Tissue-Protective Mechanisms of Bioactive Phytochemicals in Flap Surgery.

Despite careful preoperative planning, surgical flaps are prone to ischemic tissue damage and ischemia-reperfusion injury. The resulting wound breakdown and flap necrosis increase both treatment costs and patient morbidity. Hence, there is a need for strategies to promote flap survival and prevent ischemia-induced tissue damage. Phytochemicals, defined as non-essential, bioactive, and plant-derived molecules, are attractive candidates for perioperative treatment as they have little to no side effects and are well tolerated by most patients. Furthermore, they have been shown to exert beneficial combinations of pro-angiogenic, anti-inflammatory, anti-oxidant, and anti-apoptotic effects. This review provides an overview of bioactive phytochemicals that have been used to increase flap survival in preclinical animal models and discusses the underlying molecular and cellular mechanisms.

Linalool inhibits the angiogenic activity of endothelial cells by downregulating intracellular ATP levels and activating TRPM8.

Angiogenesis crucially contributes to various diseases, such as cancer and diabetic retinopathy. Hence, anti-angiogenic therapy is considered as a powerful strategy against these diseases. Previous studies reported that the acyclic monoterpene linalool exhibits anticancer, anti-inflammatory and anti-oxidative activity. However, the effects of linalool on angiogenesis still remain elusive. Therefore, we investigated the action of (3R)-(-)-linalool, a main enantiomer of linalool, on the angiogenic activity of human dermal microvascular endothelial cells (HDMECs) by a panel of angiogenesis assays. Non-cytotoxic doses of linalool significantly inhibited HDMEC proliferation, migration, tube formation and spheroid sprouting. Linalool also suppressed the vascular sprouting from rat aortic rings. In addition, Matrigel plugs containing linalool exhibited a significantly reduced microvessel density 7 days after implantation into BALB/c mice. Mechanistic analyses revealed that linalool promotes the phosphorylation of extracellular signal-regulated kinase (ERK), downregulates the intracellular level of adenosine triphosphate (ATP) and activates the transient receptor potential cation channel subfamily M (melastatin) member (TRPM)8 in HDMECs. Inhibition of ERK signaling, supplementation of ATP and blockade of TRPM8 significantly counteracted linalool-suppressed HDMEC spheroid sprouting. Moreover, ATP supplementation completely reversed linalool-induced ERK phosphorylation. In addition, linalool-induced ERK phosphorylation inhibited the expression of bone morphogenetic protein (BMP)-2 and linalool-induced TRPM8 activation caused the inhibition of ß1 integrin/focal adhesion kinase (FAK) signaling. These findings indicate an anti-angiogenic effect of linalool, which is mediated by downregulating intracellular ATP levels and activating TRPM8.

Indole-3-carbinol is a potent inhibitor of ischemia-reperfusion-induced inflammation.

BACKGROUND: Ischemia-reperfusion (I/R) induces tissue inflammation, which is characterized by an increased leukocyte-endothelial cell interaction and leukocyte transmigration. These processes are mediated by the activation of the nuclear factor (NF)κB signaling pathway, resulting in an elevated expression of specific adhesion molecules. The phytochemical indole-3-carbinol (I3C) has been shown to exert anti-inflammatory effects by interfering with NFκB signal transduction. The aim of the present study was to investigate whether I3C is capable of counteracting the pathogenesis of I/R injury. MATERIALS AND METHODS: We investigated the inhibitory effect of I3C on endothelial surface protein expression during hypoxia and reoxygenation by flow cytometry. Moreover, the subcellular localization of NFκB was analyzed by immunofluorescence and Western blot. Adhesion protein levels on leukocytes after tumor necrosis factor-α stimulation were determined using flow cytometry. Finally, leukocyte-endothelial cell interaction and leukocyte transmigration during I/R was investigated in dorsal skinfold chambers of BALB/c mice by means of repetitive intravital fluorescence microscopy and immunohistochemistry. RESULTS: I3C suppressed the expression of E-selectin and intercellular adhesion molecule-1 on human dermal microvascular endothelial cells by reducing the transcriptional activity of NFκB. Furthermore, surface protein levels of macrophage-1 antigen as well as activated lymphocyte function-associated antigen-1 were markedly reduced on I3C-treated leukocytes. In vivo, I3C treatment decreased the numbers of adherent and transmigrated leukocytes. This was associated with a reduced macromolecular leakage when compared with vehicle-treated controls. CONCLUSIONS: These novel results indicate that I3C reduces the expression of endothelial and leukocytic adhesion proteins, resulting in attenuated leukocyte-endothelial cell interactions during I/R. Accordingly, dietary supplements containing I3C may be beneficial for the treatment of I/R-induced inflammation.