RESUMEN
Keloids are defined as a benign dermal fibroproliferative disorder, with excessive fibroblast proliferation, and excessive overproduction of collagen. Although the heterogeneity during keloid development has been extensively studied, the heterogeneity across different skin states is still unclear. So, a global comparison across skin states is needed. In this study, we collected samples from 5 states of skin, including melanoma, cutaneous squamous cell carcinoma, keloid skin, scar skin, and healthy control samples. The heterogeneity of cell types and subtypes was analyzed and compared across 5 states, and we observed significant differences among them. Our results showed a cancer-like fibroblast, which is not in normal samples, may play an important role in antigen processing and presentation. We also noticed that the mesenchymal fibroblast increased in keloid samples, which highly expressed POSTN. And POSTN may participate in epithelial-mesenchymal transition and collagen overexpression to promote keloid growth. These findings help to understand the alteration among different skin states and provide potential genetic basis for keloid therapies.
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Fibroblastos , Queloide , Neoplasias Cutáneas , Humanos , Queloide/patología , Queloide/metabolismo , Queloide/genética , Fibroblastos/metabolismo , Fibroblastos/patología , Neoplasias Cutáneas/patología , Neoplasias Cutáneas/metabolismo , Neoplasias Cutáneas/genética , Análisis de la Célula Individual/métodos , Piel/patología , Piel/metabolismo , Moléculas de Adhesión Celular/metabolismo , Moléculas de Adhesión Celular/genética , Transición Epitelial-Mesenquimal/genética , Colágeno/metabolismo , MasculinoRESUMEN
INTRODUCTION: Keloids are the result of abnormal tissue scarring that occur after skin injuries leading to pain, psychological distress, and impaired quality of life. Despite the high recurrence rate after surgical treatment, excision is often inevitable for symptom control. PATIENT CONCERNS: A 32-year-old female presented with a huge keloid on the pubic area accompanied by severe pain, pruritus, and infectious discharge. She also had multiple keloids on her chest and shoulders, indicating a strong predisposition to keloid formation. INTERVENTIONS: While high potential for recurrence was anticipated, surgical excision was inevitable for symptom control. Complete keloid excision followed by split-thickness skin graft was performed. DIAGNOSIS: Pathological report revealed keloid accompanied by ruptured epidermal inclusion cyst. OUTCOMES: Although postoperative care was highly recommended for prevention of keloid recurrence, the patient refused any additional management due to her financial difficulties. At postoperative 8 months, mild degree of keloid or hypertrophic scar at marginal area of the graft was observed, suggesting the potential sign of keloid recurrence. The patient voluntarily discontinued the outpatient follow-up for 2 years, and then returned with huge keloid not only at the graft site but also at the donor site. CONCLUSION: Keloid with inflamed epidermal inclusion cyst can cause severe pain where surgical excision is unavoidable, regardless of the high potential for recurrence. Additional postoperative care is necessary to prevent recurrence. Furthermore, attempts to minimize new keloid formation at the donor site after split-thickness skin graft, such as thin skin harvest or selecting the scalp as the donor site, should be considered.
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Queloide , Recurrencia , Trasplante de Piel , Humanos , Femenino , Adulto , Queloide/cirugía , Queloide/etiología , Trasplante de Piel/métodos , Sitio Donante de Trasplante , Complicaciones Posoperatorias/etiologíaRESUMEN
Keloids are pathologic responses to cutaneous injury. Current treatments, such as topical and intralesional steroids and even surgical excision, have limited efficacy, creating a demand for improved therapies. Our study explores the functioning of dupilumab, an interleukin-4 and inter-leukin-13 signaling pathway inhibitor, in this context. We have reviewed the literature for using dupilumab to treat keloids, evaluating safety and efficacy and offering recommendations for its application. We searched PubMed and Google Scholar using "Dupilumab" and "Keloid" as keywords. To ensure relevance, we limited the search to English language publications of 2018-2023. Dupilumab exhibited efficacy in keloid treatment, with notable improvements in patients. One patient reported a 50% reduction in the fibrotic plaque and complete resolution of smaller keloids without adverse effects. Two other patients reported successful stabilization and reduction in keloids following dupilumab therapy; however, the 12-week treatment demonstrated no response or reduction in post-treatment size or height of keloidals, with disease progression observed in one patient. One report discouraged the use of dupilumab for keloids due to limited positive responses. Considering dupilumab as the last therapeutic option to treat keloids may benef patients resistant to standard therapies and/or those highly motivated to reduce keloids.
