Epidemiological studies indicate that smoking is negatively correlated with the incidence and development of Alzheimer's disease (AD). Nicotine was reported to be the active factor. However, the detailed mechanisms still remain to be fully elucidated. Early growth response gene 1 (EGR-1) plays important roles in several important biological processes such as promoting cell growth, differentiation, anti oxidative stress, and apoptosis, but few in the pathogenesis of AD. In the present study, we show that nicotine can activate the MAPK/ERK/EGR-1 signaling pathway partially through α7 nAChR. In addition, the up-regulation of EGR-1 by nicotine can also increase the phosphorylation of CyclinD1 which contributes to the attenuation of amyloid-β (Aβ(25-35)) -induced neurotoxicity. Although nicotine and Aβ(25-35) can activate EGR-1, the expression of EGR-1 is down-regulated following treatment with nicotine and Aβ(25-35). This study demonstrates that low dose nicotine attenuates Aβ(25-35)-induced neurotoxicity in vitro and in vivo through activating EGR-1 pathway.

The molecular mechanisms involved in human immunodeficiency virus (HIV)-associated neurocognitive disorder (HAND) remain poorly understood. It has been recently reported that HIV-1 Tat transactivation requires menin, suggesting that menin may be involved in HAND pathogenesis. But the role of menin is not clear. Here, we found that protein level of menin was increased in simian-human immunodeficiency chimeric virus (SHIV)-SF162.P4 and simian immunodeficiency virus (SIV) sm543-3-infected rhesus macaques compared with the controls by immunohistochemistry (IHC) and western blot. Menin mainly expressed in the frontal cortex neurons of the brain, more importantly, the number of menin-staining cells was positively correlated with cleaved-caspase-3-positive cells while it was negatively correlated with a neuron-specific nuclear protein NeuN-positive cells, suggesting that expression of menin may induce neuronal apoptosis. Further studies showed that menin level was significantly increased during Tat-induced apoptosis, while downregulation of menin by pll3.7-MEN1-shRNA attenuated the Tat-induced cleavage of caspase-3 and caspase-8 in SY5Y cells and primary neuron cultures. Together, our findings reveal a pro-apoptotic role of menin in the brains of the SIV-infected macaques and the cultured neurons, indicating that targeting menin may be potential to block the HIV-1 Tat induced neuronal damage in HAND.

The matricellular protein periostin plays a critical role in liver inflammation, fibrosis, and even carcinoma. Here, the biological function of periostin in alcohol-related liver disease (ALD) was investigated.

Alzheimer's disease (AD) is the most common cause of dementia. One of the pathological hallmarks of AD is amyloid β (Aβ) deposition. MicroRNAs (miRNAs) are small non-coding RNAs whose expression levels change significantly during neuronal pathogenesis and may be used as diagnostic markers. Some miRNAs are important in AD development by targeting genes responsible for Aβ metabolism. However, a systematic assessment of the miRNA expression profile induced by Aβ-mediated neuronal pathogenesis is still lacking. In the present study, we examined miRNA expression profile by using the APPswe/PS1ΔE9 mouse model of AD. Two sibling pairs of mice were examined, showing 30 and 24 miRNAs with significantly altered expression levels from each paired control, respectively. Nine known miRNAs were common in both groups. Prediction of putative target genes and functional annotation implied that these altered miRNAs affect many target genes mainly involved in PI3K/Akt signaling pathway. This study provides a general profile of miRNAs regulated by Aβ-associated signal pathways, which is helpful to understand the mechanism of Aβ-induced neuronal dysfunction in AD development.

There are numerous types of pathological changes in human immunodeficiency virus (HIV)-associated neurocognitive disorder (HAND), including apoptosis of neurons. HIV-1 transactivator of transcription (Tat) protein, which is encoded by HIV-1, may promote apoptosis in HAND. Forkhead box O3 (FOXO3) is a multispecific transcription factor that has roles in many biological processes, including cellular apoptosis. The aim of this study was to determine whether FOXO3 is activated by HIV-1 Tat and to investigate its role in neuronal apoptosis in HAND. We employed tissue staining and related molecular biological experimental methods to confirm our hypothesis. The in vivo experimental results demonstrated that the expression of nuclear FOXO3 increased in the apoptotic neurons of the cerebral cortexes of rhesus macaques infected with simian human immunodeficiency virus (SHIV). The in vitro investigation showed that HIV-1 Tat activated FOXO3, causing it to move from the cytoplasm to the nucleus via the c-Jun N-terminal kinase (JNK) signaling pathway in SH-SY5Y cells. Moreover, FOXO3 down-regulated expression of the anti-apoptosis gene B-cell lymphoma 2 (Bcl-2) and up-regulated the expression of the pro-apoptosis gene Bcl-2-like 11 (Bim) after entering the nucleus, eventually causing cellular apoptosis. Finally, reduction of nuclear FOXO3 reversed cellular apoptosis. Our results suggest that HIV-1 Tat induces FOXO3 to translocate from the cytoplasm to the nucleus via the JNK signaling pathway, leading to neuronal apoptosis. Agents targeting FOXO3 may provide approaches for restoring neuronal function in HAND.

During HIV-associated neurocognitive disorder (HAND), decreasing in excitatory amino acid transporter 2 (EAAT-2) in astrocyte plasma membranes leads to elevated levels of extracellular glutamate and, in turn, neuronal apoptosis. We used immunohistochemistry, western blot, qRT-PCR, and RNA interference to elucidate the molecular mechanisms underlying the decreased EAAT-2 expression during HAND at the tissue and cellular levels. We used simian immunodeficiency virus-human immunodeficiency virus chimeric virus (SHIV)-infected macaques as an in vivo model of HAND. Our results show that EAAT-2 expression was decreased in the cerebral cortex, while AEG-1 expression was increased, and the expression levels of these proteins were negatively correlated. In vitro analyses showed that HIV-1 Tat inhibited EAAT-2 expression by inducing overexpression of AEG-1. More specifically, HIV-1 Tat increased AEG-1 expression via the PI3-K signaling pathway, while increasing EAAT-2 inhibition by YinYan-1 (YY-1) via the NF-κB signaling pathway. These results warrant testing AEG-1 as a potential therapeutic target for treating HAND.