The Effects of the Transforming Growth Factor-β1 (TGF-β1) Signaling Pathway on Cell Proliferation and Cell Migration are Mediated by Ubiquitin Specific Protease 4 (USP4) in Hypertrophic Scar Tissue and Primary Fibroblast Cultures

Huang, Yong; Wang, Yuting; Wang, Xueming; Li, Lin; Wang, Peng; Sun, Junjun; Jiang, Lei

doi:10.12659/msm.920736

Cited by 15 publications

(10 citation statements)

References 29 publications

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“…Given that TGF-β1 is the predominant cytokine that stimulates the differentiation of lung fibroblasts into myofibroblasts and induces ECM production ( Sapudom et al, 2015 ; Huang et al, 2020 ), we examined the effect of anlotinib (the chemical structure is shown in Supplementary Figure S1 ) on TGF-β1-induced activation of primary mouse lung fibroblasts (MLFs). The CCK-8 assay results showed that anlotinib did not cause significant cytotoxicity at doses of 1 µM ( Figure 1A ).…”

Section: Resultsmentioning

confidence: 99%

“…Immunofluorescence analysis of α-SMA and fibronectin showed similar results ( Figures 1D,E ). We also examined whether anlotinib affected the proliferation and migration of fibroblasts, which have been shown to significantly contribute to many fibrotic pathologies ( Jarman et al, 2014 ; Huang et al, 2020 ). As shown by the EdU ( Figures 1F,G ) and CCK-8 results ( Figure 1H ), anlotinib treatment prevented the TGF-β1-induced proliferation of primary MLFs.…”

Section: Resultsmentioning

confidence: 99%

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Anlotinib Inhibits PFKFB3-Driven Glycolysis in Myofibroblasts to Reverse Pulmonary Fibrosis

et al. 2021

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Idiopathic pulmonary fibrosis (IPF) is a fatal disease in which the normal alveolar network is gradually replaced by fibrotic scars. Current evidence suggests that metabolic alterations correlate with myofibroblast activation in IPF. Anlotinib has been proposed to have antifibrotic effects, but the efficacy and mechanisms of anlotinib against lung fibrosis have not been systematically evaluated. The antifibrotic effects of anlotinib were evaluated in bleomycin-induced mouse models and transforming growth factor-beta 1 (TGF-β1)-stimulated lung fibroblasts. We measured lactate levels, 2-NBDG glucose uptake and the extracellular acidification rate (ECAR) to assess glycolysis in fibroblasts. RNA-protein coimmunoprecipitation (RIP) and polysome analyses were performed to investigate novel mechanisms of glycolytic reprogramming in pulmonary fibrosis. We found that anlotinib diminished myofibroblast activation and inhibited the augmentation of glycolysis. Moreover, we show that PCBP3 posttranscriptionally increases PFKFB3 expression by promoting its translation during myofibroblast activation, thus promoting glycolysis in myofibroblasts. Regarding mechanism, anlotinib exerts potent antifibrotic effects by downregulating PCBP3, reducing PFKFB3 translation and inhibiting glycolysis in myofibroblasts. Furthermore, we observed that anlotinib had preventative and therapeutic antifibrotic effects on bleomycin-induced pulmonary fibrosis. Therefore, we identify PCBP3 as a protein involved in the regulation of glycolysis reprogramming and lung fibrogenesis and propose it as a therapeutic target for pulmonary fibrosis. Our data suggest that anlotinib has antifibrotic effects on the lungs, and we provide a novel mechanism for this effect. Anlotinib may constitute a novel and potent candidate for the treatment of pulmonary fibrosis.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Anlotinib Inhibits PFKFB3-Driven Glycolysis in Myofibroblasts to Reverse Pulmonary Fibrosis

et al. 2021

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“…Many studies have shown that the pathophysiology of keloids is due to prolonged proliferation and delayed remodeling [ 33 , 34 ] and is caused by an excessive accumulation of ECM [ 3 ]. Importantly, it is revealed by the dysregulation of the signaling pathway by TGF-β [ 8 , 35 , 36 , 37 ], as a proinflammatory cytokine. Evidence to date suggests that inflammation triggers the subsequent immune response cascade and that ILs are associated with keloid formation [ 9 , 10 , 38 ].…”

Section: Discussionmentioning

confidence: 99%

Effect of Mortalin on Scar Formation in Human Dermal Fibroblasts and a Rat Incisional Scar Model

