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The effect of TA on collagen production in NF and KF after Sirius red staining. DMSO significantly increased collagen production in NFs. TA strikingly reduced collagen production in KFs compared with NFs. C: control, total medium; V: vehicle, 0.55% DMSO; TA, 0.55 × 10−3 M of TA was dissolved in 0.55% DMSO. P * < 0.01 , V versus C; P # < 0.05 , TA versus V; P # # < 0.05 , TA versus C; P & & < 0.01 , TA versus V; n = 4 .
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Keloid scarring is a fibroproliferative disorder due to the accumulation of collagen type I. Tolfenamic acid (TA), a nonsteroidal anti-inflammatory drug, has been found to potentially affect the synthesis of collagen in rats. In this preliminary study, we aimed to test the effects of TA on cell proliferation, cell apoptosis, and the deposition of i...
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Background:
Histologically, keloids contain excess fibroblasts and an overabundance of dermal collagen. Recently, it was reported that chymase induced a profibrotic response via transforming growth factor-β1 (TGF-β1)/Smad activation in keloid fibroblasts (KFs). However, the role of chymase in the local renin-angiotensin system (RAS) in keloids has...
Keloid scarring is an abnormal pathological scar characterized by excessive fibro proliferation and extracellular matrix deposition. Electronic beam irradiation is commonly used with surgical removal to control high recurrence rates of keloid scarring; however, the mechanism remains unknown. In this study, we used keloid-derived primary fibroblasts...
Citations
... Keloid fibroblasts are the primary cells involved in the formation of the wound healing scar, and their elevated proliferation and limited apoptosis lead to excess scarring [7][8][9]. LY2109761, a transforming growth factor-(TGF-) β receptor inhibitor, reduces tumor cell growth, intravasation, and the metastatic dissemination of hepatocellular carcinoma (HCC) cells through different molecular mechanisms [10]. We previously showed that LY2109761 inhibited human hypertrophic scar formation [11]; however, its effect on keloid formation has not been tested yet. ...
Keloids are scars characterized by abnormal proliferation of fibroblasts and overproduction of extracellular matrix components including collagen. We previously showed that LY2109761, a transforming growth factor- (TGF-) β receptor inhibitor, suppressed the secretion of matrix components and slowed the proliferation of fibroblasts derived from human hypertrophic scar tissue. However, the exact mechanism underlying this effect remains unclear. Here, we replicated the above results in keloid-derived fibroblasts and show that LY2109761 promoted apoptosis, decreased the phosphorylation of Smad2 and Smad3, and suppressed TGF-β1. These results suggest that the development and pathogenesis of keloids are positively regulated by the Smad2/3 signaling pathway and the upregulation of TGF-β1 receptors. LY2109761 and other inhibitors of these processes may therefore serve as therapeutic targets to limit excessive scarring after injury.
... Keloids have exhibited a series of tumor-like pathological features, such as increasing ATP synthesis, inflammation-induced alteration of the stem cell niche and histological heteromorphism, in which normal dermal tissue structures disappear (5)(6)(7). Due to the similarities between keloids and benign skin tumors, a large number of anti-keloid compounds have been investigated for their therapeutic values from the perspective of anti-tumor like effects on keloid formation (1,(8)(9)(10)(11)(12). ...
Keloids are benign skin tumors with a high recurrence rate following surgical excision. Abnormal intracellular signaling is one of the key mechanisms involved in its pathogenesis. Over‑activated phosphoinositide 3‑kinase/RAC‑alpha serine/threonine‑protein kinase/mammalian target of rapamycin (PI3K/Akt/mTOR) signaling pathway and overproduction of histone deacetylases 2 (HDAC2) have also been observed in keloid fibroblasts (KFs). The present study aimed to explore the possibility of reversing the KF pathological phenotype using CUDC‑907, a dual inhibitor of PI3K/Akt/mTOR pathway and HDACs. KFs and keloid xenografts were treated with CUDC‑907 to examine its inhibitory effects on the pathological activities of KFs in vitro and in vivo. CUDC‑907 inhibited cell proliferation, migration, invasion and extracellular matrix deposition of in vitro cultured KFs and also suppressed collagen accumulation and disrupted the capillaries of keloid explants ex vivo and in vivo. A mechanistic study of CUDC‑907 revealed the initiation of cell cycle arrest at G2/M phase along with the enhanced expression of cyclin‑dependent kinase inhibitor 1 and decreased expression of cyclin B in cells treated with CUDC‑907. CUDC‑907 not only inhibited AKT and mTOR phosphorylation and promoted the acetylation of histone H3, but also significantly inhibited the phosphorylation levels of Smad2/3 and Erk. These preclinical data demonstrating its anti‑keloid effects suggest that CUDC‑907 may represent a candidate drug for systemic keloid therapy.
... Its abnormal proliferation and apoptosis delay result excessive deposition of extracellular matrix, excessive healing trauma, leading to form pathological scar [3,6]. Studies showed that the induction of apoptosis and inhibition of proliferation and collagen synthesis in keloid fibroblasts help to improve the keloid formation [7][8][9]. In addition, TGF-b1/Smad pathway plays an important role in keloid formation [10]. TGF-b first binds to type II transmembrane serine/threonine kinase receptors receptor (TbRII) which then transphosphorylates type I receptor (TbRI). ...
