Gene expression profile-based drug screen identifies SAHA as a novel treatment for NAFLD.

Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease worldwide. Being part of the metabolic syndrome, NAFLD is characterized by the deposition of triglycerides (TGs) as lipid droplets in the cytoplasm of hepatic cells. Recently, the rapid development of high-throughput genome analysis technologies provided opportunities to screen for new drugs for NAFLD. In this study, we screened for potential drugs based on the gene expression profiles of 73 compounds and identified histone deacetylase (HDAC) inhibitors as a novel treatment for the accumulation of lipids in hepatocytes. In the subsequent analysis and experiments, we discovered that SAHA inhibited the fatty acid and lipid metabolism pathways in hepatic cells and induced a significant deficiency of lipid accumulation in HepG2 and SMMC-7721 cells. Furthermore, SAHA inhibited lipid synthesis in hepatic cells by directly suppressing the expression of DGAT2. Hence, our study provides a novel method to screen for effective drugs for liver diseases and identifies SAHA as a potent treatment for NAFLD.

Mesenchymal stem cells are attracted to latent HIV-1-infected cells and enable virus reactivation via a non-canonical PI3K-NFκB signaling pathway.

Persistence of latent HIV-1 in macrophages (MACs) and T-helper lymphocytes (THLs) remain a major therapeutic challenge. Currently available latency reversing agents (LRAs) are not very effective in vivo. Therefore, understanding of physiologic mechanisms that dictate HIV-1 latency/reactivation in reservoirs is clearly needed. Mesenchymal stromal/stem cells (MSCs) regulate the function of immune cells; however, their role in regulating virus production from latently-infected MACs & THLs is not known. We documented that exposure to MSCs or their conditioned media (MSC-CM) rapidly increased HIV-1 p24 production from the latently-infected U1 (MAC) & ACH2 (THL) cell lines. Exposure to MSCs also increased HIV-1 long terminal repeat (LTR) directed gene expression in the MAC and THL reporter lines, U937-VRX and J-Lat (9.2), respectively. MSCs exposed to CM from U1 cells (U1-CM) showed enhanced migratory ability towards latently-infected cells and retained their latency-reactivation potential. Molecular studies showed that MSC-mediated latency-reactivation was dependent upon both the phosphatidyl inositol-3-kinase (PI3K) and nuclear factor-κB (NFκB) signaling pathways. The pre-clinically tested inhibitors of PI3K (PX-866) and NFκB (CDDO-Me) suppressed MSC-mediated HIV-1 reactivation. Furthermore, coexposure to MSC-CM enhanced the latency-reactivation efficacy of the approved LRAs, vorinostat and panobinostat. Our findings on MSC-mediated latency-reactivation may provide novel strategies against persistent HIV-1 reservoirs.

Primary Rod and Cone Degeneration Is Prevented by HDAC Inhibition.

Photoreceptor cell death in inherited retinal degeneration is accompanied by over-activation of histone deacetylases (HDAC). Excessive HDAC activity is found both in primary rod degeneration (such as in the rd10 mouse) and in primary cone death, including the cone photoreceptor function loss 1 (cpfl1) mouse. We evaluated the potential of pharmacological HDAC inhibition to prevent photoreceptor degeneration in primary rod and cone degeneration. We show that a single in vivo treatment of cpfl1 mice with the HDAC inhibitor trichostatin A (TSA) resulted in a significant protection of cpfl1 mutant cones. Similarly, HDAC inhibition with the clinically approved HDAC inhibitor vorinostat (SAHA) resulted in a significant improvement of rod survival in rd10 retinal explant cultures. Altogether, these results highlight the feasibility of targeted neuroprotection in vivo and create hope to maintain vision in patients suffering from both rod and cone dystrophies.

A novel metabolism-based phenotypic drug discovery platform in zebrafish uncovers HDACs 1 and 3 as a potential combined anti-seizure drug target.

Despite the development of newer anti-seizure medications over the past 50 years, 30-40% of patients with epilepsy remain refractory to treatment. One explanation for this lack of progress is that the current screening process is largely biased towards transmembrane channels and receptors, and ignores intracellular proteins and enzymes that might serve as efficacious molecular targets. Here, we report the development of a novel drug screening platform that harnesses the power of zebrafish genetics and combines it with in vivo bioenergetics screening assays to uncover therapeutic agents that improve mitochondrial health in diseased animals. By screening commercially available chemical libraries of approved drugs, for which the molecular targets and pathways are well characterized, we were able to reverse-identify the proteins targeted by efficacious compounds and confirm the physiological roles that they play by utilizing other pharmacological ligands. Indeed, using an 870-compound screen in kcna1-morpholino epileptic zebrafish larvae, we uncovered vorinostat (Zolinza™; suberanilohydroxamic acid, SAHA) as a potent anti-seizure agent. We further demonstrated that vorinostat decreased average daily seizures by ∼60% in epileptic Kcna1-null mice using video-EEG recordings. Given that vorinostat is a broad histone deacetylase (HDAC) inhibitor, we then delineated a specific subset of HDACs, namely HDACs 1 and 3, as potential drug targets for future screening. In summary, we have developed a novel phenotypic, metabolism-based experimental therapeutics platform that can be used to identify new molecular targets for future drug discovery in epilepsy.