Excessive mitochondrial fission is a prominent early event and contributes to mitochondrial dysfunction, synaptic failure, and neuronal cell death in the progression of Alzheimer's disease (AD). However, it remains to be determined whether inhibition of excessive mitochondrial fission is beneficial in mammal models of AD. To determine whether dynamin-related protein 1 (Drp1), a key regulator of mitochondrial fragmentation, can be a disease-modifying therapeutic target for AD, we examined the effects of Drp1 inhibitor on mitochondrial and synaptic dysfunctions induced by oligomeric amyloid-β (Aβ) in neurons and neuropathology and cognitive functions in Aβ precursor protein/presenilin 1 double-transgenic AD mice. Inhibition of Drp1 alleviates mitochondrial fragmentation, loss of mitochondrial membrane potential, reactive oxygen species production, ATP reduction, and synaptic depression in Aβ-treated neurons. Furthermore, Drp1 inhibition significantly improves learning and memory and prevents mitochondrial fragmentation, lipid peroxidation, BACE1 expression, and Aβ deposition in the brain in the AD model. These results provide evidence that Drp1 plays an important role in Aβ-mediated and AD-related neuropathology and in cognitive decline in an AD animal model. Therefore, inhibiting excessive Drp1-mediated mitochondrial fission may be an efficient therapeutic avenue for AD. Mitochondrial fission relies on the evolutionary conserved dynamin-related protein 1 (Drp1). Drp1 activity and mitochondria fragmentation are significantly elevated in the brains of sporadic Alzheimer's disease (AD) cases. In the present study, we first demonstrated that the inhibition of Drp1 restored amyloid-β (Aβ)-mediated mitochondrial dysfunctions and synaptic depression in neurons and significantly reduced lipid peroxidation, BACE1 expression, and Aβ deposition in the brain of AD mice. As a result, memory deficits in AD mice were rescued by Drp1 inhibition. These results suggest that neuropathology and combined cognitive decline can be attributed to hyperactivation of Drp1 in the pathogenesis of AD. Therefore, inhibitors of excessive mitochondrial fission, such as Drp1 inhibitors, may be a new strategy for AD.

BACE1 is the rate-limiting enzyme for amyloid-β peptides (Aβ) generation, a key event in the pathogenesis of Alzheimer's disease (AD). By an unknown mechanism, levels of BACE1 and a BACE1 mRNA-stabilizing antisense RNA (BACE1-AS) are elevated in the brains of AD patients, implicating that dysregulation of BACE1 expression plays an important role in AD pathogenesis. We found that nuclear factor erythroid-derived 2-related factor 2 (NRF2/ NFE2L2) represses the expression of BACE1 and BACE1-AS through binding to antioxidant response elements (AREs) in their promoters of mouse and human. NRF2-mediated inhibition of BACE1 and BACE1-AS expression is independent of redox regulation. NRF2 activation decreases production of BACE1 and BACE1-AS transcripts and Aβ production and ameliorates cognitive deficits in animal models of AD. Depletion of NRF2 increases BACE1 and BACE1-AS expression and Aβ production and worsens cognitive deficits. Our findings suggest that activation of NRF2 can prevent a key early pathogenic process in AD.A lzheimer's disease (AD) is the most common type of dementia and is characterized by accumulation of amyloid-β (Aβ) plaques and neurofibrillary tangles, synaptic and neuronal loss, and cognitive decline. BACE1 is the only β-secretase responsible for the production of Aβ and therefore plays a key role in the pathogenesis of AD (1-3). A long noncoding RNA transcribed from the opposite strand of BACE1 (BACE1-AS) stabilizes BACE1 mRNA by forming a heteromeric RNA duplex (4). BACE1 mRNA and protein levels as well as BACE1-AS transcript are abnormally elevated in postmortem brain tissue from patients with AD (4-8). A small increase in BACE1 induces a dramatic increase in Aβ production (9), and inhibitors of BACE1 enzyme activity are being pursued as a therapeutic strategy for AD (10). Genetic reduction of BACE1 or BACE1-AS levels reduces Aβ plaque pathology in mouse models of AD (4, 11-13), suggesting that identification of transcriptional repressors of BACE1 gene expression could provide an avenue for intervention in AD.Nuclear factor erythroid-derived 2-related factor 2 (NRF2/ NFE2L2) is a transcription factor that binds to the antioxidant response elements (AREs) and regulates a variety of cytoprotective and detoxification genes (14). In the inactive state, kelch-like ECHassociated protein1 (KEAP1) binds to NRF2 and retains it in the cytoplasm where it is degraded by proteasomes (15, 16). NRF2 activators, such as sulforaphane and tert-butylhydroquinone (tBHQ), modify cysteine residues of KEAP1, leading to conformational change and disrupting the KEAP1-NRF2 interaction, and accumulated NRF2 then translocates to the nucleus and transactivates target genes by binding to their AREs (17,18). NRF2 levels are reduced, and NRF2 is localized predominately in the cytoplasm of hippocampal neurons of AD patients (19). In addition, altered expression of NRF2 target genes is associated with Aβ pathology in AD animal models (20)(21)(22). Here we show that NRF2 is a negative regulator of BACE1 expression that can am...

