Alzheimer’s disease (AD) is the most prevalent neurodegenerative disease worldwide, characterized by progressive neuron degeneration or loss due to excessive accumulation of β-amyloid (Aβ) peptides, formation of neurofibrillary tangles (NFTs), and hyperphosphorylated tau. The treatment of AD has been only partially successful as the majority of the pharmacotherapies on the market may alleviate some of the symptoms. In the occurrence of AD, increasing attention has been paid to neurodegeneration, while the resident glial cells, like microglia are also observed. Microglia, a kind of crucial glial cells associated with the innate immune response, functions as double-edge sword role in CNS. They exert a beneficial or detrimental influence on the adjacent neurons through secretion of both pro-inflammatory cytokines as well as neurotrophic factors. In addition, their endocytosis of debris and toxic protein like Aβ and tau ensures homeostasis of the neuronal microenvironment. In this review, we will systematically summarize recent research regarding the roles of microglia in AD pathology and latest microglia-associated therapeutic targets mainly including pro-inflammatory genes, anti-inflammatory genes and phagocytosis at length, some of which are contradictory and controversial and warrant to further be investigated.

The fetal origins of adult disease (FOAD) hypothesis, which was proposed by David Barker in the United Kingdom in the late 1980s, posited that adult chronic diseases originated from various adverse stimuli in early fetal development. FOAD is associated with a wide range of adult chronic diseases, including cardiovascular disease, cancer, type 2 diabetes and neurological disorders such as schizophrenia, depression, anxiety, and autism. Intrauterine hypoxia/prenatal hypoxia is one of the most common complications of obstetrics and could lead to alterations in brain structure and function; therefore, it is strongly associated with neurological disorders such as cognitive impairment and anxiety. However, how fetal hypoxia results in neurological disorders remains unclear. According to the existing literature, we have summarized the causes of prenatal hypoxia, the effects of prenatal hypoxia on brain development and behavioral phenotypes, and the possible molecular mechanisms.

Background: Paternal lifestyle, stress and environmental exposures play a crucial role in the health of offspring and are associated with non-genetic inheritance of acquired traits, however the underlying mechanisms are unclear. In this study, we aimed to find out how the sperm tsRNA involved in paternal high-fat diet induced abnormal gluconeogenesis of F1 offspring, and explore the underlying molecular mechanism of its regulation.Method: We generated a paternal high fat diet (42% kcal fat) model to investigate the mechanism by which paternal diet affects offspring metabolism. Four-week-old C57BL/6J male mice were randomly assigned into two groups to receive either a control diet (CD; 10% kcal fat) or a high-fat (HFD; 42% kcal fat) diet for 10 weeks, and mice from each group were then mated with 8-week-old females with control diet in a 1:2 ratio to generate F1. F0 sperms were isolated and small RNAs was sequenced by high-throughput sequencing. Metabolic phenotypes were examined with both F0 and F1.Results: A significant increase in body weight was observed with HFD-F0 mice at 8 weeks of age as compared to CD mice at the same age. F0 mice showed impaired glucose tolerance (GTT), resistance to insulin tolerance (ITT) and increased pyruvate tolerance (PTT) at 14 weeks. HFD-F1 male mice showed no significant difference in body weight. An increase in PTT was found at 13 weeks of age and no significant changes in GTT and ITT. PEPCK and G6Pase that related to gluconeogenesis increased significantly in the liver of HFD-F1 male mice. Sperm sequencing results showed that 5′tsRNA-Gly-GCC derived from tRNA-Gly-GCC-2 specifically was remarkably upregulated in sperm of HFD F0 mice. Q-PCR further showed that this tsRNA was also increased in the liver of HFD-F1 comparison with CD-F1 mice. In addition, we found that 5′tsRNA-Gly-GCC can regulate Sirt6-FoxO1 pathway and be involved in the gluconeogenesis pathway in liver.Conclusion: 5′tsRNA-Gly-GCC that increased in HFD mice mature sperms can promote gluconeogenesis in liver by regulating Sirt6-FoxO1 pathway, which might represent a potential paternal epigenetic factor mediating the intergenerational inheritance of diet-induced metabolic alteration.

Assisted reproductive technology (ART) has been used globally among infertile couples. However, many epidemiological investigations have indicated that ART is associated with a range of long-term adverse health outcomes in offspring, including cardiovascular disease, obesity and increased plasma lipid levels. Until now, direct evidence has been limited regarding the pathological changes in vascular function in fetuses with ART. In this study, human umbilical cords were collected from healthy normal pregnancies and IVF-ET pregnancies. Vascular functional studies involving acetylcholine (ACh), antagonists of its specific receptors, and L-type calcium channel/PKC-MLC20 phosphorylation pathway specific inhibitors were conducted. Quantitative real-time PCR, Western blotting and methylation analyses were performed on umbilical vein samples. We found that the umbilical vein constriction induced by ACh in the IVF-ET group was significantly attenuated compared with that in the healthy normal pregnancy group, which was not only associated with the hypermethylation of ACh muscarinic receptor subtype 3 (CHRM3) and decreased expression of CHRM3, PKCβ and CaV1.2, but was also related to the reduced phosphorylation of MLC20. The present study revealed that the hypermethylation of CHRM3, leading to a reduction in CHRM3 expression and downregulation of the CaV1.2/PKC-MLC20 phosphorylation pathway, was responsible for the decreased sensitivity to ACh observed in the umbilical vein under IVF-ET conditions. The hypermethylation of CHRM3 caused by IVF-ET might play an important role in altered vasoconstriction and impact cardiovascular systems in the long run.

Background Familial progressive hyper- and hypopigmentation (FPHH, MIM 145250) is a rare hereditary skin disorder that is predominantly characterized by progressive, diffuse, partly blotchy hyperpigmented lesions intermingled with scattered hypopigmented spots, lentigines and sometimes Cafe-au-lait spots (CALs). Heterozygous mutations of the KIT ligand (KITLG, MIM 184745) gene are responsible for FPHH. To date, only eight KITLG mutations have been reported to be associated with FPHH, and no clear genotype–phenotype correlations have been established. This study aimed to identify the causative mutations in the KITLG gene in two Chinese FPHH patients. Methods Direct sequencing of the coding regions of KITLG was performed. Pathogenicity prediction was performed using bioinformatics tools, including SIFT, Polyphen2, and SWISS-MODEL, and the results were further evaluated according to the 2015 American College of Medical Genetics and Genomics (ACMG) guidelines. Results The novel mutation c.104A > T (p.Asn35Ile) and the recurrent mutation c.101C > T (p.Thr34Ile) in KITLG were identified. As shown using SIFT and Polyphen-2 software, both mutations identified in this study were predicted to be detrimental variations. Three-dimensional protein structure modeling indicated that the mutant KITLG proteins might affect the affinity of KITLG for its receptor, c-KIT. According to the 2015 ACMG guidelines, the novel mutation c.104A > T was ‘likely pathogenic’. Conclusions To date, most of the identified KITLG mutations have been clustered within the conserved VTNNV motif (amino acids 33–37) in exon 2. The known mutations are only involved in 33 V, 34 T, 36 N, and 37 V but not 35 N. We have now identified a novel mutation in KITLG, c.104A > T, that was first reported in FPHH within the conserved 35 N motif. These results strengthen our understanding of FPHH and expand the mutational spectrum of the KITLG gene.