Swinhoeisterols from the South China Sea Sponge <i>Theonella swinhoei</i>

Swinhoeisterols C–F (<b>1</b>–<b>4</b>), four new steroids having a rearranged 6/6/5/7 ring system, were isolated from the Xisha sponge <i>Theonella swinhoei</i>, together with the known analogue swinhoeisterol A (<b>5</b>). Their structures were determined based on spectroscopic analysis, TDDFT-ECD and optical rotation calculations, and biogenetic correlations. In an in vitro assay, compound <b>1</b> showed an inhibitory effect on (h)­p300 with an IC₅₀ value of 8.8 μM, whereas compounds <b>2</b>–<b>4</b> were not active

Immunomodulatory Polyketides from a <i>Phoma</i>-like Fungus Isolated from a Soft Coral

Fourteen new polyketides with a <i>trans</i>-fused decalin ring system, libertalides A–N (<b>3</b>–<b>16</b>), together with two known analogues, aspermytin A and its acetate (<b>1</b>, <b>2</b>), were isolated from the fermentation extract of a coral-derived <i>Libertasomyces</i> sp. fungus. Their relative configurations were elucidated on the basis of detailed spectroscopic analysis, and the absolute configurations were determined by TDDFT-ECD and optical rotation (OR) calculations. The OR of <b>1</b> and <b>2</b> were found to have opposite signs in CH₃CN and CHCl₃, which was in agreement with the OR calculations producing alternating signs for the optical rotation depending on the applied conditions. Because the signs of the OR for <b>1</b> and <b>2</b> showed high solvent dependence, they may not be used alone to correlate the absolute configurations. Compound <b>16</b> displayed structural novelty characterized by an α-enol ether bridge conjugated with an aldehyde group. In <i>in vitro</i> immunomodulatory screening, compounds <b>1</b>, <b>4</b>, and <b>10</b> significantly induced the proliferation of CD3⁺ T cells, while compounds <b>2</b>, <b>7</b>, <b>11</b>, and <b>14</b> significantly increased the CD4⁺/CD8⁺ ratio at 3 μM. A preliminary structure–activity analysis revealed a crucial role of Δ⁷ and a terminal OH group in the regulation of CD3⁺ T cell proliferation. This is the first report of immunoregulatory activity for metabolites of this kind

Identification of a novel small-molecule Keap1–Nrf2 PPI inhibitor with cytoprotective effects on LPS-induced cardiomyopathy

<p>A new Keap1–Nrf2 protein–protein interaction (PPI) inhibitor <b>ZJ01</b> was identified from our compound library by fluorescence polarization assay, surface plasmon resonance, molecular docking and molecular dynamics simulation. <b>ZJ01</b> could <i>in vitro</i> trigger Nrf2 nuclear translocation, subsequently resulting in increased mRNA levels of Nrf2 target genes HO-1 and NQO1. Meanwhile, <b>ZJ01</b> suppressed LPS-induced production of ROS and the mRNA levels of pro-inflammatory cytokines TNF-α, IL-1β and IL-6 in H9c2 cardiac cells. Moreover, in an <i>in vivo</i> mouse model of septic cardiomyopathy induced by intraperitoneal injection of lipopolysaccharide, <b>ZJ01</b> demonstrated a cytoprotective effect, upregulated Nrf2 protein nuclear accumulation, and remarkably suppressed the abovementioned cytokine levels in cardiomyocytes. The results presented herein provided a novel chemotype for the development of direct Keap1–Nrf2 PPI inhibitors and suggested that compound <b>ZJ01</b> is a promising drug lead for septic cardiomyopathy treatment.</p> <p><b>ZJ01</b> was identified as a new Keap1–Nrf2 PPI inhibitor and drug lead for septic cardiomyopathy treatment by <i>in vitro</i> and <i>in vivo</i> experiments.</p