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Cancer can be identified as a chaotic cell state, which breaks the rules that govern growth and reproduction, with main characteristics such as uncontrolled division, invading other tissues, usurping resources, and eventually killing its host. It was once believed that cancer is caused by a progressive series of genetic aberrations, and certain mutations of genes, including oncogenes and tumor suppressor genes, have been identified as the cause of cancer. However, piling evidence suggests that epigenetic modifications working in concert with genetic mechanisms to regulate transcriptional activity are dysregulated in many diseases, including cancer. Cancer epigenetics explain a wide range of heritable changes in gene expression, which do not come from any alteration in DNA sequences. Aberrant DNA methylation, histone modifications, and expression of long non-coding RNAs (lncRNAs) are key epigenetic mechanisms associated with tumor initiation, cancer progression, and metastasis. Within the past decade, cancer epigenetics have enabled us to develop novel biomarkers and therapeutic target for many types of cancers. In this review, we will summarize the major epigenetic changes involved in cancer biology along with clinical and preclinical results developed as novel cancer therapeutics.

Effective dopamine (DA) neuron differentiation from neural precursor cells (NPCs) is prerequisite for precursor/ stem cell-based therapy of Parkinson's disease (PD). Nurr1, an orphan nuclear receptor, has been reported as a transcription factor that can drive DA neuron differentiation from non-dopaminergic NPCs in vitro. However, Nurr1 alone neither induces full neuronal maturation nor expression of proteins found specifically in midbrain DA neurons. In addition, Nurr1 expression is inefficient in inducing DA phenotype expression in NPCs derived from certain species such as mouse and human. We show here that Foxa2, a forkhead transcription factor whose role in midbrain DA neuron development was recently revealed, synergistically cooperates with Nurr1 to induce DA phenotype acquisition, midbrain-specific gene expression, and neuronal maturation. Thus, the combinatorial expression of Nurr1 and Foxa2 in NPCs efficiently yielded fully differentiated nigral (A9)-type midbrain neurons with clearly detectable DA neuronal activities. The effects of Foxa2 in DA neuron generation were observed regardless of the brain regions or species from which NPCs were derived. Furthermore, DA neurons generated by ectopic Foxa2 expression were more resistant to toxins. Importantly, Foxa2 expression resulted in a rapid cell cycle exit and reduced cell proliferation. Consistently, transplantation of NPCs transduced with Nurr1 and Foxa2 generated grafts enriched with midbrain-type DA neurons but reduced number of proliferating cells, and significantly reversed motor deficits in a rat PD model. Our findings can be applied to ongoing attempts to develop an efficient and safe precursor/stem cell-based therapy for PD. STEM CELLS 2010;28:501-512

