The Natural Stilbenoid (-)-Hopeaphenol Inhibits HIV Transcription by Targeting Both PKC and NF-κB Signaling and Cyclin-Dependent Kinase 9.

Despite effective combination antiretroviral therapy (cART), people living with HIV (PLWH) continue to harbor replication-competent and transcriptionally active virus in infected cells, which in turn can lead to ongoing viral antigen production, chronic inflammation, and increased risk of age-related comorbidities. To identify new agents that may inhibit postintegration HIV beyond cART, we screened a library of 512 pure compounds derived from natural products and identified (-)-hopeaphenol as an inhibitor of HIV postintegration transcription at low to submicromolar concentrations without cytotoxicity. Using a combination of global RNA sequencing, plasmid-based reporter assays, and enzyme activity studies, we document that hopeaphenol inhibits protein kinase C (PKC)- and downstream NF-κB-dependent HIV transcription as well as a subset of PKC-dependent T-cell activation markers, including interleukin-2 (IL-2) cytokine and CD25 and HLA-DRB1 RNA production. In contrast, it does not substantially inhibit the early PKC-mediated T-cell activation marker CD69 production of IL-6 or NF-κB signaling induced by tumor necrosis factor alpha (TNF-α). We further show that hopeaphenol can inhibit cyclin-dependent kinase 9 (CDK9) enzymatic activity required for HIV transcription. Finally, it inhibits HIV replication in peripheral blood mononuclear cells (PBMCs) infected in vitro and dampens viral reactivation in CD4+ cells from PLWH. Our study identifies hopeaphenol as a novel inhibitor that targets a subset of PKC-mediated T-cell activation pathways in addition to CDK9 to block HIV expression. Hopeaphenol-based therapies could complement current antiretroviral therapy otherwise not targeting cell-associated HIV RNA and residual antigen production in PLWH.

Capillasterin A, a Novel Pyrano[2,3-f]chromene from the Australian Crinoid Capillaster multiradiatus.

Capillasterin A (1), a novel pyrano[2,3-f]chromene, together with seven known naphthopyrones including comaparvin (2), TMC-256C1 (3), 6-methoxycomaparvin-5- methyl ether (4), 5,8-dihydroxy-6-methoxy-2-propyl-4H-naphtho[2,3-b]pyran-4-one (5), 5,8-dihydroxy-6,10-dimethoxy-2-propyl-4H-naphtho[2,3-b]pyran-4-one (6), TMC-256A1 (7) and 6-methoxycomaparvin (8) were isolated from an EtOH/H2O extract from the Australian crinoid Capillaster multiradiatus. The structures of all the compounds were determined by detailed spectroscopic (1D/2D NMR and MS) data analysis. This is the first report of a natural product that contains the pyrano[2,3-f]chromene skeleton. Compounds 2⁻6 were observed to display moderate inhibition of in vitro HIV-1 replication in a T cell line with EC50 values ranging from 7.5 to 25.5 µM without concomitant cytotoxicity.

Systematic review of simulation-based education in strabismus assessment and management.

BACKGROUND: Strabismus is a dynamic condition for which simulation-based training is valuable, given the variable complexity and relatively reduced exposure compared with other ophthalmic presentations. This study assessed the performance of simulation models available for medical training in the assessment and management of strabismus. METHODS: A systematic review of relevant peer-reviewed academic databases was conducted, without publication date restrictions. English-language publications evaluating the performance of simulation models for education on strabismus were included. Risk of bias was assessed using the Cochrane RoB-2 tool and CLARITY Risk of Bias Instrument for Cross-Sectional Surveys of Attitudes and Practices. Validity of evidence was evaluated using the Kirkpatrick framework. RESULTS: Of the total 3,298 citations exported for title and abstract screening, 54 advanced to full-text screening, and 7 were included in final review. Model types were either dry (2), wet (4), or virtual reality (1). All models were deemed to be successful, but few standardized parameters were specified. Costs of models ranged from a few dollars (ball and wood), to moderate (non-cadaveric), to costly (virtual reality). All studies scored a moderate or high risk of bias, and the majority (4/7) of studies scored level 1 on the Kirkpatrick scale. CONCLUSIONS: Research on simulation for strabismus assessment and management is limited and varied for model fidelity and testing audiences. All models were deemed individually successful compared to non-simulation-based teaching methodologies, although no direct comparisons were made. The limited evidence available suggests that low-fidelity and low-cost models can be used for trainees without sacrificing educational quality.