Functional and mechanistic investigation of Shikonin in scarring

Xie, Yun; Fan, Chen; Dong, Ying; Lynam, Emily; Leavesley, David I.; Li, Kun; Su, Yonghua; Yang, Yinxue; Upton, Zee

doi:10.1016/j.cbi.2014.12.037

Cited by 21 publications

(19 citation statements)

References 31 publications

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“…The present study demonstrated that shikonin treatment affects the gene expression of apoptosis-associated proteins, including the downregulation of Bcl-2 and upregulation of Bax, p53 and caspase-3. These results are in agreement with those of previous studies indicating that shikonin treatment downregulates the expression of Bcl-2 and stimulates the activation of pro-caspase-3 to caspase-3 ( 38 ).…”

Section: Discussionsupporting

confidence: 94%

Shikonin causes apoptosis by disrupting intracellular calcium homeostasis and mitochondrial function in human hepatoma cells

Wang

Liu

et al. 2017

Exp Ther Med

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Shikonin is known to suppress proliferation and induce apoptosis in a variety of cancer cell lines. In the present study, SMMC-7721 human hepatocellular carcinoma cells were treated with shikonin (1, 2 or 4 µM) for 12–48 h. Cell morphological alterations and DNA damage were determined. Furthermore, changes in cell cycle, mitochondrial transmembrane potential, calcium homeostasis and levels of reactive oxygen species were measured. Shikonin-treated SMMC-7721 cells exhibited morphological changes and DNA damage. Shikonin inhibited cell proliferation causing cell cycle arrest at the G0/G1 phase and induced apoptosis in a dose- and time-dependent manner. Shikonin-induced apoptosis was associated with activation of caspases-3, −8 and −9, elevated levels of intracellular Ca2+ and reactive oxygen species, reduced mitochondrial membrane potential and enhanced efflux of Ca2+ and K+. Gene expression B-cell lymphoma 2 (Bcl-2)-associated X protein (Bax), p53 and caspase-3 was up-regulated, whereas Bcl-2 expression was downregulated. Shikonin caused apoptosis by inhibiting cell cycle progression, disrupting Ca2+ homeostasis, inducing oxidative stress and triggering mitochondrial dysfunction. Activation of caspases-3, −8 and −9, K+ efflux, and regulation of Bax, Bcl-2, p53 and caspase-3 expression are involved in the process. These results provide in-depth insight into the mechanisms of action of shikonin in the treatment of cancer.

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Section: Discussionsupporting

confidence: 94%

Shikonin causes apoptosis by disrupting intracellular calcium homeostasis and mitochondrial function in human hepatoma cells

Wang

Liu

et al. 2017

Exp Ther Med

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“…Fan and colleagues demonstrated that Shikonin keratinocytes did not respond to Shikonin unlike human scar-derived fibroblasts which where stimulated to undergo apoptosis [ 106 ]. Shikonin induced apoptosis by altering the expression of capsase-3, B-cell lymphoma (BCL)-2, phosphorylation of ERK1/2 and p38 [ 107 ]. Further, Shikonin down-regulates collagen (type I and III) and smooth muscle actin gene expression in scar-derived fibroblasts [ 107 ].…”

Section: Reviewmentioning

confidence: 99%

“…Shikonin induced apoptosis by altering the expression of capsase-3, B-cell lymphoma (BCL)-2, phosphorylation of ERK1/2 and p38 [ 107 ]. Further, Shikonin down-regulates collagen (type I and III) and smooth muscle actin gene expression in scar-derived fibroblasts [ 107 ].…”

Section: Reviewmentioning

confidence: 99%

“…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 ] …”

Section: Reviewmentioning

confidence: 99%

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

2016

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Though survival rate following severe thermal injuries has improved, the incidence and treatment of scarring have not improved at the same speed. This review discusses the formation of scars and in particular the formation of hypertrophic scars. Further, though there is as yet no gold standard treatment for the prevention or treatment of scarring, a brief overview is included. A number of natural therapeutics have shown beneficial effects both in vivo and in vitro with the potential of becoming clinical therapeutics in the future. These natural therapeutics include both plant-based products such as resveratrol, quercetin and epigallocatechin gallate as examples and includes the non-plant-based therapeutic honey. The review also includes potential mechanism of action for the therapeutics, any recorded adverse events and current administration of the therapeutics used. This review discusses a number of potential ‘treatments’ that may reduce or even prevent scarring particularly hypertrophic scarring, which is associated with thermal injuries without compromising wound repair.

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“…Currently available therapies for hypertrophic scars are not satisfactory due to their undesirable side-effects, complex delivery routes, requirements for long-term use, and expense ( Xie et al, 2015 ). An anti-scar therapy which is simple to use, with minimal side-effects and low cost is urgently needed.…”

Section: Introductionmentioning

confidence: 99%

Development of a Porcine Full-Thickness Burn Hypertrophic Scar Model and Investigation of the Effects of Shikonin on Hypertrophic Scar Remediation

et al. 2018

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Hypertrophic scars formed after burns remain a challenge in clinical practice. Development of effective scar therapies relies on validated animal models that mimic human hypertrophic scars. A consistent porcine full-thickness burn hypertrophic scar model has yet to be developed. We have previously reported that Shikonin induces apoptosis and reduces collagen production in hypertrophic scar fibroblasts in vitro and may therefore hold potential as a novel scar remediation therapy. In this study, we aimed to validate the potential of Shikonin on scar remediation in vivo. A novel porcine hypertrophic scar model was created after full-thickness burn wounds, and the effect of Shikonin on scar remediation was investigated. Clinical scar assessments, histology, and immunohistochemistry were used to evaluate scar appearance, morphology, and protein expression. Eight weeks after scar formation, clinical scar assessment indicated that the score of hypertrophic scars treated with Shikonin was significantly lower than that of the control group. Hypertrophic scars treated with Shikonin appeared flat, pink, and pliable. In addition, histological analysis indicated that hypertrophic scars treated with Shikonin exhibited reduced thickness of the epidermis and dermis, thin and even epithelial layers, reduced numbers of keratinocytes, uniform distribution of fibroblasts, and a parallel and loose arrangement of collagen fibers in the dermis. Moreover, immunohistochemical analysis indicated that Shikonin inhibited the expression of p63, cytokeratin 10, alpha-smooth muscle actin, transforming growth factor-beta 1, and collagen I, which play important roles in hypertrophic scar formation. Based on these results, we conclude that Shikonin has potential as a novel scar therapy.

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Functional and mechanistic investigation of Shikonin in scarring

Cited by 21 publications

References 31 publications

Shikonin causes apoptosis by disrupting intracellular calcium homeostasis and mitochondrial function in human hepatoma cells

Shikonin causes apoptosis by disrupting intracellular calcium homeostasis and mitochondrial function in human hepatoma cells

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

Development of a Porcine Full-Thickness Burn Hypertrophic Scar Model and Investigation of the Effects of Shikonin on Hypertrophic Scar Remediation

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