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1.
J Drugs Dermatol ; 23(7): 510-514, 2024 Jul 01.
Article in English | MEDLINE | ID: mdl-38954622

ABSTRACT

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.


Subject(s)
Keloid , Melanosis , Skin Pigmentation , Social Media , Vitiligo , Social Media/statistics & numerical data , Humans , Vitiligo/therapy , Vitiligo/diagnosis , Vitiligo/psychology , Keloid/epidemiology , Melanosis/diagnosis , Dermatologists/statistics & numerical data
2.
BMJ Open ; 14(7): e084939, 2024 Jul 09.
Article in English | MEDLINE | ID: mdl-38986560

ABSTRACT

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).


Subject(s)
Betamethasone , Keloid , Lasers, Dye , Humans , Keloid/therapy , Keloid/drug therapy , Betamethasone/administration & dosage , Betamethasone/therapeutic use , Lasers, Dye/therapeutic use , Adult , Female , Randomized Controlled Trials as Topic , Male , Combined Modality Therapy , Glucocorticoids/administration & dosage , Glucocorticoids/therapeutic use , Treatment Outcome , Middle Aged , Young Adult , Adolescent
3.
Hum Genomics ; 18(1): 80, 2024 Jul 16.
Article in English | MEDLINE | ID: mdl-39014455

ABSTRACT

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.


Subject(s)
Keloid , RNA-Seq , Keloid/genetics , Keloid/diagnosis , Keloid/pathology , Keloid/immunology , Keloid/drug therapy , Humans , Transcriptome/genetics , Gene Expression Profiling , Fibroblasts/metabolism , Fibroblasts/pathology , Fibroblasts/immunology , Gene Regulatory Networks , Tretinoin/pharmacology , Tretinoin/therapeutic use , Single-Cell Analysis/methods , Cell Differentiation/genetics , Sequence Analysis, RNA/methods , Machine Learning , Single-Cell Gene Expression Analysis
4.
Radiat Oncol ; 19(1): 91, 2024 Jul 17.
Article in English | MEDLINE | ID: mdl-39020400

ABSTRACT

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.


Subject(s)
Keloid , Humans , Keloid/radiotherapy , Keloid/surgery , Female , Male , Retrospective Studies , Adult , Middle Aged , Young Adult , Aged , Adolescent , Treatment Outcome , Prognosis , Child , Combined Modality Therapy , Follow-Up Studies , Recurrence
5.
PLoS One ; 19(7): e0305927, 2024.
Article in English | MEDLINE | ID: mdl-39024326

ABSTRACT

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.


Subject(s)
Adenosine Monophosphate , Alanine , Fibroblasts , Fibrosis , Signal Transduction , Skin , Transforming Growth Factor beta1 , Animals , Signal Transduction/drug effects , Transforming Growth Factor beta1/metabolism , Fibrosis/drug therapy , Alanine/analogs & derivatives , Alanine/pharmacology , Alanine/therapeutic use , Fibroblasts/drug effects , Fibroblasts/metabolism , Adenosine Monophosphate/analogs & derivatives , Adenosine Monophosphate/pharmacology , Adenosine Monophosphate/metabolism , Mice , Skin/drug effects , Skin/pathology , Skin/metabolism , Humans , Autophagy/drug effects , Keloid/drug therapy , Keloid/metabolism , Keloid/pathology , Antiviral Agents/pharmacology , TOR Serine-Threonine Kinases/metabolism , Bleomycin , Phosphatidylinositol 3-Kinases/metabolism , Male , Proto-Oncogene Proteins c-akt/metabolism , Smad Proteins/metabolism
6.
Pathol Oncol Res ; 30: 1611789, 2024.
Article in English | MEDLINE | ID: mdl-38903488

ABSTRACT

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%.