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Anticuerpos Monoclonales Humanizados , Queloide , Queloide/tratamiento farmacológico , Humanos , Anticuerpos Monoclonales Humanizados/uso terapéutico , Anticuerpos Monoclonales Humanizados/farmacología , Resultado del Tratamiento , Agentes Inmunomoduladores/uso terapéutico , Agentes Inmunomoduladores/farmacologíaRESUMEN
OBJECTIVE: To explore the complex mechanisms of keloid, new approaches have been developed by different strategies. However, conventional treatment did not significantly reduce the recurrence rate. This study aimed to identify new biomarkers and mechanisms for keloid progression through bioinformatics analyses. METHODS: In our study, microarray datasets for keloid were downloaded from the GEO database. Differentially expressed genes (DEGs) were identified by R software. Multiple bioinformatics tools were used to identify hub genes, and reverse predict upstream miRNAs and lncRNA molecules of target hub genes. Finally, the total RNA-sequencing technique and miRNA microarray were combined to validate the identified genes. RESULTS: Thirty-one DEGs were screened out and the upregulated hub gene SPP1 was finally identified, which was consistent with our RNA-sequencing analysis results and validation dataset. In addition, a ceRNA network of mRNA (SPP1)-miRNA (miR-181a-5p)-lncRNA (NEAT1, MALAT1, LINC00667, NORAD, XIST and MIR4458HG) was identified by the bioinformatics databases. The results of our miRNA microarray showed that miR-181a-5p was upregulated in keloid, also we found that the lncRNA NEAT1 could affect keloid progression by retrieving the relevant literature. CONCLUSIONS: We speculate that SPP1 is a potential candidate biomarker and therapeutic target for patients with keloid, and NEAT1/miR-181a-5p/SPP1 might be the RNA regulatory pathway that regulates keloid formation.
Identify new biomarkers in keloid, potentially improve disease diagnosis and treatment.Through a variety of bioinformatics analysis tools, we found that the miRNA pathway NEAT1/miR-181a-5p/SPP1 may participant in controlling disease progression in the keloid.Providing insight into the mechanisms of disease development in the keloid at the transcriptome level.
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Biología Computacional , Redes Reguladoras de Genes , Queloide , MicroARNs , Osteopontina , ARN Largo no Codificante , Queloide/genética , Queloide/metabolismo , Humanos , Biología Computacional/métodos , MicroARNs/genética , MicroARNs/metabolismo , ARN Largo no Codificante/genética , ARN Largo no Codificante/metabolismo , Osteopontina/genética , Osteopontina/metabolismo , Perfilación de la Expresión Génica , Regulación hacia Arriba , ARN Mensajero/metabolismo , ARN Mensajero/genética , Análisis de Secuencia de ARNRESUMEN
Introduction: Pathological scars, such as hypertrophic scars and keloids, are characterized by the proliferation of fibroblasts and the deposition of collagen that often cause pruritus, pain, and disfigurement. Due to their high incidence and deformity, pathological scars have resulted in severe physical and psychological trauma for patients. Intralesional injection of 5-fluorouracil (5-Fu) is a recommended option for treating pathological scars. However, the efficacy of 5-Fu injection was limited and unstable due to limited drug penetration and short retention time. Methods: Liposomes are promising carriers that have advantages, such as high biocompatibility, controlled release property, and enhanced clinical efficacy. Here, we constructed a transdermal 5-Fu-loaded liposome (5-Fu-Lip) to provide a more effective and safer modality to scar treatment. Results: Compared to 5-Fu, 5-Fu-Lip showed superior ability in inhibiting primary keloid fibroblasts proliferation, migration, and collagen deposition, and also significantly inhibited human umbilical vein endothelial cells (HUVECs) proliferation and microvessel construction. In vivo experiments demonstrated that 5-Fu-Lip can significantly reduce the severity of hypertrophic scars in a rabbit ear wounding model. Discussion: 5-Fu-Lip provides a promising strategy to improve drug efficacy, which has great potential in the treatment of pathological scars.
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Proliferación Celular , Cicatriz Hipertrófica , Fibroblastos , Fluorouracilo , Células Endoteliales de la Vena Umbilical Humana , Queloide , Liposomas , Fluorouracilo/administración & dosificación , Fluorouracilo/farmacología , Fluorouracilo/química , Conejos , Animales , Liposomas/química , Humanos , Cicatriz Hipertrófica/tratamiento farmacológico , Fibroblastos/efectos de los fármacos , Queloide/tratamiento farmacológico , Queloide/patología , Proliferación Celular/efectos de los fármacos , Células Endoteliales de la Vena Umbilical Humana/efectos de los fármacos , Colágeno/química , Movimiento Celular/efectos de los fármacos , Administración CutáneaRESUMEN
BACKGROUND: Keloid, a fibroproliferative disorder, significantly impacts patients' quality of life, yet effective therapies remain elusive. This study explored the role of silent information regulator 6 (SIRT6) in modulating the proliferation, invasion, and collagen synthesis of keloid fibroblasts. METHODS: Keloid and normal skin specimens were collected, and fibroblasts were isolated from the keloid tissue. SIRT6 recombinant adenovirus (Ad) was constructed to infect keloid fibroblasts to overexpress SIRT6. This study entails three groups: Control group, adenovirus-Negative Control (Ad-NC) group, and Ad-SIRT6 group. SIRT6 protein and mRNA levels were measured via Western blotting and Quantitative reverse transcription polymerase chain reaction (qRT-PCR), respectively. Cell viability was determined using 5-ethynyl-2'-deoxyuridine (EdU) assay. Flow cytometry was exploited to measure cell apoptosis. To investigate cell migration, wound healing assay and Transwell assay were employed. Western blotting was also utilized to study the expression levels of apoptotic proteins, collagen deposition-related proteins, and Mitogen-Activated Protein Kinases (MAPK)/extracellular regulated protein kinases (ERK) pathway-related proteins. RESULTS: Compared to the control and Ad-NC groups, the Ad-SIRT6 group exhibited significantly elevated SIRT6 level; diminished cell proliferation, migration and invasion; reduced protein levels of α-smooth muscle actin (α-SMA), collagen I, collagen III, phospho SMAD Family Member 3 (p-Smad3), transforming growth factor-ß 1 (TGF-ß1), and MAPK/ERK pathway proteins (phospho extracellular signal-regulated protein kinase 1/2 (p-ERK1/2), phospho MAP kinase-ERK kinase (p-MEK) and phospho-c-Raf (p-c-Raf)). Treatment with epidermal growth factor (EGF), an MAPK/ERK pathway agonists, reversed the inhibitory effect of SIRT6 on cell activity and inhibited apoptosis in keloid fibroblasts. CONCLUSION: SIRT6 overexpression in keloid fibroblasts attenuates proliferation, invasion, and collagen synthesis, while fostering apoptosis, likely through the suppression of MAPK/ERK pathway activity. This suggests a potential therapeutic target for keloid treatment.
