RESUMO
Keloid scarring is a fibroproliferative disorder of the skin with unknown pathophysiology, characterised by fibrotic tissue that extends beyond the boundaries of the original wound. Therapeutic options are few and commonly ineffective, with keloids very commonly recurring even after surgery and adjunct treatments. Epigenetics, defined as alterations to the DNA not involving the base-pair sequence, is a key regulator of cell functions, and aberrant epigenetic modifications have been found to contribute to many pathologies. Multiple studies have examined many different epigenetic modifications in keloids, including DNA methylation, histone modification, microRNAs and long non-coding RNAs. These studies have established that epigenetic dysregulation exists in keloid scars, and successful future treatment of keloids may involve reverting these aberrant modifications back to those found in normal skin. Here we summarise the clinical and experimental studies available on the epigenetics of keloids, discuss the major open questions and future perspectives on the treatment of this disease.
Assuntos
Epigênese Genética , Queloide/genética , Reprogramação Celular/genética , Metilação de DNA/genética , Regulação da Expressão Gênica , Histonas/genética , HumanosRESUMO
Hypertrophic scars and keloids are common fibroproliferative diseases following injury. Patients with pathologic scars suffer from impaired quality of life and psychological health due to appearance disfiguration, itch, pain, and movement disorders. Recently, the advancement of hydrogels in biomedical fields has brought a variety of novel materials, methods and therapeutic targets for treating hypertrophic scars and keloids, which exhibit broad prospects. This review has summarized current research on hydrogels and loaded components used in preventing and treating hypertrophic scars and keloids. These hydrogels attenuate keloid and hypertrophic scar formation and progression by loading organic chemicals, drugs, or bioactive molecules (such as growth factors, genes, proteins/peptides, and stem cells/exosomes). Among them, smart hydrogels (a very promising method for loading many types of bioactive components) are currently favoured by researchers. In addition, combining hydrogels and current therapy (such as laser or radiation therapy, etc.) could improve the treatment of hypertrophic scars and keloids. Then, the difficulties and limitations of the current research and possible suggestions for improvement are listed. Moreover, we also propose novel strategies for facilitating the construction of target multifunctional hydrogels in the future.
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Cicatriz Hipertrófica , Queloide , Humanos , Queloide/tratamento farmacológico , Cicatriz Hipertrófica/tratamento farmacológico , Cicatriz Hipertrófica/patologia , Hidrogéis , Qualidade de Vida , PruridoRESUMO
Recent studies have demonstrated that N6-methyladenosine (m6A), the most abundant, dynamic, and reversible epigenetic RNA modification in eukaryotes, is regulated by a series of enzymes, including methyltransferases (writers), demethylases (erasers), and m6A recognition proteins (readers). Aberrant regulation of m6A modification is pivotal for tumorigenesis, progression, invasion, metastasis, and apoptosis of malignant tumors. Immune checkpoint inhibitors (ICIs) has revolutionized cancer treatment, as recognized by the 2018 Nobel Prize in Medicine and Physiology. However, not all cancer patients response to ICI therapy, which is thought to be the result of intricate immune escape mechanisms. Recently, numerous studies have suggested a novel role for m6A epigenetic modification in the regulation of tumor immune evasion. Herein, we review the relevant mechanisms of m6A regulators in regulating various key signaling pathways in cancer biology and how m6A epigenetic modifications regulate the expression of immune checkpoints, opening a new window to understand the roles and mechanisms of m6A epigenetic modifications in regulating tumor immune evasion. In addition, we highlight the prospects and development directions of future combined immunotherapy strategies based on m6A modification targeting, providing directions for promoting the treatment outcomes of immune checkpoint inhibitors.
