Halofuginone regulates keloid fibroblast fibrotic response to TGF-β induction

Marty, Pierre; Chatelain, B.; Lihoreau, Thomas; Tissot, Marcel; Dirand, Zélie; Humbert, Philippe; Senez, Clémence; Secomandi, Eleonora; Isidoro, Ciro; Rolin, Gwenaël

doi:10.1016/j.biopha.2020.111182

Cited by 18 publications

(5 citation statements)

References 46 publications

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“…The excessive ECM production and abnormal increase in fibroblast proliferation and migration are risk factors in the development of keloid. 31,33 In addition, Xie et al found that keloid-derived fibroblasts expressed high levels of ECM proteins collagen I and collagen III, 34 which was consistent with our results. Furthermore, we found that keloid patient- derived exosomal hsa_circ_0020792 obviously promoted the viability, migration and inhibited the apoptosis of NFs.…”

Section: Discussionsupporting

confidence: 92%

Keloid Patient Plasma-Derived Exosomal hsa_circ_0020792 Promotes Normal Skin Fibroblasts Proliferation, Migration, and Fibrogenesis via Modulating miR-193a-5p and Activating TGF-β1/Smad2/3 Signaling

Hu¹,

Mao²,

Zheng³

et al. 2022

DDDT

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Background: Keloids are fibroproliferative disorders, which seriously affect the quality of life of patients with keloids. Additionally, circRNAs are enriched within exosomes derived from human blood samples, whereas their relationship with keloids remains largely unknown. It has been reported that hsa_circ_0020792 was abnormally upregulated in keloid tissues. However, the role of keloid patient plasma-derived exosomal hsa_circ_0020792 in the formation and development of keloids is not well understood. Methods: Exosomes were isolated from the peripheral blood plasma of the patients with keloids (keloid patient-Exo) and healthy controls (Healthy control-Exo). The hsa_circ_0020792 and miR-193a-5p levels in keloid patient-Exo and healthy control-Exo, as well as in keloid fibroblasts and normal skin fibroblasts (NFs) were evaluated by RT-qPCR. Results: The level of hsa_circ_0020792 was remarkably increased in keloid patient-Exo and keloid fibroblasts compared with that in Healthy control-Exo and NFs, respectively. In addition, keloid patient-Exo obviously enhanced the viability, migration, and extracellular matrix (ECM) synthesis, but reduced the apoptosis of NFs. Moreover, keloid patient-Exo notably promoted the fibrogenesis of NFs, as characterized by enhanced TGF-β signaling, increased expressions of phosphorylated Smad2/3. However, downregulation of hsa_circ_0020792 markedly reversed the promoting effects of keloid patient-Exo on cell growth, migration, and myofibroblast activation and fibrogenesis. Furthermore, downregulation of hsa_circ_0020792 significantly reduced the viability, migration, and fibrogenesis in NFs, whereas these phenomena were reversed by miR-193a-5p inhibitor. Conclusion: Collectively, keloid patient plasma-derived exosomal hsa_circ_0020792 could promote the proliferation, migration, and fibrogenesis of NFs via modulating miR-193a-5p and activating TGF-β1/Smad2/3 signaling.

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Section: Discussionsupporting

confidence: 92%

Keloid Patient Plasma-Derived Exosomal hsa_circ_0020792 Promotes Normal Skin Fibroblasts Proliferation, Migration, and Fibrogenesis via Modulating miR-193a-5p and Activating TGF-β1/Smad2/3 Signaling

Hu¹,

Mao²,

Zheng³

et al. 2022

DDDT

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“…More significantly, HF is a well-known inhibitor of collagen type I synthesis due to the repression of the TGF-β pathway [110]. Further, HF prevents keloid fibrosis by reducing the deposition of ECM and decreasing the proliferation and migration of TGF-β-activated myofibroblasts [111]. In agreement with this, HF found clinical application as a therapeutic agent in fibrotic disease [112] and in some types of malignancies, such as lung and bladder cancer [113,114].…”

