With the advent of next-generation sequencing, an increasing number of cases of de novo variants in domestic animals have been reported in scientific literature primarily associated with clinically ...severe phenotypes. The emergence of new variants at each generation is a crucial aspect in understanding the pathology of early-onset diseases in animals and can provide valuable insights into similar diseases in humans. With the aim of collecting deleterious de novo variants in domestic animals, we searched the scientific literature and compiled reports on 42 de novo variants in 31 genes in domestic animals. No clear disease-associated phenotype has been established in humans for three of these genes (NUMB, ANKRD28 and KCNG1). For the remaining 28 genes, a strong similarity between animal and human phenotypes was recognized from available information in OMIM and OMIA, revealing the importance of comparative studies and supporting the use of domestic animals as natural models for human diseases, in line with the One Health approach.
De novo mutations (DNMs) are variants that occur anew in the offspring of noncarrier parents. They are not inherited from either parent but rather result from endogenous mutational processes ...involving errors of DNA repair/replication. These spontaneous errors play a significant role in the causation of genetic disorders, and their importance in the context of molecular diagnostic medicine has become steadily more apparent as more DNMs have been reported in the literature. In this study, we examined 46,489 disease-associated DNMs annotated by the Human Gene Mutation Database (HGMD) to ascertain their distribution across gene and disease categories.
Most disease-associated DNMs reported to date are found to be associated with developmental and psychiatric disorders, a reflection of the focus of sequencing efforts over the last decade. Of the 13,277 human genes in which DNMs have so far been found, the top-10 genes with the highest proportions of DNM relative to gene size were H3-3 A, DDX3X, CSNK2B, PURA, ZC4H2, STXBP1, SCN1A, SATB2, H3-3B and TUBA1A. The distribution of CADD and REVEL scores for both disease-associated DNMs and those mutations not reported to be de novo revealed a trend towards higher deleteriousness for DNMs, consistent with the likely lower selection pressure impacting them. This contrasts with the non-DNMs, which are presumed to have been subject to continuous negative selection over multiple generations.
This meta-analysis provides important information on the occurrence and distribution of disease-associated DNMs in association with heritable disease and should make a significant contribution to our understanding of this major type of mutation.
Although fruit juices are a natural source of sugars, there is a controversy whether their sugar content has similar harmful effects as beverages’ added-sugars. We aimed to study the role of fruit ...juice sugars in inducing overweight, hyperglycaemia, glycation and oxidative stress in normal and diabetic animal models. In diabetic Goto-Kakizaki (GK) rats, we compared the effects of four different fruit juices (4-weeks) with sugary solutions having a similar sugar profile and concentration. In vitro, the sugary solutions were more susceptible to AGE formation than fruit juices, also causing higher postprandial glycaemia and lower erythrocytes’ antioxidant capacity in vivo (single intake). In GK rats, ad libitum fruit juice consumption (4-weeks) did not change body weight, glycaemia, oxidative stress nor glycation. Consumption of a matched volume of sugary solutions aggravated fasting glycaemia but had a moderate impact on caloric intake and oxidative stress/glycation markers in tissues of diabetic rats. Ad libitum availability of the same sugary solutions impaired energy balance regulation, leading to higher caloric intake than ad libitum fruit juices and controls, as well as weight gain, fasting hyperglycaemia, insulin intolerance and impaired oxidative stress/glycation markers in several tissues. We demonstrated the distinct role of sugars naturally present in fruit juices and added sugars in energy balance regulation, impairing oxidative stress, glycation and glucose metabolism in an animal model of type 2 diabetes.
