From a Traditional Medicinal Plant to a Rational Drug: Understanding the Clinically Proven Wound Healing Efficacy of Birch Bark Extract

Abstract

BackgroundBirch bark has a long lasting history as a traditional medicinal remedy to accelerate wound healing. Recently, the efficacy of birch bark preparations has also been proven clinically. As active principle pentacyclic triterpenes are generally accepted. Here, we report a comprehensive study on the underlying molecular mechanisms of the wound healing properties of a well-defined birch bark preparation named as TE (triterpene extract) as well as the isolated single triterpenes in human primary keratinocytes and porcine ex-vivo wound healing models.Methodology/Principal FindingsWe show positive wound healing effects of TE and betulin in scratch assay experiments with primary human keratinocytes and in a porcine ex-vivo wound healing model (WHM). Mechanistical studies elucidate that TE and betulin transiently upregulate pro-inflammatory cytokines, chemokines and cyclooxygenase-2 on gene and protein level. For COX-2 and IL-6 this increase of mRNA is due to an mRNA stabilizing effect of TE and betulin, a process in which p38 MAPK and HuR are involved. TE promotes keratinocyte migration, putatively by increasing the formation of actin filopodia, lamellipodia and stress fibers. Detailed analyses show that the TE components betulin, lupeol and erythrodiol exert this effect even in nanomolar concentrations. Targeting the actin cytoskeleton is dependent on the activation of Rho GTPases.Conclusion/SignificanceOur results provide insights to understand the molecular mechanism of the clinically proven wound healing effect of birch bark. TE and betulin address the inflammatory phase of wound healing by transient up-regulation of several pro-inflammatory mediators. Further, they enhance migration of keratinocytes, which is essential in the second phase of wound healing. Our results, together with the clinically proven efficacy, identify birch bark as the first medical plant with a high potential to improve wound healing, a field which urgently needs effective remedies.

Antioxidant, antimicrobial and wound healing properties ofStruthanthus vulgaris

“…Fibroblasts are known to play an essential role in cutaneous wound healing, and cell migration is one of the most essential steps, during the proliferative phase, responsible for wound closure (Barrientos et al, 2008;Gurtner et al, 2008;Reinke & Sorg, 2012). Using the scratch assay, a convenient and suitable in vitro test that gives robust and reproducible results for the migration of fibroblasts in an artificial wounded area (Ebeling et al, 2014;Liang et al, 2007), the leaf and branch extracts mainly influenced the migration of the fibroblasts, which may contribute to the rebuilding of new granulation tissue and thus restore the normal functions of the skin. Figure 1.…”

“…Given that antioxidant and antimicrobial activities have been found to have positive effects on wound healing (Adetutu et al, 2011;Annan & Houghton, 2008;Srinivas et al, 2008;Süntar et al, 2012), while fibroblast migration and proliferation play a crucial role in the healing process by initiating the proliferative phase of repair (Ebeling et al, 2014;Fronza et al, 2009;Mensah et al, 2001), our study aimed to evaluate the antioxidant, antimicrobial, and woundhealing activities of S. vulgaris.…”

Birch Bark Dry Extract by Supercritical Fluid Technology: Extract Characterisation and Use for Stabilisation of Semisolid Systems

“…antibacterial, antiviral, anti-parasite BE: [5,6]; BA: [7][8][9]; BE/BA: [10,11]; BE/BA/OA: [12]; LU/BA: [13]; OA/BA: [14] hepatoprotective BE: [15]; BE/BA: [16]; OA: [17][18][19][20]; LU: [21]; BA: [22] antitumor BE: [23,24]; BA: [25,26] BE/BA: [27,28]; LU: [29]; OA: [18,19,30] wound healing extract: [31][32][33]; BA: [34]; OA: [35,36] anti-inflammatory BE: [5,37]; LU: [38,39]; OA: [18,40] Apart from these pharmacological effects, birch bark extract is able to act as a gelling agent and Pickering emulsifier [41][42][43]. Together with its anti-inflammatory and wound healing effects, this makes birch bark dry extract interesting for the stabilisation of semisolid systems, such as gels and creams, acting as an active ingredient and an excipient in parallel.…”

Avaliação das atividades cicatrizante, anti-inflamatória tópica e antioxidante do extrato etanólico da Sideroxylon obtusifolium (quixabeira)

“…A segunda fase inclui reepitelização, formação de tecido de granulação e matriz extracelular, além de angiogênese. E finalmente, na terceira fase, ocorre substituição do colágeno, apoptose e formação da cicatriz (Gurtner et al, 2008;Behm et al, 2011;Ebeling et al, 2014).…”