Subject(s)
Collagen , Colorectal Neoplasms , Extracellular Matrix , Keloid , Humans , Colorectal Neoplasms/pathology , Colorectal Neoplasms/metabolism , Male , Female , Prognosis , Middle Aged , Collagen/metabolism , Aged , Extracellular Matrix/pathology , Extracellular Matrix/metabolism , Keloid/pathology , Keloid/metabolism , Adult , Aged, 80 and over , Survival Rate , Follow-Up Studies
7.
Exp Dermatol ; 33(6): e15111, 2024 Jun.
Article in English | MEDLINE | ID: mdl-38840411

ABSTRACT

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.


Subject(s)
Cell Proliferation , Chemokine CXCL12 , Fibroblasts , Keloid , MicroRNAs , RNA, Long Noncoding , STAT3 Transcription Factor , Keloid/metabolism , Keloid/genetics , Keloid/pathology , Humans , MicroRNAs/metabolism , MicroRNAs/genetics , STAT3 Transcription Factor/metabolism , STAT3 Transcription Factor/genetics , RNA, Long Noncoding/genetics , RNA, Long Noncoding/metabolism , Chemokine CXCL12/metabolism , Chemokine CXCL12/genetics , Fibroblasts/metabolism , Cell Movement , Feedback, Physiological , Chromogranins/genetics , Chromogranins/metabolism , Male , Female , GTP-Binding Protein alpha Subunits, Gs/genetics , GTP-Binding Protein alpha Subunits, Gs/metabolism , Signal Transduction , Adult , Cells, Cultured , Up-Regulation
8.
Arch Dermatol Res ; 316(7): 412, 2024 Jun 15.
Article in English | MEDLINE | ID: mdl-38878082

ABSTRACT

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.


Subject(s)
Cell Proliferation , Fibroblasts , Folliculitis , Glycolysis , Keloid , Humans , Keloid/metabolism , Keloid/pathology , Fibroblasts/metabolism , Fibroblasts/pathology , Folliculitis/metabolism , Folliculitis/pathology , Mitochondria/metabolism , Mitochondria/pathology , Cells, Cultured , Oxidative Phosphorylation , Cell Movement , Adult , Skin/pathology , Skin/metabolism , Energy Metabolism , Female , Male
9.
Int J Mol Sci ; 25(11)2024 May 28.
Article in English | MEDLINE | ID: mdl-38892032

ABSTRACT

Keloids, marked by abnormal cellular proliferation and excessive extracellular matrix (ECM) accumulation, pose significant therapeutic challenges. Ethyl pyruvate (EP), an inhibitor of the high-mobility group box 1 (HMGB1) and TGF-ß1 pathways, has emerged as a potential anti-fibrotic agent. Our research evaluated EP's effects on keloid fibroblast (KF) proliferation and ECM production, employing both in vitro cell cultures and ex vivo patient-derived keloid spheroids. We also analyzed the expression levels of ECM components in keloid tissue spheroids treated with EP through immunohistochemistry. Findings revealed that EP treatment impedes the nuclear translocation of HMGB1 and diminishes KF proliferation. Additionally, EP significantly lowered mRNA and protein levels of collagen I and III by attenuating TGF-ß1 and pSmad2/3 complex expression in both human dermal fibroblasts and KFs. Moreover, metalloproteinase I (MMP-1) and MMP-3 mRNA levels saw a notable increase following EP administration. In keloid spheroids, EP induced a dose-dependent reduction in ECM component expression. Immunohistochemical and western blot analyses confirmed significant declines in collagen I, collagen III, fibronectin, elastin, TGF-ß, AKT, and ERK 1/2 expression levels. These outcomes underscore EP's antifibrotic potential, suggesting its viability as a therapeutic approach for keloids.