Section: Halofuginonementioning

confidence: 99%

Calorie Restriction for Cancer Prevention and Therapy: Mechanisms, Expectations, and Efficacy

et al. 2021

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Cancer is one of the most frequently diagnosed diseases, and despite the continuous efforts in searching for new and more effective treatments, its morbidity and mortality remain a significant health problem worldwide. Calorie restriction, a dietary manipulation that consists in a reduction of the calorie intake, is gaining attention as a potential adjuvant intervention for preventing and/ or fighting cancer. Several forms of energy reduction intake, which includes caloric restriction tout-court, dietary restrictions, and intermittent fasting, are being explored for their ability to prevent or slow down cancer progression. Additionally, another anti-cancer approach being under investigation relies on the use of nutraceuticals known as "Caloric Restriction Mimetics" that can provide caloric restriction-mediated benefits without subjecting the patients to a strict diet. Preclinical in vitro and in vivo studies consistently show that diet modifiers reducing the calorie have impact on tumor microenvironment and cancer metabolism, resulting in reduced growth and progression of cancer. Preliminary clinical studies show that patients subjected to a reduced nutrient/energy intake experience improved outcomes from chemo-and radiotherapy while better tolerating the side effects. Here, we review the state of the art on the therapeutic potential of calorie restriction and of caloric restriction mimetics in preventing or retarding tumor development by modulating a subset of cellular processes. The most recent clinical progresses with caloric restriction mimetics in the clinical practice are also discussed.

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“…Several drugs have been developed to target mechanical transduction signaling pathways. TGF-β has been shown to play an important role in the fibrosis process of keloids, and therefore, multiple therapeutic strategies (including drugs, siRNA, shRNA, and miRNA, among others) have been designed to target TGF-β/Smad signaling to interfere with fibroblast-mediated keloid progression ( Zhang et al, 2020 ; Marty et al, 2021 ). Ginsenoside Rg3 is a substance extracted from ginseng, a traditional Chinese medicine.…”

Section: Clinical Control Of Skin Tension For Keloid Prevention and T...mentioning

confidence: 99%

Biomechanical Regulatory Factors and Therapeutic Targets in Keloid Fibrosis

et al. 2022

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Keloids are fibroproliferative skin disorder caused by abnormal healing of injured or irritated skin and are characterized by excessive extracellular matrix (ECM) synthesis and deposition, which results in excessive collagen disorders and calcinosis, increasing the remodeling and stiffness of keloid matrix. The pathogenesis of keloid is very complex, and may include changes in cell function, genetics, inflammation, and other factors. In this review, we aim to discuss the role of biomechanical factors in keloid formation. Mechanical stimulation can lead to excessive proliferation of wound fibroblasts, deposition of ECM, secretion of more pro-fibrosis factors, and continuous increase of keloid matrix stiffness. Matrix mechanics resulting from increased matrix stiffness further activates the fibrotic phenotype of keloid fibroblasts, thus forming a loop that continuously invades the surrounding normal tissue. In this process, mechanical force is one of the initial factors of keloid formation, and matrix mechanics leads to further keloid development. Next, we summarized the mechanotransduction pathways involved in the formation of keloids, such as TGF-β/Smad signaling pathway, integrin signaling pathway, YAP/TAZ signaling pathway, and calcium ion pathway. Finally, some potential biomechanics-based therapeutic concepts and strategies are described in detail. Taken together, these findings underscore the importance of biomechanical factors in the formation and progression of keloids and highlight their regulatory value. These findings may help facilitate the development of pharmacological interventions that can ultimately prevent and reduce keloid formation and progression.

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Halofuginone regulates keloid fibroblast fibrotic response to TGF-β induction

Cited by 18 publications

References 46 publications

Keloid Patient Plasma-Derived Exosomal hsa_circ_0020792 Promotes Normal Skin Fibroblasts Proliferation, Migration, and Fibrogenesis via Modulating miR-193a-5p and Activating TGF-β1/Smad2/3 Signaling

Keloid Patient Plasma-Derived Exosomal hsa_circ_0020792 Promotes Normal Skin Fibroblasts Proliferation, Migration, and Fibrogenesis via Modulating miR-193a-5p and Activating TGF-β1/Smad2/3 Signaling

Calorie Restriction for Cancer Prevention and Therapy: Mechanisms, Expectations, and Efficacy

Biomechanical Regulatory Factors and Therapeutic Targets in Keloid Fibrosis

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