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Proliferación Celular , Colágeno , Fibroblastos , Queloide , Sistema de Señalización de MAP Quinasas , Sirtuinas , Humanos , Sirtuinas/metabolismo , Sirtuinas/genética , Queloide/patología , Queloide/metabolismo , Fibroblastos/metabolismo , Fibroblastos/patología , Colágeno/biosíntesis , Colágeno/metabolismo , Apoptosis/genética , Movimiento Celular , Masculino , Femenino , Células Cultivadas , AdultoRESUMEN
INTRODUCTION: Keloids, benign fibroproliferative tumours characterised by excessive fibroblast proliferation and over-deposition of extracellular matrix, pose a therapeutic challenge with high recurrence rates. Betamethasone (diprospan) injection (BI) is one of the most common non-invasive therapies for keloids. Pulsed dye laser (PDL) has the function of closing microvessels, which may become one of the auxiliary treatment methods of BI and may enhance its curative effect. Some studies suggest that the combination of a dual-wavelength dye laser (DWL) and BI may offer superior efficacy. This randomised controlled trial aims to evaluate whether the combined therapy of DWL+BI outperforms BI alone in treating keloids. METHODS AND ANALYSIS: This single-centre, parallel positive control, randomised trial evaluates the efficacy and safety of DWL (585 nm PDL+1064 nm neodymium-doped yttrium aluminium garnet) combined with BI for keloid treatment. Enrolling 66 adult patients, participants are randomised into DWL+BI or BI groups in a 1:1 ratio. Over 12 weeks, each group undergoes four treatment sessions, ensuring blinding for outcome assessors. Data collection occurs at multiple time points (4, 12, 24 and 52 weeks), with primary outcomes assessing the Vancouver Scar Scale (VSS) improvement rate 24 weeks after the last intervention. Secondary outcomes include VSS improvement rates, changes in keloid volume, changes in relative perfusion index measured by laser speckle contrast imaging, Patient and Observer Scar Assessment Scale results and patient satisfaction. Safety assessments include vital signs, laboratory tests, pregnancy tests and self-reports of adverse reactions. ETHICS AND DISSEMINATION: The results will be presented in peer-reviewed journals and at international conferences. This study is approved by the Ethics Committee of Peking Union Medical College Hospital, Chinese Academy of Medical Sciences. TRIAL REGISTRATION NUMBER: Chinese Clinical Trial Register (ChiCTR2400080148).
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Betametasona , Queloide , Láseres de Colorantes , Humanos , Queloide/terapia , Queloide/tratamiento farmacológico , Betametasona/administración & dosificación , Betametasona/uso terapéutico , Láseres de Colorantes/uso terapéutico , Adulto , Femenino , Ensayos Clínicos Controlados Aleatorios como Asunto , Masculino , Terapia Combinada , Glucocorticoides/administración & dosificación , Glucocorticoides/uso terapéutico , Resultado del Tratamiento , Persona de Mediana Edad , Adulto Joven , AdolescenteRESUMEN
BACKGROUND: The prevalence of social media as a source of medical information has grown substantially in recent years, especially for skin conditions disproportionately affecting individuals with skin of color, such as melasma, keloids, and vitiligo. OBJECTIVE: This study aims to evaluate the nature of content related to these conditions on social media platforms, Instagram and TikTok. METHODS: In March 2023, the top five hashtags for melasma, keloid, and vitiligo were identified on both platforms. For each hashtag, the 10 most popular posts were selected, based on Instagram and TikTok algorithms. A content analysis was conducted, categorizing posts as Educational, Promotional, or Inspirational. Posts were further classified by content creator type. RESULTS: For the top 50 posts related to melasma on Instagram, the majority were promotional (58%), with the most common source being non-dermatologist social media influencers (50%). Dermatologists were the primary content creators for specific hashtags, such as #Melasma on TikTok, where the content was predominantly educational. CONCLUSION: Considering the high prevalence of dermatologist-creator content on TikTok, it is crucial to continue this shift toward dermatologist-driven educational content, as social media platforms continue to grow. These platforms are valuable channels for dermatologists to educate a broader audience, facilitating the dissemination of accurate medical information.J Drugs Dermatol. 2024;23(7):510-514. doi:10.36849/JDD.7716.
