Polyphenol Extracts from Grape Seeds and Apple Can Reactivate Latent HIV-1 Transcription through Promoting P-TEFb Release from 7SK snRNP.

The principal barrier for the eradication of HIV/AIDS is the virus latency. One of the effective strategies so called "shock and kill" is to use latency-reversing agents (LRAs) to activate the latent HIV reservoirs and then combine them with the highly active antiretroviral therapy (HAART) to eradicate the virus. However, most of the current LRAs are too toxic; therefore, they have not been used clinically. Our preliminary data indicated that polyphenols from grape seeds can activate HIV in latently infected Jurkat T cells. Owing to a lot of food containing polyphenols and based on a reasoning whether all of these kinds of polyphenols contain the latency-reversing function, in this study, we screened 22 fruits/vegetables to see whether polyphenols from these can reactivate latent HIV-1 transcription. We finally proved that the polyphenols from grape seeds, apple, pomegranate, and bilberry can reactivate latent HIV-1 transcription. The activation of which can be detected on the level of protein and mRNA. The activation of which is in a dose- and time-dependent manner, while the activated polyphenol extracts have the effects to stimulate Tat-independent HIV-1 transcription. The mechanism shows that polyphenol extracts from grape seeds and apple can stimulate P-TEFb's release from 7SK snRNP to induce HIV gene transcription. These results indicate that using a few food of high-content polyphenols as latent activators and combining HARRT may be of great use for the treatment of HIV/AIDS in the future.

A natural product targets BRD4 to inhibit phase separation and gene transcription.

The BET-bromodomain protein BRD4 uses two bromodomains to target acetyl-histones and other domains to recruit P-TEFb and other transcription factors to stimulate transcription of proto-oncogenes and key cell identity genes. Recent studies show that its ability to form phase-separated condensates that cluster preferentially at the super-enhancer regions of target genes is key for BRD4 to exert its functions. Here, we describe the identification of a natural product called PCG from polygonum cuspidatum Sieb.et Zucc., a traditional Chinese medicinal herb, that directly binds to BRD4. This binding inhibits BRD4 phase separation, turns dynamic BRD4 nuclear condensates into static aggregates, and effectively shuts down transcription of BRD4-dependent genes. Thus, through PCG we have discovered a BET inhibitor that not only selectively targets BRD4 but also works by suppressing phase separation, a mechanism of action that is different from those of the other known BET inhibitors.

Onion Epithelial Membrane Scaffolds Transfer Corneal Epithelial Layers in Reconstruction Surgery.

Plants and their extracts have been used especially in China for more than ten centuries for preventing and treating disease. However, there are only few reports describing their use in animal cell culture and tissue transplantation. In this study, onion epithelial membranes (OEM) is used as scaffolds to support cultures of a variety of cells such as fibroblasts and epithelial cells notably; they maintain the phenotypic characteristics of corneal epithelial cells. This improvement includes preservation of the proliferative potential and stemness of rabbit corneal epithelial cells (RCECs). Such an outcome suggests that this cost-effective technology warrants further evaluation to determine if OEM is a viable candidate for use as scaffolds in corneal epithelial transplantation surgery. To test this possibility, rabbit corneal epithelial cells expanded on OEM are transplanted to treat corneal epithelial defects in limbal stem cell deficient rabbits. This procedure is successful because it shortens the time required for wound healing to restore losses in corneal epithelial integrity, and forms a more compact and stratified epithelium framework than the untreated group. Ultimately, should they be proven to be effective in other relevant animal model systems, their usefulness for treating wounds in a clinical setting warrants consideration.

Menin mediates Tat-induced neuronal apoptosis in brain frontal cortex of SIV-infected macaques and in Tat-treated cells.

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.

A Natural Product from Polygonum cuspidatum Sieb. Et Zucc. Promotes Tat-Dependent HIV Latency Reversal through Triggering P-TEFb's Release from 7SK snRNP.

The latent reservoirs of HIV represent a major impediment to eradication of HIV/AIDS. To overcome this problem, agents that can activate latent HIV proviruses have been actively sought after, as they can potentially be used in combination with the highly active antiretroviral therapy (HAART) to eliminate the latent reservoirs. Although several chemical compounds have been shown to activate latency, they are of limited use due to high toxicity and poor clinical outcomes. In an attempt to identify natural products as effective latency activators from traditional Chinese medicinal herbs that have long been widely used in human population, we have isolated procyanidin C-13,3',3"-tri-O-gallate (named as REJ-C1G3) from Polygonum cuspidatum Sieb. et Zucc., that can activate HIV in latently infected Jurkat T cells. REJ-C1G3 preferentially stimulates HIV transcription in a process that depends on the viral encoded Tat protein and acts synergistically with prostratin (an activator of the NF-κB pathway) or JQ1 (an inhibitor of Brd4) to activate HIV latency. Our mechanistic analyses further show that REJ-C1G3 accomplishes these tasks by inducing the release of P-TEFb, a host cofactor essential for Tat-activation of HIV transcription, from the cellular P-TEFb reservoir 7SK snRNP.