It has been reported that Dickkopf-3 (DKK3) down-regulation was examined in keloid fibroblasts, but the biological functions of DKK3 have not yet been investigated. In this study, we examined the expression of DKK3 in human keloid tissues, further evaluated the biological function of DKK3 and explored its potential molecular mechanism in transforming growth factor-β1 (TGF-β1)-induced keloid fibroblasts. Our results showed that DKK3 mRNA expression in human keloid tissues is down-regulated. DKK3 overexpression inhibited cell proliferation in TGF-β1-induced keloid fibroblasts transfected with pcDNA3.1-DKK3. Furthermore, DKK3 overexpression remarkably upregulated the protein expression levels of Bax and caspase-3, but decreased the protein expression of Bcl-2. In addition, DKK3 overexpression dramatically inhibited the protein and mRNA levels of collagen I (Col-I), collagen III (Col-III) and α-smooth muscle actin (α-SMA). Moreover, the protein expression of TGF-β receptor I (TGF-β RI), TGF-β receptor II (TGF-β RII), the phosphorylation of Smad2 (p-Smad2) and Smad3 (p-Smad3) was dramatically inhibited by pcDNA3.1-DKK3. LY2109761, a TGF-β receptor inhibitor, also suppressed cell proliferation, apoptosis and collagen synthesis in TGF-β1-induced keloid fibroblasts. Taken together, DKK3 overexpression could inhibit cell proliferation, induced cell apoptosis, and suppressed collagen synthesis through TGF-β1/Smad signaling in TGF-β1-induced keloid fibroblasts. Our findings suggest that DKK3 is a novel and promising molecular target for keloid treatment.
Keloids are benign skin tumors characterized by excessive fibroblast proliferation and collagen deposition. The current treatment of keloids with hormone drug injection, surgical excision, radiotherapy, physical compression, laser therapy, cryotherapy often have unsatisfactory outcomes. The phytochemical compounds have shown great potential in treating keloids. Tripterine, a natural triterpene derived from the traditional Chinese medicine Thunder God Vine (Tripterygium wilfordii), was previously reported to exhibit an anti-scarring bioactivity in mouse embryonic fibroblast NIH/3T3 cells. Accordingly, our study was dedicated to explore its role in regulating the pathological phenotypes of keloid fibroblasts. Human keloid fibroblasts were treated with tripterine (0-10 μM) for 24 h. Cell viability, proliferation, migration, apoptosis and extracellular matrix (ECM) deposition were determined by CCK-8, EdU, wound healing, Transwell, flow cytometry, western blotting and RT-qPCR assays. The effects of tripterine treatment on ROS generation and JNK activation in keloid fibroblasts were assessed by DCFH-DA staining and western blotting analysis. Tripterine at the concentrations higher than 4 μM attenuated the viability of human keloid fibroblasts in a dose-dependent manner. Treatment with tripterine (4, 6, and 8 μM) dose-dependently inhibited cell proliferation and migration, promoted cell apoptosis, reduced α-SMA, Col1, and Fn expression, induced ROS production, and enhanced JNK phosphorylation in keloid fibroblasts. Collectively, tripterine ameliorates the pathological characteristics of keloid fibroblasts that are associated with keloid formation and growth by inducing ROS generation and activating JNK signaling pathway.
Background:
Keloid is a fibrous tissue proliferative disease in which proliferative scars grow beyond the boundary of the original wound skin. Long non-coding RNAs (lncRNAs), as competing endogenous RNAs (ceRNAs), bind to microRNAs (miRNAs) to regulate various biological processes. This study was aim to illuminate the mechanism of Calcium Voltage-Gated Channel Subunit Alpha1 G antisense RNA 1 (CACNA1G-AS1) in human keloid fibroblasts.
Methods:
CACNA1G-AS1 and miR-205 levels were detected using quantitative real-time polymerase chain reaction (qRT-PCR). Cell Counting Kit-8 (CCK-8) assay was used to measure the proliferation and transwell assay was performed to evaluate cell invasion. Furthermore, the apoptosis rates of cells were evaluated by flow cytometry analysis, and the activity of caspase-3 in keloid fibroblasts was tested by Caspase-3 activity assay. Dual luciferase reporter assay was carried out to examine the relationship between CACNA1G-AS1 and miR-205 and RNA immunoprecipitation (RIP) assay was conducted to further confirm the relation.
Results:
CACNA1G-AS1 level was up-regulated in keloid tissues and keloid fibroblasts. CACNA1G-AS1 overexpression promoted proliferation and invasion and suppressed apoptosis of keloid fibroblasts. Moreover, miR-205 was targeted by CACNA1G-AS1 and miR-205 was markedly decreased in keloid tissues and keloid fibroblasts. Also, miR-205 expression was negatively regulated by CACNA1G-AS1 and miR-205 silencing enhanced proliferation and invasion and inhibited apoptosis. Furthermore, CACNA1G-AS1 and miR-205 played the antagonistic role in miR-205 expression, proliferation, invasion and apoptosis of keloid fibroblasts.
Conclusion:
CACNA1G-AS1 suppressed miR-205 expression to promote proliferation and invasion and inhibit apoptosis in human keloid fibroblasts.