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Inibidores de Checkpoint Imunológico , Imunoterapia , Humanos , Inibidores de Checkpoint Imunológico/uso terapêutico , Adenosina , Apoptose , CarcinogêneseRESUMO
Background: Although lipid metabolism has been proven to play a key role in the development of cancer, its significance in uveal melanoma (UM) has not yet been elucidated in the available literature. Methods: To identify the expression patterns of lipid metabolism in 80 UM patients from the TCGA database, 47 genes involved in lipid metabolism were analyzed. Consensus clustering revealed two distinct molecular groups. ESTIMATE, TIMER, and ssGSEA analyses were done to identify the differences between the two subgroups in tumor microenvironment (TME) and immune state. Using Cox regression and Lasso regression analysis, a risk model based on differentially expressed genes (DEGs) was developed. To validate the expression of monoacylglycerol lipase (MGLL) and immune infiltration in diverse malignancies, a pan-cancer cohort from the UCSC database was utilized. Next, a single-cell sequencing analysis on UM patients from the GEO data was used to characterize the lipid metabolism in TME and the role of MGLL in UM. Finally, in vitro investigations were utilized to study the involvement of MGLL in UM. Results: Two molecular subgroups of UM patients have considerably varied survival rates. The majority of DEGs between the two subgroups were associated with immune-related pathways. Low immune scores, high tumor purity, a low number of immune infiltrating cells, and a comparatively low immunological state were associated with a more favorable prognosis. An examination of GO and KEGG data demonstrated that the risk model based on genes involved with lipid metabolism can accurately predict survival in patients with UM. It has been demonstrated that MGLL, a crucial gene in this paradigm, promotes the proliferation, invasion, and migration of UM cells. In addition, we discovered that MGLL is strongly expressed in macrophages, specifically M2 macrophages, which may play a function in the M2 polarization of macrophages and M2 macrophage activation in cancer cells. Conclusion: This study demonstrates that the risk model based on lipid metabolism may be useful for predicting the prognosis of patients with UM. By promoting macrophage M2 polarization, MGLL contributes to the evolution of malignancy in UM, suggesting that it may be a therapeutic target for UM.
Assuntos
Melanoma , Monoacilglicerol Lipases , Humanos , Monoacilglicerol Lipases/genética , Ativação de Macrófagos , Melanoma/genética , Macrófagos , Microambiente TumoralRESUMO
Exosomes, ranging from 40 to 160 nm in diameter, are extracellular lipid bilayer microvesicles that regulate the body's physiological and pathological processes and are secreted by cells that contain proteins, nucleic acids, amino acids and other metabolites. Previous studies suggested that mesenchymal stem cell (MSC)-derived exosomes could either suppress or support keloid and hypertrophic scar progression. Although previous research has identified the potential value of MSC-exosomes in keloid and hypertrophic scar, a comprehensive analysis of different sources of MSC-exosome in keloid and hypertrophic scar is still lacking. This review mainly discusses different insights regarding the roles of MSC-exosomes in keloid and hypertrophic scar treatment and summarizes possible underlying mechanisms.
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AIM: To investigate the impact of ablative fractional carbon dioxide laser (AFCO2L) on patient-reported outcomes measures, subjective scar appearance, dermal architecture, and gene transcription in early burn scars. METHODS: Fifteen adult patients with a burn-related scar were recruited. Inclusion criteria were two non-contiguous scar areas of 1% total body surface area, similar baseline Vancouver scar scale (VSS) score and 3months since the time of injury. All participants acted as their own control. Scars were randomized to treatment or control. Treatment scars received three AFCO2L treatments at 6-week intervals. Outcome measures were recorded at baseline, 3, 6, and 12-months post-treatment. Measures included blinded VSS, Patient Observer Scar Assessment Scale (POSAS), Brisbane Burn Scar Impact Profile (BBSIP), blinded scar photo assessment, histological tissue analysis, and RNA sequencing analysis. RESULTS: No significant difference was found in VSS, scar erythema, or pigmentation. Patient POSAS improved in scar thickness and texture following AFCO2L. All elements of BBSIP improved in control and laser groups. AFCO2L-treated scars were scored better than control scars by blinded raters. RNA sequencing illustrated that AFCO2L induced sustained changes in fibroblast gene expression. CONCLUSIONS: AFCO2L treated scars had significantly altered scar thickness and texture 6 months post-laser and were rated better than controls on blinded photo analysis after 3 treatments. RNASeq results suggest laser treatment alters the transcriptome of treated fibroblasts for at least 3 months after treatment. Expansion of this research to study in more depth fibroblast changes in response to laser, as well as assessing the impact on daily activity and quality of life, will be beneficial.