We previously reported that apicidin, a novel histone deacetylase inhibitor, inhibited the proliferation of tumor cells via induction of p21 WAF1/Cip1 . In this study, we determined the molecular mechanisms by which apicidin induced the p21 WAF1/Cip1 gene expression in HeLa cells. Apicidin induced p21 WAF1/Cip1 mRNA independent of the de novo protein synthesis and activated the p21 WAF1/Cip1 promoter through Sp1-3 site located at ؊82 and ؊77 relative to the transcription start site. This transcriptional activation appears to be mediated by protein kinase C (PKC), because calphostin C, a PKC inhibitor, significantly attenuated the activation of p21 WAF1/Cip1 promoter via Sp1 sites, which was accompanied by a marked suppression of p21 WAF1/Cip1 mRNA and protein expression induced by apicidin. Consistent with the transcriptional activation of p21 WAF1/Cip1 promoter by apicidin, apicidin treatment led to the translocation of PKC⑀ from cytosolic to particulate fraction, which was reversed by pretreatment with calphostin C, indicating the involvement of PKC in the transcriptional activation of p21 WAF1/Cip1 via Sp1 sites by apicidin. However, the PKC-mediated transcriptional activation of p21 WAF1/Cip1 by apicidin appears to be independent of the histone hyperacetylation, because apicidin-induced histone hyperacetylation was not affected by calphostin C. Furthermore, a PKC activator, phorbol 12,13-dibutyrate, alone induced the transcriptional activation of p21 WAF1/Cip1 promoter, p21 WAF1/Cip1 mRNA, and protein expression without induction of the histone hyperacetylation, suggesting that the transcriptional activation of p21 WAF1/Cip1 by apicidin might have been mediated by a mechanism other than chromatin remodeling through the histone hyperacetylation. Taken together, these results suggest that the PKC signaling pathway plays a pivotal role in the transcriptional activation of the p21 WAF1/Cip1 gene by apicidin.

SUMMARY S6K1 has been implicated in a number of key metabolic responses, which contribute to obesity. Critical among these is the control of a transcriptional program required for the commitment of mesenchymal stem cells to the adipocytic lineage. However, in contrast to its role in the cytosol, the functions and targets of nuclear S6K1 are unknown. Here, we show that adipogenic stimuli trigger nuclear translocation of S6K1, leading to H2BS36 phosphorylation and recruitment of EZH2 to H3, which mediates H3K27 trimethylation. This blocks Wnt gene expression, inducing the upregulation of PPARγ and Cebpa and driving increased adipogenesis. Consistent with this finding, white adipose tissue from S6K1-deficient mice exhibits no detectable H2BS36 phosphorylation or H3K27 trimethylation, whereas both responses are highly elevated in obese humans or in mice fed a high-fat diet. These findings define an S6K1-dependent mechanism in early adipogenesis, contributing to the promotion of obesity.

Since the global outbreak of SARS-CoV-2 (COVID-19), infections of diverse human organs along with multiple symptoms continue to be reported. However, the susceptibility of the brain to SARS-CoV-2, and the mechanisms underlying neurological infection are still elusive. Here, we utilized human embryonic stem cell-derived brain organoids and monolayer cortical neurons to investigate infection of brain with pseudotyped SARS-CoV-2 viral particles. Spike-containing SARS-CoV-2 pseudovirus infected neural layers within brain organoids. The expression of ACE2, a host cell receptor for SARS-CoV-2, was sustained during the development of brain organoids, especially in the somas of mature neurons, while remaining rare in neural stem cells. However, pseudotyped SARS-CoV-2 was observed in the axon of neurons, which lack ACE2. Neural infectivity of SARS-CoV-2 pseudovirus did not increase in proportion to viral load, but only 10% of neurons were infected. Our findings demonstrate that brain organoids provide a useful model for investigating SARS-CoV-2 entry into the human brain and elucidating the susceptibility of the brain to SARS-CoV-2.