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Table 1 Natural therapeutics, where they originate from, their potential mechanism of action and known adverse events, bioavailability and drug interactions

From: The evidence for natural therapeutics as potential anti-scarring agents in burn-related scarring

Natural therapeutic agent Origin Mechanism of action(s) Administered Known adverse effects or potential issue with use
Quercetin Flavonoid found in plants, vegetables and fruits • Blocks TGF-β (inhibits receptor expression and SMAD2/3 nuclear translocation)—in turn alters collagen expression [62]
• Alters IGF-1 signalling (through reduction in receptor and intracellular signalling)—in turn affects keloid fibroblast proliferation [63]
• Reduces collagen contraction [65]
• In vitro [62, 63, 65] • Bioavailability is problematic though studies have suggested potential ways to improve its availability [152]
• Adverse events appear mild [153, 154]
• Interacts with some drugs, e.g. fluoroquinolones, taxol/paciltaxel [144, 145]
Onion extract (kaempferol, Mederma®, Contractubex®, Cybele®, Erasé gel, Kaloidon gel) Onion • Up-regulates MMP-1 [68] • In vitro (human skin fibroblasts) [68]
• In vivo (hairless mice administered with ointment) [68]
• No adverse events [69, 72]
• Moderate pruritus, all other adverse events less than the use of corticosteroids [73]
Resveratrol Grape skin, red wine and peanuts • Inhibits fibroblast cell growth, causes cell cycle arrest and induces apoptosis which result in reduced collagen expression [79]
• Reduced TGF-β1 protein in keloid fibroblasts (n = 5), reduced cell proliferation and induced apoptosis but did not decrease collagen type I, alpha smooth muscle actin or heat shock protein 47 in normal skin fibroblasts (n = 1) [81]
• In vitro (hypertrophic-derived fibroblasts, normal skin fibroblasts) [79]
• In vitro (keloid fibroblasts) [81]
• In vitro appears to have no genotoxic activity [155]
• Resveratrol (administered orally) in a number of studies in humans both symptomatic (e.g. Alzheimer’s patients, obese patients) and healthy showed minor adverse events, the most common being nausea, weight loss, diarrhoea and skin rash [140, 156, 157]
• One individual showed elevated hepatic ALT and AST (grade 4) which returned to normal after stopping the medication [140]
• Boocock et al. [149] suggested oral administration may not be sufficient for some therapeutic roles of resveratrol
Epigallocatechin gallate Green tea • Prevents PDGF-BB binding to its receptor and leads to prevention of proliferation and collagen gel contraction [83, 85]
• Known to inhibit a number of intracellular signalling pathways and thereby reducing pro-fibrotic gene expression [8688] and ECM production [84]
• In vitro (neonatal fibroblasts) [83]
• In vitro (human/rat vascular smooth muscle cells) [85]
• In vitro (post-natal human dermal fibroblasts [84]
• In vitro (rat cardiac fibroblasts) [86]
• In vitro (human gingival fibroblasts) [87]
• In vitro (human umbilical vein endothelial cells) [88]
• EGCG appears well tolerated with oral administration [158160] or used on the skin [161]
• Adverse events include mild gastrointestinal issues and skin rashes [158, 160, 161]
• Polyphenon E has been linked to elevated liver function tests but this appeared related to the LOT [141] though a case study showed a case of drug-induced hepatitis [142] and other studies have shown minor increase in liver markers [162]
• Number of chemotherapy agents [146]
Oleanolic acid Number of foods, for example, olive oil, garlic, etc • Decreased TGF-β1 and collagen I and III and increased MMP-1 [93] possibly through decreased fibroblast proliferation, increased apoptosis and degradation of collagen types I and III through enhanced MMP-2 activity [94] • In vivo (rabbit ear model for hypertrophic scars; applied as an ointment) [93, 94] • Animal model associated with male infertility [163]
• Oral administration in an animal model (dose, 22.5–135 mg/kg) for 5 days. Liver injury observed at doses of 90 mg/kg and above [138]
• Bardoxolone methyl—semi-synthetic triterpenoid based on the scaffold of oleanolic acid—caused heart failure in patients with stage 4 chronic kidney disease [139]
Curcumin Rhizome of Curcuma longa and related species. • Induced fibroblast apoptosis and reduced collagen gel contraction [99] via ROS mechanism • In vitro (human fibroblasts) [99] • Poor bioavailability especially after oral administration [164]
• Appears well tolerated up to 8 g/day up to 3 months [164, 165]
• Adverse effects may change with adaptations that are used to improve bioavailability
• Chelate iron suppresses hepcidin therefore potentially causing iron deficiency [166]
• Interacts with 5-fluorouracil and vinorelbine [140, 147, 148, 156]
Shikonin Chinese herb
Radix Arnebiae
• Induces apoptosis in fibroblasts [106]
• Down-regulates collagen types I and III and α smooth muscle actin [107]
• Appears to induce apoptosis by altering p-ERK 1/2, p-p38 and caspase-3 [107]
• In vitro (human keratinocytes, skin fibroblasts) [106]
• In vitro (human keratinocytes, human skin fibroblasts, hypertrophic scar-derived fibroblasts) [107]
• Low bioavailability due to high lipophilicity [167] altered through the formation of a complex with other proteins [150]
• Limited toxicity studies—one animal study demonstrated that it appeared safe up to concentrations of 800 mg/kg for 180 days [168]
Emodin Derived from the Himalayan rhubarb, buckthorn and Japanese knotweed • Alters the intracellular pathway of Pi3K and Akt but only in hypertrophic scar-derived fibroblasts [113] and this in turn inhibited the inflammatory response and improved the histopathology appearance of the scar [113] • In vivo and in vitro (mice model for hypertrophic scars, emodin was administered intra-peritoneally; mice derived hypertrophic scarring fibroblasts and normal fibroblasts) [113] • Not known as yet
Honey   • Accelerates wound healing due to its anti- bacterial activity, anti-oxidant activity, stimulator effects and anti-inflammatory effects [135137] • Human patients with burns—honey-impregnated gauze [135, 136] • Stinging pain on administration, local atopic reactions in paediatric group [169]
  1. TGF-β1 transforming growth factor beta 1, IGF-1 insulinlike growth factor-1, MMP matrix metalloproteinase, PDGF-BB platelet-derived growth factor-BB, ECM extracellular matrix, RGCG epigallocatechin gallate, ROS reactive oxygen species