Hui Fang

Hepatoblastoma is a malignant embryonal tumor with multiple differentiation modes and is the clearest liver malignancy in children. However, little is known about genetic and epigenetic events in Hepatoblastoma. Increased research has recently demonstrated, unique genetic and epigenetic events in Hepatoblastoma, providing insights into its origin and precise treatment. Some genetic disorders and congenital factors are associated with the risk of Hepatoblastoma development, such as the Beckwith-Wiedemann syndrome, Familial Adenomatous polyposis, and Hemihypertrophy. Epigenetic modifications such as DNA modifications, histone modifications, and non-coding RNA regulation are also essential in the development of Hepatoblastoma. Herein, we reviewed genetic and epigenetic events in Hepatoblastoma, focusing on the relationship between these events and cancer susceptibility, tumor growth, and prognosis. By deciphering the genetic and epigenetic associations in Hepatoblastoma, tumor pathogenesis can be clarified, and guide the development of new anti-cancer drugs and prevention strategies.

Clinical reports suggest a potential link between excess retinoids and development of depression. Although it has been shown that all-trans retinoic acid (ATRA) administration induces behavioral changes, further insight into how ATRA is involved is lacking. The hippocampus seems to be a major target of retinoids, and abnormal synaptic plasticity of the hippocampus is involved in depression. We examined two genes associated with synaptic function, discs large homolog 2 (DLG2), and synapse differentiation-inducing gene protein 1 (SynDIG1) in terms of hippocampal expression and correlation with behavior. Three different doses of ATRA were injected into young mice and 10 mg/kg ATRA was found to induce depression-like behavior. In the hippocampus, DLG2 mRNA was significantly decreased by ATRA. mRNA levels were positively correlated with central area duration and distance in the open-field test. Increased SynDIG1 mRNA levels were observed. There was a negative correlation between SynDIG1 mRNA levels and mobility time in the forced swimming test. Retinoic acid receptor γ mRNA was significantly positively correlated with DLG2 and negatively correlated with SynDIG1. To summarize, ATRA administration induced anxiety- and depression-like behavior accompanied by a decreased expression of DLG2 and an increased expression of SynDIG1. Moreover, DLG2 was correlated with anxiety-like behavior and SynDIG1 was correlated with depression-like behavior. These results might constitute a novel target underlying ATRA-induced anxiety- and depression-like behavior.

OBJECTIVE: Stress and fear conditioning are both involved in the development of affective disorders, but their interconnected relationship remains unclear. Here in this study we employed acute and chronic stress model to investigate their respective effect on fear conditioning and the CRFR1 signaling change in the limbic areas including mPFC, hippocampus and BLA. METHODS: Male rats were subjected to acute restraint stress or chronic unpredictable mild stress before open field test and fear condition test. In situ hybridization was used to investigate CRFR1 mRNA expression in limbic region including mPFC, hippocampus and BLA. RESULTS: Our results demonstrated that acute and chronic stress have opposite effects on the acquisition of fear conditioning, which is correlated to CRFR1 mRNA expression in hippocampus; however, they have similar effects on fear extinction and both facilitated contextual-related fear conditioning. CONCLUSION: Our findings revealed acute and chronic stress led to distinct behavioral responses in fear conditioning and indicated CRFR1 is involved in the interaction of stress and fear conditioning, which help understand the connection between stress and fear memory.

Anxiety symptoms occur in a large portion of Alzheimer’s disease (AD) patients. ApolipoproteinE-4 (ApoE ε4 allele), a risk factor for AD, has been recognized as an important contributor to psychiatric disorders. In the present study, we aimed to investigate the corticosterone level in relation to anxiety-like behavior changes in transgenic male mice with different glial fibrillary acidic protein (GFAP)-ApoE isoforms. GFAP-ApoE4 transgenic mice aged 3 months showed higher anxiety-like behavior in open field, light–dark box and elevated plus maze tasks compared with that of age-matched GFAP-ApoE3 mice. However, corticotropin releasing factor levels in the hypothalamus and plasma corticosterone secretion were similar in GFAP-ApoE3 and GFAP-ApoE4 transgenic male mice. Additionally, increased expression of the mineralocorticoid receptor (MR) and unchanged expression of the glucocorticoid receptor were observed in the hypothalamus of GFAP-ApoE4 mice. However, no significant differences were found in the expression levels of the MR in GFAP-ApoE3 and GFAP-ApoE4 mice at postnatal day 2. In conclusion, we found that MR upregulation rather than corticosterone level changes in the early stage of adulthood was associated with the higher anxiety-like level measured in GFAP-ApoE4 mice.