Subject(s)
Fibroblasts , Keloid , Pyruvates , Spheroids, Cellular , Humans , Keloid/metabolism , Keloid/pathology , Fibroblasts/metabolism , Fibroblasts/drug effects , Pyruvates/pharmacology , Spheroids, Cellular/drug effects , Spheroids, Cellular/metabolism , Matrix Metalloproteinase 1/metabolism , Matrix Metalloproteinase 1/genetics , Transforming Growth Factor beta1/metabolism , HMGB1 Protein/metabolism , HMGB1 Protein/genetics , Collagen/metabolism , Collagen/biosynthesis , Cell Proliferation/drug effects , Cells, Cultured , Matrix Metalloproteinase 3/metabolism , Matrix Metalloproteinase 3/genetics , Extracellular Matrix/metabolism , Extracellular Matrix/drug effects , Collagen Type I/metabolism , Collagen Type I/genetics , Smad2 Protein/metabolism , Smad2 Protein/genetics , Smad3 Protein/metabolism , Up-Regulation/drug effects , Male
10.
Front Immunol ; 15: 1326728, 2024.
Article in English | MEDLINE | ID: mdl-38915394

ABSTRACT

Keloids are a common connective tissue disorder with an ill-understood etiopathogenesis and no effective treatment. This is exacerbated because of the absence of an animal model. Patient-derived primary keloid cells are insufficient as they age through passaging and have a limited supply. Therefore, there is an unmet need for development of a cellular model that can consistently and faithfully represent keloid's pathognomic features. In view of this, we developed keloid-derived immortalized fibroblast (KDIF) cell lines from primary keloid fibroblasts (PKF) by transfecting the human telomerase reverse transcriptase (hTERT) gene. The TERT gene encodes the catalytic subunit of the telomerase enzyme, which is responsible for maintaining the cellular replicative potential (cellular immortalization). Primary fibroblasts from keloid-specific lesional (peripheral, middle, and top) as well as extralesional sites were isolated and evaluated for cell line development and comparative cellular characteristics by employing qRT-PCR and immunofluorescence staining. Moreover, the immortalized behavior of KDIF cell lines was evaluated by comparing with cutaneous fibrosarcoma and dermatofibrosarcoma protuberans cell lines. Stable KDIF cell lines with elevated expression of hTERT exhibited the cellular characteristics of site-specific keloid fibroblasts. Histochemical staining for ß-galactosidase revealed a significantly lower number of ß-gal-positive cells in all three KDIF cell lines compared with that in PKFs. The cell growth curve pattern was studied over 10 passages for all three KDIF cell lines and was compared with the control groups. The results showed that all three KDIF cell lines grew significantly faster and obtained a fast growing characteristic as compared to primary keloid and normal fibroblasts. Phenotypic behavior in growth potential is an indication of hTERT-mediated immortalized transformation. Cell migration analysis revealed that the top and middle KDIF cell lines exhibited similar migration trend as site-specific PKFs. Notably, peripheral KDIF cell line showed significantly enhanced cell migration in comparison to the primary peripheral fibroblasts. All KDIF cell lines expressed Collagen I protein as a keloid-associated fibrotic marker. Functional testing with triamcinolone inhibited cell migration in KDIF. ATCC short tandem repeat profiling validated the KDIF as keloid representative cell line. In summary, we provide the first novel KDIF cell lines. These cell lines overcome the limitations related to primary cell passaging and tissue supply due to immortalized features and present an accessible and consistent experimental model for keloid research.


Subject(s)
Fibroblasts , Keloid , Telomerase , Humans , Keloid/pathology , Keloid/metabolism , Fibroblasts/metabolism , Telomerase/genetics , Telomerase/metabolism , Cell Line , Cell Line, Transformed , Male , Female , Adult , Middle Aged
11.
Ann Acad Med Singap ; 53(2): 113-116, 2024 Feb 28.
Article in English | MEDLINE | ID: mdl-38920235

ABSTRACT

Ribonucleic acid (RNA) therapeutics hold great potential for the advancement of dermatological treatments due to, among other reasons, the possibility of treating previously undruggable targets, high specificity with minimal side effects, and ability to include multiple RNA targets in a single product. Although there have been research relating to RNA therapeutics for decades, there have not been many products translated for clinical use until recently. This may be because of challenges to the application of RNA therapeutics, including the dearth of effective modes of delivery to the target, and rapid degradation of RNA in the human body and environment. This article aims to provide insight on (1) the wide-ranging possibilities of RNA therapeutics in the field of dermatology as well as (2) how key challenges can be addressed, so as to encourage the development of novel dermatological treatments. We also share our experience on how RNA therapeutics have been applied in the management of hypertrophic and keloid scars.


