Oncolytic strategy using new bifunctional HDACs/BRD4 inhibitors against virus-associated lymphomas.

Primary effusion lymphoma (PEL) caused by Kaposi sarcoma-associated herpesvirus (KSHV) is an aggressive malignancy with poor prognosis even under chemotherapy. Currently, there is no specific treatment for PEL therefore requiring new therapies. Both histone deacetylases (HDACs) and bromodomain-containing protein 4 (BRD4) have been found as therapeutic targets for PEL through inducing viral lytic reactivation. However, the strategy of dual targeting with one agent and potential synergistic effects have never been explored. In the current study, we first demonstrated the synergistic effect of concurrently targeting HDACs and BRD4 on KSHV reactivation by using SAHA or entinostat (HDACs inhibitors) and (+)-JQ1 (BRD4 inhibitor), which indicated dual blockage of HDACs/BRD4 is a viable therapeutic approach. We were then able to rationally design and synthesize a series of new small-molecule inhibitors targeting HDACs and BRD4 with a balanced activity profile by generating a hybrid of the key binding motifs between (+)-JQ1 and entinostat or SAHA. Upon two iterative screenings of optimized compounds, a pair of epimers, 009P1 and 009P2, were identified to better inhibit the growth of KSHV positive lymphomas compared to (+)-JQ1 or SAHA alone at low nanomolar concentrations, but not KSHV negative control cells or normal cells. Mechanistic studies of 009P1 and 009P2 demonstrated significantly enhanced viral reactivation, cell cycle arrest and apoptosis in KSHV+ lymphomas through dually targeting HDACs and BRD4 signaling activities. Importantly, in vivo preclinical studies showed that 009P1 and 009P2 dramatically suppressed KSHV+ lymphoma progression with oral bioavailability and minimal visible toxicity. These data together provide a novel strategy for the development of agents for inducing lytic activation-based therapies against these viruses-associated malignancies.

[Adsorption Characteristics and Mechanism of Ammonia Nitrogen in Water by Nano Zero-valent Iron-modified Biochar].

The adsorption performances of ammonia nitrogen (NH+4-N) in water by unmodified biochar are ineffective. In this study, nano zero-valent iron-modified biochar (nZVI@BC) was prepared to remove NH+4-N from water. The NH+4-N adsorption characteristics of nZVI@BC were investigated through adsorption batch experiments. The composition and structure characteristics of nZVI@BC were analyzed using scanning electron microscopy, energy spectrum analysis, BET-N2 surface area (SSA), X-ray diffraction, and FTIR spectra to explore the main adsorption mechanism of NH+4-N by nZVI@BC. The results showed that the composite synthesized at the iron to biochar mass ratio of 1:30 (nZVI@BC1/30) performed well in NH+4-N adsorption at 298 K. The maximum adsorption amount of nZVI@BC1/30 at 298 K was remarkably increased by 45.96% and reached 16.60 mg·g-1. The pseudo-second-order model and Langmuir model fitted well with the adsorption process of NH+4-N by nZVI@BC1/30. There was competitive adsorption between coexisting cations and NH+4-N, and the sequence of coexisting cations to the adsorption of NH+4-N by nZVI@BC1/30 was Ca2+> Mg2+> K+> Na+. The adsorption mechanism of NH+4-N by nZVI@BC1/30 could be mainly attributed to ion exchange and hydrogen bonding. In conclusion, nano zero-valent iron-modified biochar can improve the adsorption performance of NH+4-N and enhance the application potential of biochar in the field of nitrogen removal from water.