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Queimaduras , Cicatriz Hipertrófica , Lasers de Gás , Adulto , Humanos , Cicatriz/etiologia , Cicatriz/cirurgia , Cicatriz/patologia , Lasers de Gás/uso terapêutico , Resultado do Tratamento , Estudos Prospectivos , Qualidade de Vida , Queimaduras/complicações , Dióxido de Carbono , Cicatriz Hipertrófica/patologiaRESUMO
Scars are maintained for life and increase in size during periods of growth such as puberty. Epigenetic changes in fibroblasts after injury may underpin the maintenance and growth of scars. In this study, we combined methylome and transcriptome data from normotrophic mature scar and contralateral uninjured normal skin fibroblasts to identify potential regulators of scar maintenance. In total, 219 significantly differentially expressed and 1,199 significantly differentially methylated promoters were identified, of which there were 12 genes both significantly differentially methylated and expressed. Of these, the two transcription factors, FOXF2 and MKX, were selected for further analysis. Immunocytochemistry and qPCR suggested that FOXF2 but not MKX had elevated expression in scar fibroblasts. Using RNA sequencing, FOXF2 knockdown was shown to significantly reduce the expression of extracellular matrixârelated genes, whereas MKX did not appear to affect similar pathways. Finally, FOXF2 knockdown was also shown to significantly decrease collagen I production in scar and keloid fibroblasts. This study provides insights into the maintenance of normotrophic scar, suggesting that FOXF2 is an important regulator of this process. Targeting genes responsible for maintenance of scar phenotype may ameliorate scar appearance and improve patient outcomes in the future.
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Cicatriz Hipertrófica , Queloide , Cicatriz Hipertrófica/patologia , Epigenoma , Fibroblastos/metabolismo , Fatores de Transcrição Forkhead/genética , Fatores de Transcrição Forkhead/metabolismo , Perfilação da Expressão Gênica , Humanos , Queloide/patologiaRESUMO
Scarring is a lifelong consequence of skin injury, with scar stiffness and poor appearance presenting physical and psychological barriers to a return to normal life. Lysyl oxidases are a family of enzymes that play a critical role in scar formation and maintenance. Lysyl oxidases stabilize the main component of scar tissue, collagen, and drive scar stiffness and appearance. Here we describe the development and characterisation of an irreversible lysyl oxidase inhibitor, PXS-6302. PXS-6302 is ideally suited for skin treatment, readily penetrating the skin when applied as a cream and abolishing lysyl oxidase activity. In murine models of injury and fibrosis, topical application reduces collagen deposition and cross-linking. Topical application of PXS-6302 after injury also significantly improves scar appearance without reducing tissue strength in porcine injury models. PXS-6302 therefore represents a promising therapeutic to ameliorate scar formation, with potentially broader applications in other fibrotic diseases.
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Cicatriz , Proteína-Lisina 6-Oxidase , Animais , Cicatriz/tratamento farmacológico , Colágeno , Fibrose , Camundongos , Pele , SuínosRESUMO
BACKGROUND: Fibroblasts found in keloid tissues are known to present an altered sensitivity to microenvironmental stimuli. However, the impact of changes in extracellular matrix stiffness on phenotypes of normal fibroblasts (NFs) and keloid fibroblasts (KFs) is poorly understood. OBJECTIVES: Investigation the impact of matrix stiffness on NFs and KFs mainly via detecting yes-associated protein (YAP) expression. METHODS: We used fibronectin-coated polyacrylamide hydrogel substrates with a range from physiological to pathological stiffness values with or without TGF-ß (fibrogenic inducer). Atomic force microscopy was used to measure the stiffness of fibroblasts. Cellular mechanoresponses were screened by immunocytochemistry, Western blot and Luminex assay. RESULTS: KFs are stiffer than NFs with greater expression of α-SMA. In NFs, YAP nuclear translocation was induced by increasing matrix stiffness as well as by stimulation with TGF-ß. In contrast, KFs showed higher baseline levels of nuclear YAP that was not responsive to matrix stiffness or TGF-ß. TGF-ß1 induced p-SMAD3 in both KFs and NFs, demonstrating the pathway was functional and not hyperactivated in KFs. Moreover, blebbistatin suppressed α-SMA expression and cellular stiffness in KFs, linking the elevated YAP signaling to keloid phenotype. CONCLUSIONS: These data suggest that whilst normal skin fibroblasts respond to matrix stiffness in vitro, keloid fibroblasts have elevated activation of mechanotransduction signaling insensitive to the microenvironment. This elevated signaling appears linked to the expression of α-SMA, suggesting a direct link to disease pathogenesis. These findings suggest changes to keloid fibroblast phenotype related to mechanotransduction contribute to disease and may be a useful therapeutic target.