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Queloide , Melanosis , Pigmentación de la Piel , Medios de Comunicación Sociales , Vitíligo , Medios de Comunicación Sociales/estadística & datos numéricos , Humanos , Vitíligo/terapia , Vitíligo/diagnóstico , Vitíligo/psicología , Queloide/epidemiología , Melanosis/diagnóstico , Dermatólogos/estadística & datos numéricosRESUMEN
Fibrotic skin diseases, such as keloids, are pathological results of aberrant tissue healing and are characterized by overgrowth of dermal fibroblasts. Remdesivir (RD), an antiviral drug, has been reported to have pharmacological activities in a wide range of fibrotic diseases. However, whether RD function on skin fibrosis remains unclear. Therefore, in our study, we explored the potential effect and mechanisms of RD on skin fibrosis both in vivo and in vitro. As expected, the results demonstrated that RD alleviated BLM-induced skin fibrosis and attenuates the gross weight of keloid tissues in vivo. Further studies suggested that RD suppressed fibroblast activation and autophagy both in vivo and in vitro. In addition, mechanistic research showed that RD attenuated fibroblasts activation by the TGF-ß1/Smad signaling pathway and inhibited fibroblasts autophagy by the PI3K/Akt/mTOR signaling pathway. In summary, our results demonstrate therapeutic potential of RD for skin fibrosis in the future.
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Adenosina Monofosfato , Alanina , Fibroblastos , Fibrosis , Transducción de Señal , Piel , Factor de Crecimiento Transformador beta1 , Animales , Transducción de Señal/efectos de los fármacos , Factor de Crecimiento Transformador beta1/metabolismo , Fibrosis/tratamiento farmacológico , Alanina/análogos & derivados , Alanina/farmacología , Alanina/uso terapéutico , Fibroblastos/efectos de los fármacos , Fibroblastos/metabolismo , Adenosina Monofosfato/análogos & derivados , Adenosina Monofosfato/farmacología , Adenosina Monofosfato/metabolismo , Ratones , Piel/efectos de los fármacos , Piel/patología , Piel/metabolismo , Humanos , Autofagia/efectos de los fármacos , Queloide/tratamiento farmacológico , Queloide/metabolismo , Queloide/patología , Antivirales/farmacología , Serina-Treonina Quinasas TOR/metabolismo , Bleomicina , Fosfatidilinositol 3-Quinasas/metabolismo , Masculino , Proteínas Proto-Oncogénicas c-akt/metabolismo , Proteínas Smad/metabolismoRESUMEN
BACKGROUND: Postoperative radiotherapy can significantly reduce keloid recurrence. However, consensus on the optimal radiotherapy dose and treatment schedule remains elusive. This study aims to evaluate the effectiveness of surgery followed by a short-course of radiotherapy administered every other day for keloid treatment. MATERIALS/METHODS: We conducted a retrospective analysis of 498 patients with keloids treated at our institution between January 2010 and December 2017. All patients underwent electron beam irradiation at a dose of 16 Gy, delivered in four fractions every other day, starting within 24 h post-surgery. The primary endpoint of the study was the local control rate. RESULTS: A total of 130 (26.5%) keloids recurred after a median follow-up of 68.1months (42.6-129.9 months). The local control rates at 1 year, 3 years and 5 years for all patients were 89.5%, 82.5% and 81%, respectively. The highest recurrence rate was observed in keloids located in the chest region (50.8%), followed by the suprapubic (47.8%), head and neck (38.8%), limbs (33.3%) and ear (14%). Both multivariate and univariate analyses identified the presence of pain and or pruritus as an independently prognostic factor for keloid recurrence (p<0.0001). The local control rates at 1-year, 3-years and 5-years for patients with or without symptom of pain or pruritus were 45% vs. 98.8%, 12.5% vs. 95.9%, and 8.8% vs. 95%, respectively (HR:37.829, 95%CI: 24.385-58.686, p<0.001). In the ear keloid subgroup, the 1-year, 3-year and 5-year local control rates for patients with pruritus were significantly lower than those without pain or pruritus (60.0% vs. 97.9%, 26.7% vs. 94.7%, 26.7% vs. 94.3%, HR:30.209, 95% CI:14.793-61.69, p<0.001). The same results were found in other location(p<0.001). During treatment and follow-up, two patients experienced infections, and one patient developed a cutaneous fibroblastoma. CONCLUSION: This study suggests that a combination of surgery followed by short-course, every-other-day radiotherapy can yield satisfactory local control rates for keloids. Pain and or pruritus symptom was an independently prognostic factors for recurrence of keloid. To further validate these results, a prospective randomized controlled trial is recommended.