Subject(s)
Keloid , Humans , Keloid/therapy , Cicatrix, Hypertrophic/therapy , Cicatrix, Hypertrophic/drug therapy , RNA/therapeutic use , Dermatology/methods , Skin Diseases/therapy , Skin Diseases/drug therapy , Genetic Therapy/methods
12.
Toxicol Appl Pharmacol ; 489: 117012, 2024 Aug.
Article in English | MEDLINE | ID: mdl-38906511

ABSTRACT

Keloid formation has been linked to abnormal fibroblast function, such as excessive proliferation and extracellular matrix (ECM) production. Serum deprivation protein response (SDPR) is a crucial regulator of cellular function under diverse pathological conditions, yet its role in keloid formation remains unknown. The current work investigated the function of SDPR in regulating the proliferation, motility, and ECM production of keloid fibroblasts (KFs), as well as to decipher the mechanisms involved. Analysis of RNA sequencing data from the GEO database demonstrated significant down-regulation of SDPR in KF compared to normal fibroblasts (NFs). This down-regulation was also observed in clinical keloid specimens and isolated KFs. Overexpression of SDPR suppressed the proliferation, motility, and ECM production of KFs, while depletion of SDPR exacerbated the enhancing impact of TGF-ß1 on the proliferation, motility, and ECM production of NFs. Mechanistic studies revealed that SDPR overexpression repressed TGF-ß/Smad signal cascade activation in KFs along with decreased levels of phosphorylated Samd2/3, while SDPR depletion exacerbated TGF-ß/Smad activation in TGF-ß1-stimulated NFs. SDPR overexpression also repressed ERK1/2 activation in KFs, while SDPR depletion exacerbated ERK1/2 activation in TGF-ß1-stimulated NFs. Inhibition of ERK1/2 abolished SDPR-depletion-induced TGF-ß1/Smad activation, cell proliferation, motility, and ECM production in NFs. In conclusion, SDPR represses the proliferation, motility, and ECM production in KFs by blocking the TGF-ß1/Smad pathway in an ERK1/2-dependent manner. The findings highlight the role of SDPR in regulating abnormal behaviors of fibroblasts associated with keloid formation and suggest it as a potential target for anti-keloid therapy development.


Subject(s)
Cell Movement , Cell Proliferation , Extracellular Matrix , Fibroblasts , Keloid , MAP Kinase Signaling System , Smad Proteins , Transforming Growth Factor beta1 , Humans , Keloid/pathology , Keloid/metabolism , Keloid/genetics , Fibroblasts/drug effects , Fibroblasts/metabolism , Cell Proliferation/drug effects , Cell Movement/drug effects , Transforming Growth Factor beta1/metabolism , Extracellular Matrix/metabolism , Extracellular Matrix/drug effects , Smad Proteins/metabolism , MAP Kinase Signaling System/drug effects , MAP Kinase Signaling System/physiology , Signal Transduction , Cells, Cultured , Mitogen-Activated Protein Kinase 1/metabolism , Male , Female , Mitogen-Activated Protein Kinase 3/metabolism , Adult
13.
Int Immunopharmacol ; 137: 112423, 2024 Aug 20.
Article in English | MEDLINE | ID: mdl-38861914

ABSTRACT

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.


Subject(s)
Fibrosis , Signal Transduction , ortho-Aminobenzoates , Humans , ortho-Aminobenzoates/therapeutic use , ortho-Aminobenzoates/pharmacology , Fibrosis/drug therapy , Signal Transduction/drug effects , Animals , Antifibrotic Agents/therapeutic use , Antifibrotic Agents/pharmacology , Keloid/drug therapy , Keloid/pathology , Keloid/metabolism , Transforming Growth Factor beta/metabolism
14.
J Cell Biochem ; 125(7): e30609, 2024 Jul.
Article in English | MEDLINE | ID: mdl-38860429

ABSTRACT

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.


