Browse
Submit Data
Databases
API
Help

Dataset Information

12 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Identification of sirtuin 1 as a promising therapeutic target for hypertrophic scars.

ABSTRACT:

Background and purpose

Sirtuin1 (SIRT1), the founding member of mammalian class III histone deacetylases, is reported to be a drug target involved in fibrotic diseases. However, whether it is an effective drug target in hypertrophic scar treatment is still not known.

Experimental approach

In the present study, we observed that SIRT1 localized to both the epidermis and the dermis of skin tissues by immunohistochemistry. After knock-down of SIRT1 by shRNA or up-regulating SIRT1 by resveratrol, the expression of α-SMA, Col1 and Col3 in fibroblasts were detected by western blots. A mouse excision wound healing model was used to observe the changes in collagen fibre associated with the different expression levels of SIRT1.

Key results

SIRT1 expression was inhibited in hypertrophic scar tissue. The down-regulation of SIRT1 resulted in an increased expression of α-SMA, Col1 and Col3 in hypertrophic scar-derived fibroblasts. In contrast, the up-regulation of SIRT1 not only inhibited the expression of α-SMA, Col1 and Col3 in hypertrophic scar-derived fibroblasts but also blocked the activation of TGFβ1-induced normal skin-derived fibroblasts. In the mouse model of wound healing, the deletion of SIRT1 resulted in denser collagen fibres and a more disordered structure, whereas resveratrol treatment led to a more organized and thinner collagen fibre, which was similar to that observed during normal wound healing.

Conclusions and implications

The results revealed that SIRT1 negatively regulates TGFβ1-induced fibroblast activation and inhibits excessive scar formation and is, therefore, a promising drug target for hypertrophic scar formation.

SUBMITTER: Bai XZ

PROVIDER: S-EPMC4842923 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Similar Datasets

The Role of the Mammalian Target of Rapamycin in Keloid and Hypertrophic Scars

Project description:We hypothesize that, the mTOR pathway is a dominant pathway in cultured keloid and hypertrophy scar fibriblasts compared to normal skin cells. Certain pathway changes can be detected after medication treatment. Global gene expression in RNA samples from rapamycin and tacrolimus treated fibroblasts (from normal skin and hypertrophic scars, keloid scars) is assayed to study the possibility to use mTOR inhibitors as potential drug to treat abnormal scarring. We investigated the difference between normal wound healing and hypertrophic scars and keloids as well.

2014-05-20 | E-MTAB-2509 | biostudies-arrayexpress

Dyspigmented hypertrophic scars: Beyond skin color.

Project description:Although pigment synthesis is well understood, relevant mechanisms of psychologically debilitating dyspigmentation in nascent tissue after cutaneous injuries are still unknown. Here, differences in genomic transcription of hyper- and hypopigmented tissue relative to uninjured skin were investigated using a red Duroc swine scar model. Transcription profiles differed based on pigmentation phenotypes with a trend of more upregulation or downregulation in hyper- or hypopigmented scars, respectively. Ingenuity Pathway Analysis of significantly modulated genes in both pigmentation phenotypes showed pathways related to redox, metabolic, and inflammatory responses were more present in hypopigmented samples, while those related to stem cell development differentiation were found mainly in hyperpigmented samples. Cell-cell and cell-extracellular matrix interactions and inflammation responses were predicted (z-score) active in hyperpigmented and inactive in hypopigmented. The proinflammatory high-mobility group box 1 pathway showed the opposite trend. Analysis of differentially regulated mutually exclusive genes showed an extensive presence of metabolic, proinflammatory, and oxidative stress pathways in hypopigmented scars, while melanin synthesis, glycosaminoglycans biosynthesis, and cell differentiation pathways were predominant in hyperpigmented scar. Several potential therapeutic gene targets have been identified.

| S-EPMC6697599 | biostudies-literature

Silencing KIF18B enhances radiosensitivity: identification of a promising therapeutic target in sarcoma.

