From Inflammation to Cutaneous Repair: Topical Application of Lupeol Improves Skin Wound Healing in Rats by Modulating the Cytokine Levels, NF-κB, Ki-67, Growth Factor Expression, and Distribution of Collagen Fibers

Abstract

Skin wound healing is a highly complex event that involves different mediators at the cellular and molecular level. Lupeol has been reported to possess different biological activities, such as anti-inflammatory, antioxidant, antidiabetic, and in vitro wound healing properties, which motivated us to proceed with in vivo studies. We aimed to investigate the wound healing effect of lupeol-based cream for 3, 7, and 14 days. Wound excisions were induced on the thoraco-lumbar region of rats and topically treated immediately after injury induction. Macroscopic, histopathological, and immunohistochemical analyses were performed. Cytokine levels were measured by ELISA and gene expression was evaluated by real-time RT-qPCR. Our results showed a strong wound-healing effect of lupeol-based cream after 7 and 14 days. Lupeol treatment caused a reduction in proinflammatory cytokines (TNF-a, IL-1β, and IL-6) and gene and protein NF-κB expression, and positively altered IL-10 levels, showing anti-inflammatory effects in the three treatment periods. Lupeol treatment showed involvement in the proliferative phase by stimulating the formation of new blood vessels, increasing the immunostaining of Ki-67 and gene expression, and immunolabeling of vascular endothelial growth factor (VEGF) and epidermal growth factor (EGF), and increasing gene expression of transforming growth factor beta-1 (TGF-β1) after seven days of treatment. Lupeol was also involved in the tissue regeneration phase by increasing the synthesis of collagen fibers noted in the three treatment periods analyzed. Our findings suggest that lupeol may serve as a novel therapeutic option to treat cutaneous wounds by regulating mechanisms involved in the inflammatory, proliferative, and tissue-remodeling phases.

Bio-Evaluation of the Wound Healing Activity of Artemisia judaica L. as Part of the Plant’s Use in Traditional Medicine; Phytochemical, Antioxidant, Anti-Inflammatory, and Antibiofilm Properties of the Plant’s Essential Oils

“…The pro-inflammatory markers IL-1b and IL-6 values were comparable among all the studied groups, similar to the previously published articles [ 94 , 95 ]. At the same time, tumor necrosis factor α (TNF-α) significantly increased in the negative control group compared to the intact group ( p < 0.0001).…”

“…Furthermore, TNF-α regulates blood coagulation, contributes to oxidative stress at sites of inflammation, and indirectly induces fever. The data conforms with Gushiken and Periera, where TNF-α decreased after two weeks of treatment in skin wound tissue compared to the negative control [94,95].…”

Oleogel Formulations for the Topical Delivery of Betulin and Lupeol in Skin Injuries—Preparation, Physicochemical Characterization, and Pharmaco-Toxicological Evaluation

“…Regarding the effect of lupeol, Pereira-Bessera et al observed that in vitro, lupeol has a beneficial effect on wound healing due to the fact that it has anti-inflammatory properties [33]. Subsequently, the same team of researchers proved the protective and repairing effect of lupeol in wounds, this time using a murine model [34].…”

Investigation of Lupeol as Anti-Melanoma Agent: An In Vitro-In Ovo Perspective

“…Furthermore, several studies direct the use of LUP towards the treatment of skin injuries. For instance, Beserra’s research group shows that lupeol exerts beneficial effects in cutaneous repair both in vitro by promoting wound healing in human keratinocytes and fibroblasts, and in vivo by regulating collagen distribution and the expression of several markers (i.e., cytokines, NF-κB, Ki-67, growth factor) [ 27 , 28 ]. Recent research focused on exploring the efficiency of LUP in the treatment of various cancers (i.e., lung, liver, pancreas, head, and neck), offering valuable insight into the molecular mechanisms underlying its anti-tumor properties [ 29 , 30 , 31 , 32 ].…”