Nutritional disturbances during the early postnatal period can have long-lasting effects on neurodevelopment and may be related to behavioural changes at adulthood. While such neuronal connection ...disruption can contribute to social and behaviour alterations, the dysregulation of the neuroendocrine pathways involved in nutrient-sensing balance may also cause such impairments, although the underlying mechanisms are still unclear. We aimed to evaluate sex-specific neurodevelopmental and behavioural changes upon postnatal overfeeding and determine the potential underpinning mechanisms at the central nervous system level, with a focus on the interconnection between synaptic and neuroendocrine molecular alterations. At postnatal day 3 (PND3) litters were culled to three animals (small litter procedure). Neurodevelopmental tests were conducted at infancy, whereas behavioural tests to assess locomotion, anxiety, and memory were performed at adolescence, together with molecular analysis of the hippocampus, hypothalamus, and prefrontal cortex. At infancy, females presented impaired acquisition of an auditory response, eye opening, olfactory discrimination, and vestibular system development, suggesting that female offspring neurodevelopment/maturation was deeply affected. Male offspring presented a transitory delay in locomotor performance., while both offspring had lower upper limb strength. At adolescence, both sexes presented anxious-like behaviour without alterations in short-term memory retention. Both males and females presented lower NPY1R levels in a region-specific manner. Furthermore, both sexes presented synaptic changes in the hippocampus (lower GABAA in females and higher GABAA levels in males), while, in the prefrontal cortex, similar higher GABAA receptor levels were observed. At the hypothalamus, females presented synaptic changes, namely higher vGLUT1 and PSD95 levels. Thus, we demonstrate that postnatal overfeeding modulates offspring behaviour and dysregulates nutrient-sensing mechanisms such as NPY and GABA in a sex- and brain-region-specific manner.
Oxidative stress is involved in the metabolic dysregulation of type 2 diabetes (DM2).
(Aa) fruit pulp has been described for the treatment of several diseases, and recently we have proved that its ...leaves have phenolic compounds with a marked antioxidant effect. We aimed to assess whether they can improve metabolic, redox and vascular functions in DM2. Control Wistar (W-Ctrl) and non-obese type 2 diabetic Goto-Kakizaki (GK-Ctrl) rats were treated for 30 days with 200 mg.kg
aqueous extract of Aa (EA-Aa) (Wistar, W-EA-Aa/GK, GK-EA-Aa). EA-Aa was able to reduce fasting glycaemia and triglycerides of GK-EA-Aa by improving proteins related to glucose and lipid metabolism, such as GLUT-4, PPARγ, AMPK, and IR, when compared to GK-Ctrl. It also improved viability of 3T3-L1 pre-adipocytes exposed by H
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EA-Aa also increased the levels of catalase in the aorta and kidney, reduced oxidative stress and increased relaxation of the aorta in GK-treated rats in relation to GK-Ctrl, in addition to the protective effect against oxidative stress in HMVec-D cells. We proved the direct antioxidant potential of the chemical compounds of EA-Aa, the increase in antioxidant defences in a tissue-specific manner and hypoglycaemic properties, improving vascular function in type 2 diabetes. EA-Aa and its constituents may have a therapeutic potential for the treatment of DM2 complications.
Obesogenic environments such as Westernized diets, overnutrition, and exposure to glycation during gestation and lactation can alter peripheral neuroendocrine factors in offspring, predisposing for ...metabolic diseases in adulthood. Thus, we hypothesized that exposure to obesogenic environments during the perinatal period reprograms offspring energy balance mechanisms. Four rat obesogenic models were studied: maternal diet-induced obesity (DIO); early-life obesity induced by postnatal overfeeding; maternal glycation; and postnatal overfeeding combined with maternal glycation. Metabolic parameters, energy expenditure, and storage pathways in visceral adipose tissue (VAT) and the liver were analyzed. Maternal DIO increased VAT lipogenic NPY receptor-1 (NPY1R), NPY receptor-2 (NPY2R), and ghrelin receptor, but also lipolytic/catabolic mechanisms dopamine-1 receptor (D1R) and p-AMP-activated protein kinase (AMPK) in male offspring, while reducing NPY1R in females. Postnatally overfed male animals only exhibited higher NPY2R levels in VAT, while females also presented NPY1R and NPY2R downregulation. Maternal glycation reduces VAT expandability by decreasing NPY2R in overfed animals. Regarding the liver, D1R was decreased in all obesogenic models, while overfeeding induced fat accumulation in both sexes and glycation the inflammatory infiltration. The VAT response to maternal DIO and overfeeding showed a sexual dysmorphism, and exposure to glycotoxins led to a thin-outside-fat-inside phenotype in overfeeding conditions and impaired energy balance, increasing the metabolic risk in adulthood.