Subject(s)
Bone Morphogenetic Protein 1 , Fibroblasts , Inflammation , Keloid , Keloid/metabolism , Keloid/pathology , Keloid/genetics , Humans , Fibroblasts/metabolism , Fibroblasts/pathology , Bone Morphogenetic Protein 1/metabolism , Bone Morphogenetic Protein 1/genetics , Animals , Mice , Inflammation/metabolism , Inflammation/pathology , Inflammation/genetics , Male , Mice, Nude , Cell Proliferation , Female , Cell Movement , Fibrosis , Adult , Transforming Growth Factor beta/metabolism , MAP Kinase Signaling System
15.
PeerJ ; 12: e17551, 2024.
Article in English | MEDLINE | ID: mdl-38887622

ABSTRACT

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.


Subject(s)
Cyclohexylamines , Ferroptosis , Fibroblasts , Fibrosis , Keloid , NF-E2-Related Factor 2 , Phenylenediamines , Phospholipid Hydroperoxide Glutathione Peroxidase , Humans , Ferroptosis/drug effects , Keloid/pathology , Keloid/metabolism , Keloid/drug therapy , Fibroblasts/drug effects , Fibroblasts/metabolism , Fibroblasts/pathology , Cyclohexylamines/pharmacology , Fibrosis/metabolism , Fibrosis/pathology , Phenylenediamines/pharmacology , NF-E2-Related Factor 2/metabolism , NF-E2-Related Factor 2/genetics , Phospholipid Hydroperoxide Glutathione Peroxidase/metabolism , Phospholipid Hydroperoxide Glutathione Peroxidase/genetics , Male , Lipid Peroxidation/drug effects , Female , Adult , Iron/metabolism , Amino Acid Transport System y+/metabolism , Amino Acid Transport System y+/genetics , Receptors, Transferrin/metabolism , Receptors, Transferrin/genetics , Piperazines/pharmacology , Actins/metabolism , Actins/genetics , Mitochondria/drug effects , Mitochondria/metabolism , Mitochondria/pathology , Membrane Potential, Mitochondrial/drug effects
17.
Arch Dermatol Res ; 316(7): 368, 2024 Jun 08.
Article in English | MEDLINE | ID: mdl-38850361

ABSTRACT

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.


Subject(s)
Keloid , Triamcinolone Acetonide , Keloid/drug therapy , Keloid/pathology , Humans , Triamcinolone Acetonide/pharmacokinetics , Triamcinolone Acetonide/administration & dosage , Adult , Female , Tissue Distribution , Male , Middle Aged , Injections, Intralesional , Skin/metabolism , Skin/pathology , Skin/diagnostic imaging , Cryoultramicrotomy/methods , Young Adult , Imaging, Three-Dimensional , Drug Delivery Systems/methods
18.
Zhong Nan Da Xue Xue Bao Yi Xue Ban ; 49(2): 197-206, 2024 Feb 28.
Article in English, Chinese | MEDLINE | ID: mdl-38755716

ABSTRACT

Scars are classified into 5 types: Superficial scars, hypertrophic scars, atrophic scars, depressed scars, and keloid. These types are primarily characterized by abnormal production of fibroblasts and collagen, as well as the disorderly arrangement of connective tissue. Laser treatment for scars involves the coordinated activation of various signaling pathways and cytokines. However, the exact pathological mechanism for scar formation remains unclear, leading to a lack of radical treatment. Recently, laser treatment has gained popularity as a new minimally invasive approach for scar treatment. The emergence of new theories such as fractional, picosecond laser, and laser-assisted drug delivery has led to continuous advance in laser treatment. Up to now, it has been developed numerous novel treatments, including combined with drug, physical, and other treatments, which have shown superior therapeutic effects. In order to optimize laser treatment in the future, it is crucial to combine new materials with postoperative care. This will help clinicians develop more comprehensive treatment strategies. Therefore, it is important to explore treatment options that have broader applicability.