Jung

Roh

et al. 2022

IJMS

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Wound healing is a complicated cascading process; disequilibrium among reparative processes leads to the formation of pathologic scars. Herein, we explored the role of mortalin in scar formation and its association with the interleukin-1α receptor using in vitro and in vivo models. To investigate the effects of mortalin, we performed an MTT cell viability assay, qRT-PCR, and Western blot analyses, in addition to immunofluorescence and immunoprecipitation studies using cultured fibroblasts. A rat incisional wound model was used to evaluate the effect of a mortalin-specific shRNA (dE1-RGD/GFP/shMot) Ad vector in scar tissue. In vitro, the mortalin-treated human dermal fibroblast displayed a significant increase in proliferation of type I collagen, α-smooth muscle actin, transforming growth factor-β, phospho-Smad2/3-complex, and NF-κB levels. Immunofluorescence staining revealed markedly increased mortalin and interleukin-1α receptor protein in keloid tissue compared to those in normal tissue, suggesting that the association between mortalin and IL-1α receptor was responsible for the fibrogenic effect. In vivo, mortalin-specific shRNA-expressing Ad vectors significantly decreased the scar size and type-I-collagen, α-SMA, and phospho-Smad2/3-complex expression in rat incisional scar tissue. Thus, dE1-RGD/GEP/shMot can inhibit the TGF-β/α-SMA axis and NF-κB signal pathways in scar formation, and blocking endogenous mortalin could be a potential therapeutic target for keloids.

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“…It inhibits the growth of fibroblasts and reduces endothelial budding and synthesis of procollagen and glycosaminoglycan. Also, it enhances the degeneration of collagen and fibroblasts (26) and triggers a significant decrease in VEGF, α-1-antitrypsin, and α-2-macroglobulin levels (27)(28)(29)(30).…”

Section: Introductionmentioning

confidence: 99%

Network Meta-Analysis of Different Clinical Commonly Used Drugs for the Treatment of Hypertrophic Scar and Keloid

Yang

Luo

2021

Front. Med.

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Background: There is no uniform treatment for pathological scars, including keloids and hypertrophic scars, in clinic currently. Previously, multiple randomized controlled trials have examined the clinical efficacy of different treatments. Nonetheless, the results are inconsistent, and many treatments have not been directly compared. This makes it difficult to conclude which approach is more favorable, in terms of efficacy and safety, for the treatment of pathological scarring. This study aimed at evaluating the efficacy of different injection and topical treatment strategies for hypertrophic scar and keloid.Methods: Relevant literature from PubMed, Medline, Embase, Scopus, the Cochrane Central Register of Controlled Trials (CCRCT), and WHO International Clinical Trials Registry Platform (WHO-ICTRP) were searched, from database inception through November 2020. Randomized clinical trials evaluating different treatment strategies of pathological scars, including triamcinolone acetonide (TAC), verapamil (VER), 5-fluorouracil (5-FU), botulinum toxin A (BTA), bleomycin (BLM), and silicone gels were included in the study.Results: The network meta-analysis included a total of 2,009 patients from 29 studies. A network meta-analysis of injection and topical treatment strategies showed that the efficacy of TAC combined with BTA was best in the treatment of pathological scars. Combination therapies of TAC with 5-FU and TAC with BTA significantly improved the clinical efficiency. However, there was no statistically significant difference between other treatment strategies. The order of efficacy predicted by the surface under the cumulative ranking (SUCRA) curve was as follows: TAC+BTA (82.2%) > TAC+5-FU (69.8%) > BTA (67.3%) > 5-FU+silicone (59.4%) > TAC+silicone (58.3%) > 5-FU (49.8%) > BLM (42.0%) > TAC (26.7%) > VER (26.2%) > silicone (18.3%). There was no publication bias revealed based on the funnel diagram.Conclusion: This study recommends intralesional injection of TAC-BTA and TAC-5-FU combined therapies. But for patients who cannot tolerate the side effects, the use of silicone gels in combination with TAC is recommended. However, these conclusions need to be further confirmed by more randomized controlled trials.

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The Effects of the Transforming Growth Factor-β1 (TGF-β1) Signaling Pathway on Cell Proliferation and Cell Migration are Mediated by Ubiquitin Specific Protease 4 (USP4) in Hypertrophic Scar Tissue and Primary Fibroblast Cultures

Cited by 15 publications

References 29 publications

Anlotinib Inhibits PFKFB3-Driven Glycolysis in Myofibroblasts to Reverse Pulmonary Fibrosis

Anlotinib Inhibits PFKFB3-Driven Glycolysis in Myofibroblasts to Reverse Pulmonary Fibrosis

Effect of Mortalin on Scar Formation in Human Dermal Fibroblasts and a Rat Incisional Scar Model

Network Meta-Analysis of Different Clinical Commonly Used Drugs for the Treatment of Hypertrophic Scar and Keloid

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