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Queloide , Humanos , Queloide/radioterapia , Queloide/cirugía , Femenino , Masculino , Estudios Retrospectivos , Adulto , Persona de Mediana Edad , Adulto Joven , Anciano , Adolescente , Resultado del Tratamiento , Pronóstico , Niño , Terapia Combinada , Estudios de Seguimiento , RecurrenciaRESUMEN
BACKGROUND: Keloid is a disease characterized by proliferation of fibrous tissue after the healing of skin tissue, which seriously affects the daily life of patients. However, the clinical treatment of keloids still has limitations, that is, it is not effective in controlling keloids, resulting in a high recurrence rate. Thus, it is urgent to identify new signatures to improve the diagnosis and treatment of keloids. METHOD: Bulk RNA seq and scRNA seq data were downloaded from the GEO database. First, we used WGCNA and MEGENA to co-identify keloid/immune-related DEGs. Subsequently, we used three machine learning algorithms (Randomforest, SVM-RFE, and LASSO) to identify hub immune-related genes of keloid (KHIGs) and investigated the heterogeneous expression of KHIGs during fibroblast subpopulation differentiation using scRNA-seq. Finally, we used HE and Masson staining, quantitative reverse transcription-PCR, western blotting, immunohistochemical, and Immunofluorescent assay to investigate the dysregulated expression and the mechanism of retinoic acid in keloids. RESULTS: In the present study, we identified PTGFR, RBP5, and LIF as KHIGs and validated their diagnostic performance. Subsequently, we constructed a novel artificial neural network molecular diagnostic model based on the transcriptome pattern of KHIGs, which is expected to break through the current dilemma faced by molecular diagnosis of keloids in the clinic. Meanwhile, the constructed IG score can also effectively predict keloid risk, which provides a new strategy for keloid prevention. Additionally, we observed that KHIGs were also heterogeneously expressed in the constructed differentiation trajectories of fibroblast subtypes, which may affect the differentiation of fibroblast subtypes and thus lead to dysregulation of the immune microenvironment in keloids. Finally, we found that retinoic acid may treat or alleviate keloids by inhibiting RBP5 to differentiate pro-inflammatory fibroblasts (PIF) to mesenchymal fibroblasts (MF), which further reduces collagen secretion. CONCLUSION: In summary, the present study provides novel immune signatures (PTGFR, RBP5, and LIF) for keloid diagnosis and treatment, and identifies retinoic acid as potential anti-keloid drugs. More importantly, we provide a new perspective for understanding the interactions between different fibroblast subtypes in keloids and the remodeling of their immune microenvironment.
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Queloide , RNA-Seq , Queloide/genética , Queloide/diagnóstico , Queloide/patología , Queloide/inmunología , Queloide/tratamiento farmacológico , Humanos , Transcriptoma/genética , Perfilación de la Expresión Génica , Fibroblastos/metabolismo , Fibroblastos/patología , Fibroblastos/inmunología , Redes Reguladoras de Genes , Tretinoina/farmacología , Tretinoina/uso terapéutico , Análisis de la Célula Individual/métodos , Diferenciación Celular/genética , Análisis de Secuencia de ARN/métodos , Aprendizaje Automático , Análisis de Expresión Génica de una Sola CélulaRESUMEN
Background: Keloid is a chronic proliferative fibrotic disease caused by abnormal fibroblasts proliferation and excessive extracellular matrix (ECM) production. Numerous fibrotic disorders are significantly influenced by ferroptosis, and targeting ferroptosis can effectively mitigate fibrosis development. This study aimed to investigate the role and mechanism of ferroptosis in keloid development. Methods: Keloid tissues from keloid patients and normal skin tissues from healthy controls were collected. Iron content, lipid peroxidation (LPO) level, and the mRNA and protein expression of ferroptosis-related genes including solute carrier family 7 member 11 (SLC7A11), glutathione peroxidase 4 (GPX4), transferrin receptor (TFRC), and nuclear factor erythroid 2-related factor 2 (Nrf2) were determined. Mitochondrial morphology was observed using transmission electron microscopy (TEM). Keloid fibroblasts (KFs) were isolated from keloid tissues, and treated with ferroptosis inhibitor ferrostatin-1 (fer-1) or ferroptosis activator erastin. Iron content, ferroptosis-related marker levels, LPO level, mitochondrial membrane potential, ATP content, and mitochondrial morphology in KFs were detected. Furthermore, the protein levels of α-smooth muscle actin (α-SMA), collagen I, and collagen III were measured to investigate whether ferroptosis affect fibrosis in KFs. Results: We found that iron content and LPO level were substantially elevated in keloid tissues and KFs. SLC7A11, GPX4, and Nrf2 were downregulated and TFRC was upregulated in keloid tissues and KFs. Mitochondria in keloid tissues and KFs exhibited ferroptosis-related pathology. Fer-1 treatment reduced iron content, restrained ferroptosis and mitochondrial dysfunction in KFs, Moreover, ferrostatin-1 restrained the protein expression of α-SMA, collagen I, and collagen III in KFs. Whereas erastin treatment showed the opposite results. Conclusion: Ferroptosis exists in keloid. Ferrostatin-1 restrained ECM deposition and fibrosis in keloid through inhibiting ferroptosis, and erastin induced ECM deposition and fibrosis through intensifying ferroptosis.