Project description:BackgroundSarcomas are rare heterogeneous tumours, derived from primitive mesenchymal stem cells, with more than 100 distinct subtypes. Radioresistance remains a major clinical challenge for sarcomas, demanding urgent for effective biomarkers of radiosensitivity.MethodsThe radiosensitive gene Kinesin family member 18B (KIF18B) was mined through bioinformatics with integrating of 15 Gene Expression Omnibus (GEO) datasets and The Cancer Genome Atlas (TCGA) database. We used radiotherapy-sh-KIF18B combination to observe the anti-tumour effect in sarcoma cells and subcutaneous or orthotopic xenograft models. The KIF18B-sensitive drug T0901317 (T09) was further mined to act as radiosensitizer using the Genomics of Drug Sensitivity in Cancer (GDSC) database.FindingsKIF18B mRNA was significantly up-regulated in most of the subtypes of bone and soft tissue sarcoma. Multivariate Cox regression analysis showed that KIF18B high expression was an independent risk factor for prognosis in sarcoma patients with radiotherapy. Silencing KIF18B or using T09 significantly improved the radiosensitivity of sarcoma cells, delayed tumour growth in subcutaneous and orthotopic xenograft model, and elongated mice survival time. Furthermore, we predicted that T09 might bind to the structural region of KIF18B to exert radiosensitization.InterpretationThese results indicated that sarcomas with low expression of KIF18B may benefit from radiotherapy. Moreover, the radiosensitivity of sarcomas with overexpressed KIF18B could be effectively improved by silencing KIF18B or using T09, which may provide promising strategies for radiotherapy treatment of sarcoma.FundingsA full list of funding can be found in the Funding Sources section.

| S-EPMC7648128 | biostudies-literature

Identification of crucial noncoding RNAs and mRNAs in hypertrophic scars via RNA sequencing.

Project description:Hypertrophic scarring (HS) is a dermal fibroproliferative disorder characterized by excessive deposition of collagen and other extracellular matrix components. The aim of this study is to explore crucial long noncoding RNAs (lncRNAs) and circular RNAs (circRNAs) associated with HS and provide a better understanding of the molecular mechanism of HS. To investigate the lncRNA, circRNA and mRNA expression profiles, we performed RNA sequencing of human HS and normal skin tissues. After the identification of differentially expressed mRNAs (DEmRNAs), lncRNAs (DElncRNAs) and circRNAs (DEcircRNAs), we performed functional enrichment of DEmRNAs. Further on, we constructed DElncRNA/DEcircRNA-DEmRNA coexpression networks and competing endogenous RNA regulatory networks, and performed functional analyses of the DEmRNAs in the constructed networks. In total, 487 DEmRNAs, 92 DElncRNAs and 17 DEcircRNAs were identified. DEmRNAs were significantly enriched in processes such as collagen fibril organization, extracellular matrix-receptor interaction and the phosphatidylinositol 3-kinase (PI3K)-Akt signaling pathway. In addition, we detected 580 DElncRNA-DEmRNA and 505 DEcircRNA-DEmRNA coexpression pairs. The competing endogenous RNA network contained 18 circRNA-microRNA (miRNA) pairs, 18 lncRNA-miRNA pairs and 409 miRNA-mRNA pairs, including 10 circRNAs, 5 lncRNAs, 15 miRNAs and 160 mRNAs. We concluded that MIR503HG/hsa-miR-204-3p/ACAN, MIR503HG/hsa-miR-431-5p/TNFRSF9, MEG3/hsa-miR-6884-5p/ADAMTS14, AC000035.1-ADAMTS14 and hsa_circ_0069865-COMP/ADAM12 interaction pairs may play a central role in HS.

| S-EPMC8167876 | biostudies-literature

Identification of RAD54 homolog B as a promising therapeutic target for breast cancer.

Project description:Breast cancer is a recognized threat to the health of women globally. Due to the lack of the knowledge about the molecular pathogenesis of breast cancer, therapeutic strategies remain inadequate, especially for aggressive breast cancer. In the present study, sequential bioinformatics analysis was performed using data from the GSE20711 dataset, and the results demonstrated that three genes may impact the survival of patients with breast cancer. One of these genes, RAD54 homolog B (RAD54B), may be a potential prognostic factor for breast cancer. A signature was established that could evaluate the overall survival for patients with breast cancer based on the risk score calculated from RAD54B expression and the Tumor-Node-Metastasis (TNM) stage [risk score=expRAD54B × 0.236 + TNM stage (I/II=0 or III/IV=1) ×1.025]. In addition, based on the GSE85871 dataset and inhibitory assay, the study identified a natural compound, Japonicone A, which may reduce the proliferation of breast cancer cells by inhibiting the expression of RAD54B. Overall, the present study identified a novel candidate gene and a candidate compound as promising therapeutic targets for the treatment of breast cancer.