Stress is increasingly present in everyday life in our fast-paced society and involved in the pathogenesis of many psychiatric diseases. Corticotrophin-releasing-hormone (CRH) plays a pivotal role in regulating the stress responses. The tree shrews are highly vulnerable to stress which makes them the promising animal models for studying stress responses. However, the mechanisms underlying their high stress-susceptibility remained unknown. Here we confirmed that cortisol was the dominate corticosteroid in tree shrew and was significantly increased after acute stress. Our study showed that the function of tree shrew CRH - hypothalamic-pituitary-adrenal (HPA) axis was nearly identical to human that contributed little to their hyper-responsiveness to stress. Using CRH transcriptional regulation analysis we discovered a peculiar active glucocorticoid receptor response element (aGRE) site within the tree shrew CRH promoter, which continued to recruit co-activators including SRC-1 (steroid receptor co-activator-1) to promote CRH transcription under basal or forskolin/dexamethasone treatment conditions. Basal CRH mRNA increased when the aGRE was knocked into the CRH promoter in human HeLa cells using CAS9/CRISPR. The aGRE functioned critically to form the “Stress promoter” that contributed to the higher CRH expression and susceptibility to stress. These findings implicated novel molecular bases of the stress-related diseases in specific populations.

The apolipoprotein E (ApoE) ɛ4 allele (ApoE4) is an important genetic risk factor for the pathogenesis of Alzheimer's disease (AD). In addition to genetic factors, environmental factors such as stress may play a critical role in AD pathogenesis. This study was designed to investigate the anxiety-like behavioral and cognitive changes in different human glial fibrillary acidic protein (GFAP)-ApoE transgenic adult male mice under chronic stress conditions. On the open field test, anxiety-like behavior was increased in the non-stressed GFAP-ApoE4 transgenic mice relative to the corresponding GFAP-ApoE3 (ApoE ɛ3 allele) mice. Anxiety-like behavior was increased in the stressed GFAP-ApoE3 mice relative to non-stressed GFAP-ApoE3 mice, but was unexpectedly decreased in the stressed GFAP-ApoE4 mice relative to non-stressed GFAP-ApoE4 mice. On the novel object recognition task, both GFAP-ApoE4 and GFAP-ApoE3 mice exhibited long-term non-spatial memory impairment after chronic stress. Interestingly, short-term non-spatial memory impairment (based on the novel object recognition task) was observed only in the stressed GFAP-ApoE4 male mice relative to non-stressed GFAP-ApoE4 transgenic mice. In addition, short-term spatial memory impairment was observed in the stressed GFAP-ApoE3 transgenic male mice relative to non-stressed GFAP-ApoE3 transgenic male mice; however, short-term spatial memory performance of GFAP-ApoE4 transgenic male mice was not reduced compared to non-stressed control mice based on the Y-maze task. In conclusion, our findings suggested that chronic stress affects anxiety-like behavior and spatial and non-spatial memory in GFAP-ApoE transgenic mice in an ApoE isoform-dependent manner.

Previous studies reported that environmental enrichment might induce various beneficial effects in the central nervous system. However, the effect of environmental factors on endogenous estrogen level was not investigated. The present study was designed to examine the effect of enriched environment on endogenous estrogen in hippocampus and behavioral outcomes. Behavioural measurements, including open field, elevated plus maze and Morris water maze, were used to evaluate anxiety and learning and memory of the male C57BL/6J mice that were housed in enriched environment for five months. In addition, the estrogen and brain-derived neurotrophic factor (BDNF) expression in the hippocampus were measured. We found that environmental enrichment decreased anxiety-like behaviors and facilitated spatial learning and memory in male C57BL/6J mice. In addition, the mice raised in enriched environment showed decreased endogenous estrogen levels both in the hippocampus and plasma compared to controls. Furthermore, our results indicated that environmental enrichment up-regulated BDNF mRNA expression level in the hippocampus. In conclusion, environmental enrichment decreased anxiety-like behaviors and facilitated spatial learning and memory in male C57BL/6J mice. Lastly, environmental enrichment up-regulated BDNF mRNA expression level in the hippocampus and decreased plasma estrogen level. The possible mechanism remained to be determined.