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Ciclohexilaminas , Ferroptosis , Fibroblastos , Fibrosis , Queloide , Factor 2 Relacionado con NF-E2 , Fenilendiaminas , Fosfolípido Hidroperóxido Glutatión Peroxidasa , Humanos , Ferroptosis/efectos de los fármacos , Queloide/patología , Queloide/metabolismo , Queloide/tratamiento farmacológico , Fibroblastos/efectos de los fármacos , Fibroblastos/metabolismo , Fibroblastos/patología , Ciclohexilaminas/farmacología , Fibrosis/metabolismo , Fibrosis/patología , Fenilendiaminas/farmacología , Factor 2 Relacionado con NF-E2/metabolismo , Factor 2 Relacionado con NF-E2/genética , Fosfolípido Hidroperóxido Glutatión Peroxidasa/metabolismo , Fosfolípido Hidroperóxido Glutatión Peroxidasa/genética , Masculino , Peroxidación de Lípido/efectos de los fármacos , Femenino , Adulto , Hierro/metabolismo , Sistema de Transporte de Aminoácidos y+/metabolismo , Sistema de Transporte de Aminoácidos y+/genética , Receptores de Transferrina/metabolismo , Receptores de Transferrina/genética , Piperazinas/farmacología , Actinas/metabolismo , Actinas/genética , Mitocondrias/efectos de los fármacos , Mitocondrias/metabolismo , Mitocondrias/patología , Potencial de la Membrana Mitocondrial/efectos de los fármacosRESUMEN
Keloid scars and folliculitis keloidalis nuchae (FKN) are benign fibroproliferative dermal lesions of unknown aetiology and ill-defined treatment, which typically present in genetically susceptible individuals. Their pathognomonic hallmarks include local aggressive invasive behaviour plus high recurrence post-therapy. In view of this, we investigated proliferative and key parameters of bioenergetic cellular characteristics of site-specific keloid-derived fibroblasts (intra(centre)- and peri(margin)-lesional) and FKN compared to normal skin and normal flat non-hypertrophic scar fibroblasts as negative controls.The results showed statistically significant (P < 0.01) and variable growth dynamics with increased proliferation and migration in keloid fibroblasts, while FKN fibroblasts showed a significant (P < 0.001) increase in proliferation but similar migration profile to controls. A statistically significant metabolic switch towards aerobic glycolysis in the fibroblasts from the disease conditions was noted. Furthermore, an increase in basal glycolysis with a concomitant increase in the cellular maximum glycolytic capacity was also demonstrated in perilesional keloid and FKN fibroblasts (P < 0.05). Mitochondrial function parameters showed increased oxidative phosphorylation in the disease conditions (P < 0.05) indicating functional mitochondria. These findings further suggest that Keloids and FKN demonstrate a switch to a metabolic phenotype of aerobic glycolysis. Increased glycolytic flux inhibition is a potential mechanistic basis for future therapy.
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Proliferación Celular , Fibroblastos , Foliculitis , Glucólisis , Queloide , Humanos , Queloide/metabolismo , Queloide/patología , Fibroblastos/metabolismo , Fibroblastos/patología , Foliculitis/metabolismo , Foliculitis/patología , Mitocondrias/metabolismo , Mitocondrias/patología , Células Cultivadas , Fosforilación Oxidativa , Movimiento Celular , Adulto , Piel/patología , Piel/metabolismo , Metabolismo Energético , Femenino , MasculinoRESUMEN
Background: The desmoplastic reaction is considered a promising prognostic parameter for colorectal cancer. However, intermediate desmoplastic reaction is characterized by sizeable stromal heterogeneity, including both small amounts of keloid-like collagen (KC) in the fibrotic stroma and thick tufts of KC circumferentially surrounding cancer nests and occupying most of the fields of view. The present study aimed to evaluate the diagnostic and prognostic significance of KC histophenotyping with a quantitative visual assessment of its presence in the stroma of the invasive margin of TNM (The "tumor-node-metastasis" classification) stage II/III colorectal cancer (CRC). Methods and results: 175 resected tumors from patients with TNM stage II/III CRC were examined. Keloid-like collagen was assessed according to Ueno H. criteria. KC was assessed at the primary tumor invasive margin using Hematoxylin & Eosin and Masson's trichrome staining. The cut-off point for KC was examined using "the best cutoff approach by log-rank test." Using a cutoff point of 30%, we histologically divided fibrous stroma in the invasive area into two groups: "type A"-KC ≤ 0.3 and "type B"-KC>0.3. Type A stroma was observed in 48% of patients, type B-in 52%. The association between collagen amount and 5-year recurrence-free survival (5-RFS) was assessed using Cox regression analysis. Kaplan-Meier analysis and log-rank tests were used to assess the significance of survival analysis. Analysis of categorical variables showed that increased KC in CRC stroma predicted adverse outcomes for 5-RFS (hazard ratio [HR] = 3.143, 95%, confidence interval [CI] = 1.643-6.012, p = 0.001). Moreover, in Kaplan-Meier analysis, the log-rank test showed that type B exhibited worse 5-RFS than type A (p = 0.000). Conclusion: KC is an independent predictor of 5-year overall and RFS in patients with TNM stage II/III CRC treated with surgery, with worse survival rates when the amount of KC increases by >30%.
