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  • In support of our findings

    2019-07-24

    In support of our findings, in several population-based studies investigating the relationship between family diabetic history and the metabolic function of children and adolescents, paternal hyperglycemia was found to have a long-term effect on metabolic regulation of the next generation. Children whose fathers are diabetic are at a higher risk for developing BMS 986120 diseases [53], lower birth weight, higher BMI and higher plasma leptin concentrations in childhood [54,55]. Similarly, in a comparative survey of children of parents with diabetes mellitus and metabolic syndrome, the results revealed that BMI, SBP, and total cholesterol were higher in the group of children with diabetic fathers with metabolic syndrome but healthy mothers than in the group with both healthy parents [56]. Although controversies exist regarding how much paternal glycaemia can define the offspring metabolic state [3,57], most of the studies on human population have shown the intergenerational effects of father's diabetes status on the future offspring. It should be noted that the visualization of the PPARa MeDIP analysis showed that the intragenic regions were different between the groups. DNA methylation of the promoter region is a well-studied repressive modification for gene expression. However, emerging evidence shows the correlation between gene expression and DNA methylation status in other regions of the genome besides the promoter [[58], [59], [60], [61]]. Therefore, the possible contribution of DNA methylation to Ppara expression cannot be ruled out by our present study, and tis worthy of further investigations.
    Conclusions The following are the supplementary data related to this article.
    Transparency document
    Introduction Alzheimer's disease (AD), a degenerative disease of the central nervous system, was discovered by Alois Alzheimer in 1906. According to the World Alzheimer Report 2016 [1], 46.8 million individuals had AD in 2015, and that number will reach 131.5 million by 2050. Thus, AD will cause a substantial financial burden to society and families. Current drugs used to treat AD in the clinic include donepezil, galantamine, rivastigmine and memantine; however, these drugs are not highly effective. Therefore, the development of effective interventions as treatments for AD is urgently needed. AD is characterized by intracellular neurofibrillary tangles (NFTs), extracellular amyloid plaque deposits and neuronal loss, as well as behavioural deficits, such as learning and memory impairments. Based on mounting evidence, the accumulation of β-amyloid (Aβ) is the earliest and the most important event in AD pathogenesis [2,3], and the Aβ burden is significantly increased as the disease progresses [4]. Aβ accumulates in response to the imbalance between Aβ production and clearance. APP is degraded through the following two pathways: the non-amyloidogenic pathway and the amyloidogenic pathway. In the non-amyloidogenic pathway, α-secretase first cleaves APP, generating N-terminal sAPPα and CTF. Currently, the non-amyloidogenic pathway offers a new therapeutic option for AD because of the neuroprotective effect of sAPPα [5]. In the amyloidogenic pathway, Aβ peptides are generated from APP through a two-step proteolysis mediated by β-secretase and γ-secretase [6]. Familial AD accounts for <5%, while sporadic AD, also referred to as late-onset AD, accounts for approximately 95% of total AD cases. The main aetiology of sporadic AD is substantial Aβ deposition in the brain due to normal Aβ production, but defective Aβ clearance. Recently, BMS 986120 several clinical trials that reduced the production of Aβ using targeted drugs, such as β- or γ-secretase inhibitors, failed to improve cognitive impairments in patients with AD [7,8]. Due to the low permeability of the blood-brain barrier, the Aβ antibody only eliminated soluble Aβ in peripheral blood, which had little effect on AD treatment [9]. Therefore, small molecule therapeutic drugs that easily pass through the blood-brain barrier and improve Aβ clearance should be highly attractive.