Potential Molecular Mechanisms Involved in 5-Aminolevulinic Acid–Based Photodynamic Therapy against Human Hypertrophic Scars

Chang, Mengling; Ma, Xiaojing; Ouyang, Tao; Lin, Jun; Li, Jun; Yan, Xinfeng; Chen, Huiping; Yu, Jie; Huang, Yingying; Xu, Miao

doi:10.1097/prs.0000000000001626

Cited by 20 publications

(14 citation statements)

References 33 publications

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“…In recent years, PDT, an effective therapeutic approach with great spatiotemporal accuracy and minimal invasiveness, has aroused tremendous interests in keloid therapy [3] , [4] . The therapeutic procedure consists of three essential elements: a photosensitizer (5-ALA), laser irradiation, and production of reactive oxygen species (ROS).…”

Section: Introductionmentioning

confidence: 99%

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Efficacy of 5-aminolevulinic acid–based photodynamic therapy against keloid compromised by downregulation of SIRT1-SIRT3-SOD2-mROS dependent autophagy pathway

Liu

Ouyang

et al. 2019

Redox Biology

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Keloids exhibit cancer-like properties without spontaneous regression and usually recur post excision. Although photodynamic therapy (PDT) is a promising treatment, details of the mechanisms remain to be elucidated. In this study, we investigated mechanisms involved in 5-Aminolevulinic Acid (5-ALA)–based PDT against keloid. Found that 5-ALA-PDT induced superoxide anion-dependent autophagic cell death. Application of autophagy inhibitor 3-Methyladenine (3-MA) significantly prevented the effect that 5-ALA-PDT induced keloid–derived fibroblasts death, but Z-VAK-FMK (apoptotic inhibitor) did not. Interestingly, 5-ALA-PDT promoted the SIRT3 protein expression and the activity of mitochondrial superoxide dismutase 2 (SOD2), but SIRT1 protein expression level was decreased. SOD2 as a key enzyme can decrease mitochondrial ROS (mROS) level, Deacetylation of SOD2 by SIRT3 regulates SOD2 enzymatic activity has been identified. Then we explored SOD2 acetylation level with immunoprecipitation, found that 5-ALA-PDT significantly increased the acetylation levels of SOD2. In order to confirm deacetylation of SOD2 regulated by SIRT3, 3-TYP (SIRT3 inhibitor) was used. Found that inhibition of SIRT3 by 3-TYP significantly increased the level of SOD2 acetylation level compared with control group or 5-ALA-PDT group. To explore the connection of SIRT1 and SIRT3, cells were treated with EX527(SIRT1 inhibitor) or SRT1720 (SIRT1 activator), and EX527 increased SIRT3 protein level, however, SRT1720 displayed the opposite effect in the present or absence of 5-ALA-PDT. Moreover SIRT1-inhibited cells are more resistant to 5-ALA-PDT and showing decreased ROS accumulation. These results may demonstrate that 5-ALA-PDT induced SIRT1 protein level decreased, which promoted the effect of SIRT3 increased activity of SOD2 that can reduce mROS level, and then compromised 5-ALA-PDT induced autophagic cell death.

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Section: Introductionmentioning

confidence: 99%

“…Many studies have investigated the mechanisms Involved in 5-ALA-PDT, but these findings almost highlight the role of apoptosis in 5-ALA-PDT [4] , [7] . However, our previous assays demonstrated that apoptotic inhibitor did not prevent 5-ALA-PDT induced cells death.…”

Section: Introductionmentioning

confidence: 99%

Efficacy of 5-aminolevulinic acid–based photodynamic therapy against keloid compromised by downregulation of SIRT1-SIRT3-SOD2-mROS dependent autophagy pathway

Liu

Ouyang

et al. 2019

Redox Biology

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“…The p53-related apoptotic pathway is important in treating hypertrophic scar patients [28]. Our Cellular Physiology and Biochemistry Cellular Physiology and Biochemistry mRNA-seq data revealed that the down-regulated mRNAs in AC067945.2 overexpression group were enriched in the p53 signalling pathway.…”

Section: Discussionmentioning

confidence: 75%

Overexpression of LncRNA AC067945.2 Down-Regulates Collagen Expression in Skin Fibroblasts and Possibly Correlates with the VEGF and Wnt Signalling Pathways