Type 2 diabetes
(DM) continues to escalate, necessitating innovative therapeutic approaches that target distinct pathways and address DM complications. Flavonoids have been shown to possess several ...pharmacological activities that are important for DM. This study aimed to evaluate the in vivo effects of the flavonoid melanoxetin using Goto-Kakizaki rats. Over a period of 14 days, melanoxetin was administered subcutaneously to investigate its antioxidant, anti-inflammatory, and antidiabetic properties. The results show that melanoxetin reduced insulin resistance in adipose tissue by targeting protein tyrosine phosphatase 1B. Additionally, melanoxetin counteracted oxidative stress by reducing nitrotyrosine levels and modulating superoxide dismutase 1 and hemeoxygenase in adipose tissue and decreasing methylglyoxal-derived hydroimidazolone (MG-H1), a key advanced glycation end product (AGE) implicated in DM-related complications. Moreover, the glyoxalase 1 expression decreased in both the liver and the heart, correlating with reduced AGE levels, particularly MG-H1 in the heart. Melanoxetin also demonstrated anti-inflammatory effects by reducing serum prostaglandin E
levels, and increasing the antioxidant status of the aorta wall through enhanced acetylcholine-dependent relaxation in the presence of ascorbic acid. These findings provide valuable insights into melanoxetin's therapeutic potential in targeting multiple pathways involved in type 2 DM, particularly in mitigating oxidative stress and glycation.
Lactation is a crucial postnatal programming window which can interfere with child development and predispose to metabolic disorders later in life, as insulin resistance and obesity. Although ...breastfeeding is known to prevent many diseases in the newborn, changes in milk composition have been correlated with alterations in central nervous system maturation and differentiation. Changes in milk quality and quantity may predispose to metabolic disorders later in life but have also been linked to the development of neuronal diseases. Maternal metabolic condition, diet and behaviours have been considered determinant for metabolic programming in the child, although the mechanisms involved remain to be elucidated. Some of such mechanisms may also be related with the increasing prevalence of neurodevelopmental and behavioural diseases in the younger generations. This review focuses on the interconnected risks between changes of maternal metabolic status/unbalanced diets during lactation and offspring's development of metabolic and neurodevelopmental disorders. Furthermore, the present review reunites the current knowledge about the mechanisms underlying the association between these disorders and highlights the need of further exploring the impact of lactation period on neurodevelopmental and metabolic outcomes.
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X-linked loci have a unique pattern of inheritance and are therefore a valuable resource in population genetics. X-linked adrenoleukodystrophy (ALD) is a rare genetic disease and the most common ...leukodystrophy. It is a progressive disease that affects the adrenal cortex and the central and peripheral nervous system. Although is X-linked and male patients show the most severe clinical manifestations of the disease, 80% of female patients have a progression that resembles adrenomyeloneuropathy (AMN) that is a form of X-ALD.Patients affected by ALD have deleterious variants in the ABCD1 gene. The ABCD1 gene codes an ATP-binding cassette sub-family D member 1 (ABCD1), a transmembrane protein that carries very long chain fatty acids (VLCFA), such are CoAesters, to the peroxisome where β-oxidation occurs. Deleterious variants in this gene disrupt normal metabolism and lead to the accumulation of very long-chain fatty acids (VLCFA) in the plasma, spinal cord, the white matter of the brain, and adrenal cortex. Current knowledge is still insufficient to accurately predict the severity of the disease, because even within the same family different manifestations of the disease can occur. This wide range of clinical phenotyopes has been observed, even in monozygotic twins carrying the same deleterious variant. This indicates that genetic modifiers (intragenic and/or intergenic) exist and can modulate the phenotype, similarly to what was observed in other human genes.To evaluate the possibility that intragenic polymorphic variants can act as genetic modifiers of the disease the polymorphic variants of the ABCD1 gene were examined in this work. The analyses were conducted at the population level to assess differences in allelic frequencies. Conservation scores were also utilized as a measure to predict the potential impact of each polymorphism. Our findings indicate that among the most common polymorphism of the ABCD1gene, Val583Ala and Val604Ile, may have a modulating effect, therefore, future investigation should include experimental analyses to determine if there are differences in the activity of each allele and the influence when co-occurring with other alleles in the same genetic background.
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