# Synergistic wound healing mechanisms of Heliotropium curassavicum extracts via redox modulation, inflammation suppression, and tissue remodeling: linking phytochemical diversity to antioxidant and anti-inflammatory effects

## TL;DR

This study shows that Heliotropium curassavicum extracts, especially the n-butanol fraction, promote wound healing by reducing inflammation and oxidative stress.

## Contribution

The study reports four new pyrrolizidine alkaloids in the genus and identifies synergistic interactions among metabolites in promoting wound healing.

## Key findings

- The n-butanol extract of H. curassavicum achieved near-complete wound closure by day 14.
- The extract significantly reduced oxidative stress markers and inflammatory cytokines.
- Histopathology showed improved re-epithelialization and collagen deposition in treated wounds.

## Abstract

This study assessed the wound-healing potential of Heliotropium curassavicum via a comparative metabolite profiling of its ethanol (HC-EtOH), ethyl acetate (HC-EtOAc), and n-butanol (HC-BuOH) extracts, alongside in vivo assessment. UHPLC-ESI-MS/MS analysis annotated 86 metabolites, including 13 pyrrolizidine alkaloids (4 of which, viz. uplandicine, uluganine, curassavine, and curassavine N-oxide are newly reported in the genus), 12 phenylpropanoids, and 8 fatty acid amides. Topical application of the extracts accelerated wound closure in a dose-dependent manner, with HC-BuOH exhibiting the strongest activity. HC-BuOH (200 mg/kg) achieved near-complete closure by day 14 and improved healing by 39% compared with Intrasite Gel. This was accompanied by significant modulation of oxidative and inflammatory markers, including a 66% reduction in MDA, a 220% increase in GSH, a 94% reduction in TNF-α, and restoration of PGE-2 toward normal levels (p < 0.05). Histopathology confirmed complete re-epithelialization, organized collagen deposition, and localized Ki-67 expression in HC-BuOH–treated wounds. Multivariate data and interaction analyses, supported by PLSR model demonstrated that the superior wound-healing activity of HC-BuOH is attributed for synergistic interactions among pyrrolizidine alkaloids, phenylpropanoids, and fatty acyl amides. These findings highlight H. curassavicum, particularly the HC-BuOH fraction, as a promising natural wound-healing agent. These effects are likely attributed to plant richness, in pyrrolizidine alkaloids, phenylpropanoids, and fatty acyl amides, highlighting its potential as a natural wound healing agent.

The online version contains supplementary material available at 10.1007/s10787-025-02096-z.