Chen¹,

Li²,

Li³

et al. 2018

Cell Physiol Biochem

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Background/Aims: Long non-coding RNAs (lncRNAs) are thought to play crucial roles in human diseases. However, the function of lncRNAs in hypertrophic scar formation remains poorly understood. Methods: Utilizing qRT-PCR, we explored the expression changes of AC067945.2. Overexpression of AC067945.2 in normal skin fibroblasts was performed by transient plasmid transfection. Western blot was used to check the proteins' expression changes. Cell Counting Kit-8 (CCK-8) assay and Annexin V/7-AAD staining were used to examine cell proliferation and apoptosis, respectively. mRNA-seq was applied to dissect the differentially expressed mRNAs in AC067945.2 overexpressed cells. We also performed ELISA to detect the VEGF secretion. Results: AC067945.2 was down-regulated in hypertrophic scar tissues. Overexpression of AC067945.2 did not affect cell proliferation, but it mildly promoted early apoptosis in normal skin fibroblasts. Furthermore, AC067945.2 overexpression inhibited the expression of COL1A1, COL1A2, COL3A1 and α-SMA proteins. Transforming growth factor-β1 (TGF-β1) could inhibit the expression of AC067945.2. Based on mRNA-seq data, compared with mRNAs in the control group, 138 mRNAs were differentially expressed, including 14 upregulated and 124 down-regulated transcripts, in the AC067945.2 overexpression group. Gene ontology and pathway analyses revealed that AC067945.2 overexpression was correlated with developmental processes, binding, extracellular region, and the vascular endothelial

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“…The role of p21 and MEK/ERK signaling in HS has been discussed in previous studies. Chang et al (21) demonstrated that 5-aminolevulinic acid-based anti-HS photodynamic therapy induced increased expression of p53/p21 in HSFBs, which may further active the downstream molecules and promoted cell apoptosis. Furthermore, Li et al (22) observed that kynurenine treatment increased the expression of MEK and the phosphorylation of ERK1/2 in human dermal fibroblasts.…”

Section: Discussionmentioning

confidence: 99%

MicroRNA-22 may promote apoptosis and inhibit the proliferation of hypertrophic scar fibroblasts by regulating the mitogen-activated protein kinase kinase/extracellular signal-regulated kinase/p21 pathway

Dong

Sun

2017

Experimental and Therapeutic Medicine

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Abstract. Hypertrophic scarring (HS) is a common skin disorder that occurs during the wound healing process, and the pathogenesis of HS remains unclear. Increasing evidence indicated that specific microRNAs (miRs) may be involved in the onset and progression of HS. In the present study, the association between miR-22 and HS was investigated. Reverse transcription-quantitative polymerase chain reaction (RT-qPCR) was performed to examine the expression of miR-22 in 30 HS and matched normal skin tissues. In addition, human hypertrophic scar fibroblasts (HSFBs) were cultured and transfected with miR-22 mimics, and MTT and Annexin V apoptosis assays were performed to investigate the role of miR-22 in the proliferation and apoptosis of the human HSFBs. Next, RT-qPCR and western blot assays were performed to compare the expression levels of mitogen-activated protein kinase kinase (MEK), extracellular signal-regulated kinase (ERK) and p21 in untransfected and miR-22 mimic-transfected skin fibroblasts. The results identified that miR-22 was significantly downregulated in HS tissues as compared with the normal skin. Furthermore, transfection with miR-22 mimics in human HSFBs led to inhibited cell proliferation, increased apoptosis, as well as to decreased MEK expression and ERK1/2 phosphorylation, and increased expression of p21. In conclusion, the present study was the first to prove that aberrant expression of miR-22 may serve an important role in the pathogenesis of HS by regulating the MEK/ERK/p21 pathway, thus suggesting that miR-22 has the potential to become a therapeutic target for the treatment of HS.

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Potential Molecular Mechanisms Involved in 5-Aminolevulinic Acid–Based Photodynamic Therapy against Human Hypertrophic Scars

Abstract: Therapeutic, V.

Cited by 20 publications

References 33 publications

Efficacy of 5-aminolevulinic acid–based photodynamic therapy against keloid compromised by downregulation of SIRT1-SIRT3-SOD2-mROS dependent autophagy pathway

Efficacy of 5-aminolevulinic acid–based photodynamic therapy against keloid compromised by downregulation of SIRT1-SIRT3-SOD2-mROS dependent autophagy pathway

Overexpression of LncRNA AC067945.2 Down-Regulates Collagen Expression in Skin Fibroblasts and Possibly Correlates with the VEGF and Wnt Signalling Pathways

MicroRNA-22 may promote apoptosis and inhibit the proliferation of hypertrophic scar fibroblasts by regulating the mitogen-activated protein kinase kinase/extracellular signal-regulated kinase/p21 pathway

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