[Research progress of super enhancer in cancer].

Super enhancers (SEs) are composed of clusters of enhancers in close genomic proximity. They constitute a large family of regulatory elements that specify gene expression patterns and cell identity. SE regions consist of unusually strong enrichment of binding sites for transcriptional factors, cofactors, and enhancers associated with epigenetic modifications. SEs play important roles in regulating the aberrant gene expression in tumor cells. Via SEs, cancer cells activate the expression of various oncogenes, and promote cell proliferation, invasion and migration properties. Hence suppression of SEs activities could inhibit the growth and survival of cancer cells. In this review, we summarize the fundamental principles, functions and regulation of super enhancers and therapeutic potential in targeting SEs in cancer cells, thereby introducing and providing new conceptions for development of antineoplastic drugs.

[The sensitivity of transmitted/founder HIV-1 to anti-HIV drugs].

The majority of mucosal HIV-1 infection is initially established by a few HIV-1 viral variants, followed by the development of overt systemic infection, and these viral variants are known as transmitted/ founder viruses(T/F viruses). Investigation of the sensitivity of T/F virus to different anti-HIV-1 drugs will provide the best strategies of pre-exposure prophylaxis(Pr EP) for high-risk groups of HIV-infected patients. Herein we constructed for the first time, a luciferase reporter system for HIV-1 T/F viruses, and then compared the drug sensitivity between T/F viruses and chronic infection virus. The result showed that the 50% inhibitory concentration (IC(50)) of nucleoside reverse transcriptase inhibitors(NRTIs), integrase inhibitors(INIs) and protease inhibitors(PIs) were not significantly different between the T/F viruses and chronic infection viruses of the same subtype(P < 0.05), while non-nucleoside reverse transcriptase inhibitors(NNRTIs) showed a moderate resistance to T/F viruses, with a significant increase in IC50(P < 0.05). The conclusion suggests that when patients are in high-risk or in the acute infection of HIV-1, NNRTIs should be avoided in the first-line antiretroviral therapy regimens.

[Identification and characterization of HIV-1 transmitted /founder viruses].

During the spread of human immunodeficiency virus type 1 (HIV-1) in the mucosa, the entire genetic diversity of the viruses is significantly reduced. The vast majority of HIV-1 mucosal infections are established by one or a few viruses and ultimately develop into systemic infections, thus the initial virus is called transmitted/founder virus (T/F virus). The study of T/F virus will benefit understanding its key characteristics resulting in successful viral replication in the new host body, which may provide novel strategies for the development of AIDS vaccines, pre-exposure prophylaxis and other therapeutic interventions. In this review, we summarize the discovery and evolutionary characteristics of T/F virus as well as early immune response after HIV-1 infection, which will establish the basis to explore the features of T/F viruses.

Genetic variance in the HIV-1 founder virus Vpr affects its ability to induce cell cycle G2arrest and cell apoptosis.

In the event of acute infection, only a few HIV-1 viral variants can establish the initial productive clinical infection, and these viral variants are known as transmitted/founder viruses (T/F viruses). As one of the accessory proteins of HIV-1, viral protein R (Vpr) plays an important role in viral replication. Therefore, the characterization of T/F virus Vpr is beneficial to understand how virus replicates in a new host. In this study, flow cytometry was used to analyze the effect of G2arrest and cell apoptosis induced by the T/F virus Vpr and the chronic strain MJ4 Vpr. The results showed that the ability of T/F virus ZM246 Vpr and ZM247 Vpr inducing G2arrest and cell apoptosis are more potent than the MJ4 Vpr. The comparison of protein sequences indicated that the amino acids of 77, 85 and 94 contain high freqency mutations, suggesting that these sites may be involved in inducing G2arrest and cell apoptosis. Taken together, our work suggests that in acute infections, T/F viruses increase the capacity of G2arrest and cell apoptosis and promote viral replication and transmission in a new host by Vpr genetic mutation.

Central administration of neuronostatin induces antinociception in mice.

Neuronostatin, a recently discovered endogenous bioactive peptide, was encoded by pro-mRNA of somatostatin that contributes to modulation of nociception. However, nociceptive effect of neuronostatin is still not fully known. The aim of this study was to evaluate effect of neuronostatin on nociception and elucidate its possible mechanism of action. Intracerebroventricular (i.c.v.) administration of neuronostatin (0.3, 3, 6, 12nmol/mouse) produced a dose- and time-related antinociceptive effect in the tail immersion assay in mice, an acute pain model. The antinociceptive effect of neuronostatin was significantly antagonized by naloxone, and was strongly inhibited by co-injection with ß-funaltrexamine or nor-binaltorphimine, but not by naltrindole. Also, melanocortin 3/4 receptor antagonist, SHU9119, completely blocked the effect of neuronostatin. These data indicated the involvement of both µ- and κ-opioid receptors and central melanocortin system in the analgesic response induced by neuronostatin. In addition, neuronostatin (6nmol, i.c.v.) increased c-Fos protein expression in the periaqueductal gray (PAG) and the nucleus raphe magnus (NRM) that have a pivotal role in regulating descending pain pathways. Taken together, this study is the first to reveal that neuronostatin produces antinociceptive effect via opioid and central melanocortin systems, which is associated with an increase in neuronal activity the PAG and NRM.

Intracerebroventricular administration of neuronostatin induces depression-like effect in forced swim test of mice.

Neuronostatin is a recently discovered endogenous bioactive peptide that is encoded by pro-mRNA of somatostatin. In the present study, we investigated the effect of neuronostatin on mood regulation in the forced swim test of mice. Our results showed intracerebroventricular (i.c.v.) administration of neuronostatin produced an increase in the immobility time, suggesting that neuronostatin induced depression-like effect. In order to rule out the possibility that neuronostatin had increased immobility time by a non-specific reduction in general activity, the effect of neuronostatin on locomotor activity was examined. Neuronostatin had no influence on locomotor activity in mice. In addition, the depression-like effect of neuronostatin was completely reversed by melanocortin 3/4 receptor antagonist SHU9119 or GABAA receptor antagonist bicuculline, but not by opioid receptor antagonist naloxone. These data suggested that the depression-like effect induced by i.c.v. administered neuronostatin was dependent upon the central melanocortin system and GABAA receptor. In conclusion, the results of this study report that neuronostatin induces depression-like effect. These findings reveal that neuronostatin is a new neuropeptide with an important role in regulating depressive behavior.