Subject(s)
Cicatrix , Keloid , Laser Therapy , Humans , Cicatrix/therapy , Laser Therapy/methods , Keloid/radiotherapy , Keloid/therapy , Cicatrix, Hypertrophic/radiotherapy , Cicatrix, Hypertrophic/therapy
19.
Biomater Sci ; 12(13): 3321-3334, 2024 Jun 25.
Article in English | MEDLINE | ID: mdl-38812375

ABSTRACT

Keloid is a type of scar formed by the overexpression of extracellular matrix substances from fibroblasts following inflammation after trauma. The existing keloid treatment methods include drug injection, surgical intervention, light exposure, cryotherapy, etc. However, these methods have limitations such as recurrence, low treatment efficacy, and side effects. Consequently, studies are being conducted on the treatment of keloids from the perspective of inflammatory mechanisms. In this study, keloid models are created to understand inflammatory mechanisms and explore treatment methods to address them. While previous studies have used animal models with gene mutations, chemical treatments, and keloid tissue transplantation, there are limitations in fully reproducing the characteristics of keloids unique to humans, and ethical issues related to animal welfare pose additional challenges. Consequently, studies are underway to create in vitro artificial skin models to simulate keloid disease and apply them to the development of treatments for skin diseases. In particular, herein, scaffold technologies that implement three-dimensional (3D) full-thickness keloid models are introduced to enhance mechanical properties as well as biological properties of tissues, such as cell proliferation, differentiation, and cellular interactions. It is anticipated that applying these technologies to the production of artificial skin for keloid simulation could contribute to the development of inflammatory keloid treatment techniques in the future.


Subject(s)
Keloid , Skin, Artificial , Keloid/therapy , Humans , Animals , Models, Biological , Tissue Engineering , Tissue Scaffolds/chemistry , Skin/metabolism , Skin/pathology
20.
Int J Mol Sci ; 25(10)2024 May 13.
Article in English | MEDLINE | ID: mdl-38791322

ABSTRACT

A keloid is a benign fibroproliferative hypertrophy of scar tissue that extends outside the original wound and invades adjacent healthy skin. Keloid formation is thought to be a complex process including overactivity of the interleukin-6 signaling pathway and genetic susceptibility. The aim of the study was to investigate possible associations between rs1800797, rs1800796, and rs1800795 polymorphisms in the promoter of the IL6 gene encoding interleukin-6 and the rs2228145 polymorphism in the IL6R gene encoding the interleukin-6 receptor subunit alpha with the predisposition to keloids in Polish patients. The genetic polymorphisms were identified either using Polymerase Chain Reaction-Restriction Fragment Length Polymorphism (PCR-RFLP) or sequencing of samples of genomic DNA extracted from blood leukocytes of 86 adult patients with keloids and 100 newborns comprising a control group. No significant differences in the distributions of IL6 or IL6R alleles or genotypes were found between keloid patients and newborn controls. There were also no significant differences between both groups in the distribution of IL6 haplotypes. The IL6 rs1800797, rs1800796 and rs1800795 and IL6R rs2228145 polymorphisms were not found to predispose individuals in the study group to keloids. IL6 promoter haplotypes were not found to be associated with a higher risk of keloids in the studied group.


Subject(s)
Genetic Predisposition to Disease , Interleukin-6 , Keloid , Polymorphism, Single Nucleotide , Receptors, Interleukin-6 , Humans , Keloid/genetics , Keloid/pathology , Interleukin-6/genetics , Receptors, Interleukin-6/genetics , Male , Female , Adult , Poland , Middle Aged , Promoter Regions, Genetic , Case-Control Studies , Haplotypes , Alleles , Adolescent , Young Adult , Gene Frequency , Genotype , Infant, Newborn , Genetic Association Studies
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