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Fibroblastos/metabolismo , Queloide/patologia , Mecanotransdução Celular , Pele/patologia , Actinas/metabolismo , Adolescente , Adulto , Idoso , Células Cultivadas , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Cultura Primária de Células , Transdução de Sinais , Pele/citologia , Fator de Crescimento Transformador beta1/metabolismo , Proteínas de Sinalização YAP/metabolismoRESUMO
Pulmonary fibrosis is characterised by excessive scarring in the lung which leads to compromised lung function, serious breathing problems and in some diseases, death. It includes several lung disorders with idiopathic pulmonary fibrosis (IPF) the most common and most severe. Pulmonary fibrosis is considered to be perpetuated by aberrant wound healing which leads to fibroblast accumulation, differentiation and activation, and deposition of excessive amounts of extracellular matrix (ECM) components, in particular, collagen. Recent studies have identified the importance of changes in the composition and structure of lung ECM during the development of pulmonary fibrosis and the interaction between ECM and lung cells. There is strong evidence that increased matrix stiffness induces changes in cell function including proliferation, migration, differentiation and activation. Understanding how changes in the ECM microenvironment influence cell behaviour during fibrogenesis, and the mechanisms regulating these changes, will provide insight for developing new treatments.
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Matriz Extracelular/metabolismo , Mecanotransdução Celular , Fibrose Pulmonar/patologia , Animais , Colágeno/metabolismo , Humanos , Fibrose Pulmonar/metabolismoRESUMO
Keloid scarring is a dermal fibroproliferative response characterized by excessive and progressive deposition of collagen; aetiology and molecular pathology underlying keloid formation and progression remain unclear. Genetic predisposition is important in the pathogenic processes of keloid formation, however, environmental factors and epigenetic mechanisms may also play pivotal roles. Epigenetic modification is a recent area of investigation in understanding the molecular pathogenesis of keloid scarring and there is increasing evidence that epigenetic changes may play a role in induction and persistent activation of fibroblasts in keloid scars. Here we have reviewed three epigenetic mechanisms: DNA methylation, histone modification and the role of non-coding RNAs. We also review the evidence that these mechanisms may play a role in keloid formation - in future, it may be possible that epigenetic markers may be used instead of prognostic or diagnostic markers here. However, there is a significant amount of work required to increase our current understanding of the role of epigenetic modification in keloid disease.
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Colágeno/metabolismo , Epigênese Genética/genética , Fibroblastos/citologia , Queloide/genética , Animais , Células Cultivadas , Metilação de DNA/genética , Fibroblastos/metabolismo , HumanosRESUMO
Fibrosis is a common pathological state characterized by the excessive accumulation of extracellular matrix components, but the pathogenesis of the disease is still not clear. Previous studies have shown that microRNA-29 (miR-29) can play pivotal roles in the regulation of a variety of organ fibrosis, including cardiac fibrosis, hepatic fibrosis, lung fibrosis, systemic sclerosis, and keloid. In this review, we outline the structure, expression, and regulation of miR-29 as well as its role in fibrotic diseases.
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Fibrose/genética , MicroRNAs/fisiologia , Regulação da Expressão Gênica , Humanos , Queloide/genética , Rim/patologia , Cirrose Hepática/genética , Miocárdio/patologia , Fibrose Pulmonar/genética , Escleroderma Sistêmico/genéticaRESUMO
Melanoma is a common skin cancer associated with ultraviolet light exposure and genetic variance. However, the etiology and molecular mechanisms of melanoma remain unknown. Recent studies have shown that microRNAs (miRNAs) can play key roles in the development and prognosis of this disease. In this study, we reviewed several pivotal miRNAs that may contribute to melanoma by involvement in the processes of invasion, migration, and metastasis of melanoma cells.