From a traditional medicinal plant to a rational drug: understanding the clinically proven wound healing efficacy of birch bark extract
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From a traditional medicinal plant to a rational drug: understanding the clinically proven wound healing efficacy of birch bark extract. / Ebeling, Sandra; Naumann, Katrin; Pollok, Simone; Wardecki, Tina; Vidal-Y-Sy, Sabine; Nascimento, Juliana M; Boerries, Melanie; Schmidt, Gudula; Brandner, Johanna M; Merfort, Irmgard.
in: PLOS ONE, Jahrgang 9, Nr. 1, 01.01.2014, S. e86147.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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T1 - From a traditional medicinal plant to a rational drug: understanding the clinically proven wound healing efficacy of birch bark extract
AU - Ebeling, Sandra
AU - Naumann, Katrin
AU - Pollok, Simone
AU - Wardecki, Tina
AU - Vidal-Y-Sy, Sabine
AU - Nascimento, Juliana M
AU - Boerries, Melanie
AU - Schmidt, Gudula
AU - Brandner, Johanna M
AU - Merfort, Irmgard
PY - 2014/1/1
Y1 - 2014/1/1
N2 - BACKGROUND: Birch 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 FINDINGS: We 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/SIGNIFICANCE: Our 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.
AB - BACKGROUND: Birch 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 FINDINGS: We 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/SIGNIFICANCE: Our 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.
KW - Actins
KW - Animals
KW - Betula
KW - Cell Movement
KW - Cell Proliferation
KW - Cyclooxygenase 2
KW - Cytokines
KW - Disease Models, Animal
KW - Gene Expression Regulation
KW - Hu Paraneoplastic Encephalomyelitis Antigens
KW - Humans
KW - Inflammation Mediators
KW - Keratinocytes
KW - NF-kappa B
KW - Plant Bark
KW - Plant Extracts
KW - Plants, Medicinal
KW - RNA Stability
KW - RNA, Messenger
KW - STAT3 Transcription Factor
KW - Skin
KW - Swine
KW - Triterpenes
KW - Wound Healing
KW - p38 Mitogen-Activated Protein Kinases
KW - rho GTP-Binding Proteins
U2 - 10.1371/journal.pone.0086147
DO - 10.1371/journal.pone.0086147
M3 - SCORING: Journal article
C2 - 24465925
VL - 9
SP - e86147
JO - PLOS ONE
JF - PLOS ONE
SN - 1932-6203
IS - 1
ER -
