsy. Afterwards, type 1 diabetes mellitus ensued, highlighting the complexity of intertwined conditions. Show less

Objective To analyze the morphological and functional characteristics of primary macronodular adrenal hyperplasia (PMAH) nodules carrying or not carrying ARMC5 mutations and the consequences of the presence of mutations in terms of the pattern of macronodule composition and functional state. Subjects and methods The analyses were performed by hematoxylin-eosin staining, immunohistochemistry, microdissection of spongiocyte tissue and RT-qPCR of histological sections from 16 patients diagnosed with PMAH with germline (5) or germline/somatic mutations (5) and without mutations (6) in the ARMC5 gene. Results Hyperplastic nodules were predominantly composed of spongiocytes in mutated and nonmutated sections. ARMC5 mRNA expression in spongiocytes was higher in ARMC5-mutated nodules than in ARMC5-nonmutated nodules, and homogenous ARMC5 protein distribution was observed. The presence of arginine-vasopressin receptor (AVP1AR) and ectopic ACTH production were observed in both cell populations regardless of ARMC5 mutations; the numbers of serotonin receptor (5HT4R)- and proliferating cell nuclear antigen (PCNA)-positive cells were higher in macronodules carrying ARMC5 mutations than in those without mutations. Conclusions Our results suggest that the presence of ARMC5 mutations does not interfere with the pattern of distribution of spongiocytes and compact cells or with the presence of AVP1AR, gastric-inhibitory polypeptide receptor (GIPR) and ectopic ACTH. Nevertheless, the higher numbers of PCNA-positive cells in mutated nodules than in nonmutated nodules suggest that mutated ARMC5 can be related to higher proliferation rates in these cells. In conclusion, our results provide more information about the crosstalk among abnormal GPCRs, ectopic ACTH in steroidogenesis and the ARMC5 gene, which may be relevant in understanding the pathogenesis and diagnosis of patients with PMAH. Show less

Maternal smoking is a risk factor for progeny obesity. We have previously shown, in a rat model of neonatal tobacco smoke exposure, a mild increase in food intake and a considerable increase in visceral adiposity in the adult offspring. Males also had secondary hyperthyroidism, while females had only higher T4. Since brown adipose tissue (BAT) hypofunction is related to obesity, here we tested the hypothesis that higher levels of thyroid hormones are not functional in BAT, suggesting a lower metabolic rate. We evaluated autonomic nerve activity in BAT and its function in adult rats that were exposed to tobacco smoke during lactation. At birth, litters were adjusted to 3 male and 3 female pups/litter. From postnatal day (PND) 3 to 21, Wistar lactating rats and their pups were divided into SE group, smoke-exposed in a cigarette smoking machine (4 times/day) and C group, exposed to filtered air. Offspring were sacrificed at PND180. Adult SE rats of both genders had lower interscapular BAT autonomic nervous system activity, with higher BAT mass but no change in morphology. BAT UCP1 and CPT1a protein levels were decreased in the SE groups of both genders. Male SE rats had lower β3-AR, TRα1, and TRβ1 expression while females showed lower PGC1α expression. BAT Dio2 mRNA and hypothalamic POMC and MC4R levels were similar between groups. Hypothalamic pAMPK level was higher in SE males and lower in SE females. Thus, neonatal cigarette smoke exposure induces lower BAT thermogenic capacity, which can be obesogenic at adulthood. Show less