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] | • 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 [86–88] 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 [158–160] 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 [135–137] | • Human patients with burns—honey-impregnated gauze [135, 136] | • Stinging pain on administration, local atopic reactions in paediatric group [169] |