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Colágeno , Neoplasias Colorrectales , Matriz Extracelular , Queloide , Humanos , Neoplasias Colorrectales/patología , Neoplasias Colorrectales/metabolismo , Masculino , Femenino , Pronóstico , Persona de Mediana Edad , Colágeno/metabolismo , Anciano , Matriz Extracelular/patología , Matriz Extracelular/metabolismo , Queloide/patología , Queloide/metabolismo , Adulto , Anciano de 80 o más Años , Tasa de Supervivencia , Estudios de SeguimientoRESUMEN
Intralesional corticosteroid injections are a first-line treatment for keloids; yet clinical treatment results are highly variable and often suboptimal. Variation in triamcinolone acetonide (TAC) biodistribution may be an important reason for the variable effects of TAC treatment in keloids. In this exploratory study we investigated the biodistribution of TAC in keloids and normal skin using different drug delivery techniques. Fluorescent-labeled TAC suspension was administered into keloids and normal skin with a hypodermic needle and an electronic pneumatic jet injector. TAC biodistribution was represented by the fluorescent TAC volume and 3D biodistribution shape of TAC, using a 3D-Fluorescence-Imaging Cryomicrotome System. Twenty-one keloid and nine normal skin samples were analyzed. With needle injections, the mean fluorescent TAC volumes were 990 µl ± 479 in keloids and 872 µl ± 227 in normal skin. With the jet injector, the mean fluorescent TAC volumes were 401 µl ± 252 in keloids and 249 µl ± 67 in normal skin. 3D biodistribution shapes of TAC were highly variable in keloids and normal skin. In conclusion, TAC biodistribution in keloids is highly variable for both needle and jet injection. This may partly explain the variable treatment effects of intralesional TAC in keloids. Future research is needed to confirm this preliminary finding and to optimize drug delivery in keloids.
Asunto(s)
Queloide , Triamcinolona Acetonida , Queloide/tratamiento farmacológico , Queloide/patología , Humanos , Triamcinolona Acetonida/farmacocinética , Triamcinolona Acetonida/administración & dosificación , Adulto , Femenino , Distribución Tisular , Masculino , Persona de Mediana Edad , Inyecciones Intralesiones , Piel/metabolismo , Piel/patología , Piel/diagnóstico por imagen , Crioultramicrotomía/métodos , Adulto Joven , Imagenología Tridimensional , Sistemas de Liberación de Medicamentos/métodosAsunto(s)
Comorbilidad , Dermatitis Atópica , Queloide , Humanos , Dermatitis Atópica/epidemiología , Dermatitis Atópica/complicaciones , Queloide/epidemiología , Femenino , Masculino , Adulto , Estados Unidos/epidemiología , Bases de Datos Factuales/estadística & datos numéricos , Persona de Mediana Edad , Adolescente , Adulto Joven , Factores de Riesgo , NiñoRESUMEN
Keloids are pathological scar tissue resulting from skin trauma or spontaneous formation, often accompanied by itching and pain. Although GNAS antisense RNA 1 (GNAS-AS1) shows abnormal upregulation in keloids, the underlying molecular mechanism is unclear. The levels of genes and proteins in clinical tissues from patients with keloids and human keloid fibroblasts (HKFs) were measured using quantitative reverse transcription PCR, western blot and enzyme-linked immunosorbent assay. The features of HKFs, including proliferation and migration, were evaluated using cell counting kit 8 and a wound healing assay. The colocalization of GNAS-AS1 and miR-196a-5p in HKFs was measured using fluorescence in situ hybridization. The relationships among GNAS-AS1, miR-196a-5p and C-X-C motif chemokine ligand 12 (CXCL12) in samples from patients with keloids were analysed by Pearson correlation analysis. Gene interactions were validated by chromatin immunoprecipitation and luciferase reporter assays. GNAS-AS1 and CXCL12 expression were upregulated and miR-196a-5p expression was downregulated in clinical tissues from patients with keloids. GNAS-AS1 knockdown inhibited proliferation, migration, and extracellular matrix (ECM) accumulation of HKFs, all of which were reversed by miR-196a-5p downregulation. Signal transducer and activator of transcription 3 (STAT3) induced GNAS-AS1 transcription through GNAS-AS1 promoter interaction, and niclosamide, a STAT3 inhibitor, decreased GNAS-AS1 expression. GNAS-AS1 positively regulated CXCL12 by sponging miR-196-5p. Furthermore, CXCL12 knockdown restrained STAT3 phosphorylation in HKFs. Our findings revealed a feedback loop of STAT3/GNAS-AS1/miR-196a-5p/CXCL12/STAT3 that promoted HKF proliferation, migration and ECM accumulation and affected keloid progression.
