Protective Effects of Picropodophyllotoxin on CLP-Induced Sepsis in Mice

Sepsis is a life-threatening condition caused by a dysregulated host response to infection and is characterized by systemic inflammation, multiorgan dysfunction, and high mortality. Picropodophyllotoxin (PPT), a naturally occurring tyrosine kinase inhibitor derived from the roots of Podophyllum hexandrum, has demonstrated anticancer activity, but its effects on sepsis and the underlying mechanisms remain largely unknown. This study investigated the effects of PPT in a murine model of cecal ligation and puncture (CLP)-induced sepsis. Mice were assigned to six groups: sham control, CLP alone, CLP plus maslinic acid (MA), and CLP plus PPT at 0.5, 1.0, or 2.0 mg/kg. Survival, changes in body weight, inflammatory cytokine levels, and histopathological changes were evaluated. In parallel, human endothelial cells were stimulated with high-mobility group box 1 (HMGB1) and treated with PPT to assess cell viability. Inflammatory markers and protein expression were analyzed using ELISA and Western blotting, respectively. In CLP-induced sepsis, PPT treatment improved survival and attenuated body weight loss compared with untreated controls. PPT also reduced TNF-α, IL-1β, nitric oxide (NO), and other markers of renal inflammation. In HMGB1-stimulated endothelial cells, PPT reduced TLR4 and TNF-α expression and activated PI3K/AKT signaling, with a concomitant increase in cell survival. These findings demonstrate that PPT exerts anti-inflammatory and endothelial-protective effects in experimental sepsis. The observed changes in TLR/NF-κB and PI3K/AKT signaling are correlative, and further studies are required to establish the causal mechanisms involved.