Asunto(s)
Proliferación Celular , Quimiocina CXCL12 , Fibroblastos , Queloide , MicroARNs , ARN Largo no Codificante , Factor de Transcripción STAT3 , Queloide/metabolismo , Queloide/genética , Queloide/patología , Humanos , MicroARNs/metabolismo , MicroARNs/genética , Factor de Transcripción STAT3/metabolismo , Factor de Transcripción STAT3/genética , ARN Largo no Codificante/genética , ARN Largo no Codificante/metabolismo , Quimiocina CXCL12/metabolismo , Quimiocina CXCL12/genética , Fibroblastos/metabolismo , Movimiento Celular , Retroalimentación Fisiológica , Cromograninas/genética , Cromograninas/metabolismo , Masculino , Femenino , Subunidades alfa de la Proteína de Unión al GTP Gs/genética , Subunidades alfa de la Proteína de Unión al GTP Gs/metabolismo , Transducción de Señal , Adulto , Células Cultivadas , Regulación hacia ArribaRESUMEN
Fibrosis is the excessive deposition of extracellular matrix in an organ or tissue that results from an impaired tissue repair in response to tissue injury or chronic inflammation. The progressive nature of fibrotic diseases and limited treatment options represent significant healthcare challenges. Despite the substantial progress in understanding the mechanisms of fibrosis, a gap persists translating this knowledge into effective therapeutics. Here, we discuss the critical mediators involved in fibrosis and the role of tranilast as a potential antifibrotic drug to treat fibrotic conditions. Tranilast, an antiallergy drug, is a derivative of tryptophan and has been studied for its role in various fibrotic diseases. These include scleroderma, keloid and hypertrophic scars, liver fibrosis, renal fibrosis, cardiac fibrosis, pulmonary fibrosis, and uterine fibroids. Tranilast exerts antifibrotic effects by suppressing fibrotic pathways, including TGF-ß, and MPAK. Because it disrupts fibrotic pathways and has demonstrated beneficial effects against keloid and hypertrophic scars, tranilast could be used to treat other conditions characterized by fibrosis.
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Fibrosis , Transducción de Señal , ortoaminobenzoatos , Humanos , ortoaminobenzoatos/uso terapéutico , ortoaminobenzoatos/farmacología , Fibrosis/tratamiento farmacológico , Transducción de Señal/efectos de los fármacos , Animales , Antifibróticos/uso terapéutico , Antifibróticos/farmacología , Queloide/tratamiento farmacológico , Queloide/patología , Queloide/metabolismo , Factor de Crecimiento Transformador beta/metabolismoRESUMEN
Keloid formation, characterized by aberrant fibroproliferation and immune dysregulation, remains a challenging clinical concern. This study aims to elucidate the neuroimmune mechanisms underlying keloid pathogenesis and explores the efficacy of a combined treatment approach involving modulation of the α7 nicotinic acetylcholine receptor (α7nAchR), a key player in neural transmission, and programmed death ligand 1 (PD-L1), an immune checkpoint molecule, for keloid intervention. A key innovation lies in the identification of signal peptide-CUB-EGF-like domain-containing protein 3 (SCUBE3) as a potential target gene influenced by this dual treatment. We elucidate the underlying mechanism, wherein the hypoxic keloid microenvironment fosters an upsurge in SCUBE3 secretion. Subsequently, SCUBE3 forms complexes with TGF-ß, initiating the activation of the PI3K/AKT/NF-κB signaling pathway. Notably, SCUBE3 is secreted in the form of exosomes, thereby exerting a profound influence on the differentiation of T cells and macrophages within the keloid milieu. This research not only provides a comprehensive understanding of the molecular mechanisms involved but also offers a promising avenue for the development of targeted therapies to address keloid-associated fibrosis and immune dysregulation. In conclusion, the combined inhibition of α7nAchR and PD-L1 represents a promising therapeutic strategy with SCUBE3 as a pivotal molecular target in the complex landscape of keloid pathophysiology.
Asunto(s)
Antígeno B7-H1 , Queloide , Receptor Nicotínico de Acetilcolina alfa 7 , Humanos , Antígeno B7-H1/metabolismo , Queloide/metabolismo , Queloide/patología , Queloide/inmunología , Receptor Nicotínico de Acetilcolina alfa 7/metabolismo , Transducción de Señal , Fosfatidilinositol 3-Quinasas/metabolismoRESUMEN
Keloid is a typical fibrotic and inflammatory skin disease with unclear mechanisms and few therapeutic targets. In this study, we found that BMP1 was significantly increased in a collagen high-expressing subtype of fibroblast by reanalyzing a public single-cell RNA-sequence data set of keloid. The number of BMP1-positive fibroblast cells was increased in keloid fibrotic loci. Increased levels of BMP1 were further validated in the skin tissues and fibroblasts from keloid patients. Additionally, a positive correlation between BMP1 and the Keloid Area and Severity Index was found in keloid patients. In vitro analysis revealed collagen production, the phosphorylation levels of p65, and the IL-1ß secretion decreased in BMP1 interfered keloid fibroblasts. Besides, the knockdown of BMP1 inhibited the growth and migration of keloid fibroblast cells. Mechanistically, BMP1 inhibition downregulated the noncanonical TGF-ß pathways, including p-p38 and p-ERK1/2 signaling. Furthermore, we found the delivery of BMP1 siRNAs could significantly alleviate keloid in human keloid-bearing nude mice. Collectively, our results indicated that BMP1 exhibited various pathogenic effects on keloids as promoting cell proliferation, migration, inflammation, and ECM deposition of fibroblast cells by regulating the noncanonical TGF-ß/p38 MAPK, and TGF-ß/ERK pathways. BMP1-lowing strategies may appear as a potential new therapeutic target for keloid.