| S-EPMC6781656 | biostudies-literature

Dyspigmented hypertrophic scars: Beyond skin color

2020-09-17 | GSE158155 | GEO

P-TEFb as A Promising Therapeutic Target.

Project description:The positive transcription elongation factor b (P-TEFb) was first identified as a general factor that stimulates transcription elongation by RNA polymerase II (RNAPII), but soon afterwards it turned out to be an essential cellular co-factor of human immunodeficiency virus (HIV) transcription mediated by viral Tat proteins. Studies on the mechanisms of Tat-dependent HIV transcription have led to radical advances in our knowledge regarding the mechanism of eukaryotic transcription, including the discoveries that P-TEFb-mediated elongation control of cellular transcription is a main regulatory step of gene expression in eukaryotes, and deregulation of P-TEFb activity plays critical roles in many human diseases and conditions in addition to HIV/AIDS. P-TEFb is now recognized as an attractive and promising therapeutic target for inflammation/autoimmune diseases, cardiac hypertrophy, cancer, infectious diseases, etc. In this review article, I will summarize our knowledge about basic P-TEFb functions, the regulatory mechanism of P-TEFb-dependent transcription, P-TEFb's involvement in biological processes and diseases, and current approaches to manipulating P-TEFb functions for the treatment of these diseases.

| S-EPMC7070488 | biostudies-literature

Update on FXR Biology: Promising Therapeutic Target?

Project description:Farnesoid X receptor (FXR), a metabolic nuclear receptor, plays critical roles in the maintenance of systemic energy homeostasis and the integrity of many organs, including liver and intestine. It regulates bile acid, lipid, and glucose metabolism, and contributes to inter-organ communication, in particular the enterohepatic signaling pathway, through bile acids and fibroblast growth factor-15/19 (FGF-15/19). The metabolic effects of FXR are also involved in gut microbiota. In addition, FXR has various functions in the kidney, adipose tissue, pancreas, cardiovascular system, and tumorigenesis. Consequently, the deregulation of FXR may lead to abnormalities of specific organs and metabolic dysfunction, allowing the protein as an attractive therapeutic target for the management of liver and/or metabolic diseases. Indeed, many FXR agonists have been being developed and are under pre-clinical and clinical investigations. Although obeticholic acid (OCA) is one of the promising candidates, significant safety issues have remained. The effects of FXR modulation might be multifaceted according to tissue specificity, disease type, and/or energy status, suggesting the careful use of FXR agonists. This review summarizes the current knowledge of systemic FXR biology in various organs and the gut?liver axis, particularly regarding the recent advancement in these fields, and also provides pharmacological aspects of FXR modulation for rational therapeutic strategies and novel drug development.

| S-EPMC6073382 | biostudies-literature

Emerging Role of IL-10 in Hypertrophic Scars.

Project description:Hypertrophic scars (HS) arise from traumatic or surgical injuries and the subsequent abnormal wound healing, which is characterized by continuous and histologically localized inflammation. Therefore, inhibiting local inflammation is an effective method of treating HS. Recent insight into the role of interleukin-10 (IL-10), an important anti-inflammatory cytokine, in fibrosis has increased our understanding of the pathophysiology of HS and has suggested new therapeutic targets. This review summarizes the recent progress in elucidating the role of IL-10 in the formation of HS and its therapeutic potential based on current research. This knowledge will enhance our understanding of the role of IL-10 in scar formation and shed new light on the regulation and potential treatment of HS.

| S-EPMC7481393 | biostudies-literature

Keloids and hypertrophic scars: update and future directions.

Project description:SummaryThe development of cutaneous pathological scars, namely, hypertrophic scars (HSs) and keloids, involves complex pathways, and the exact mechanisms by which they are initiated, evolved, and regulated remain to be fully elucidated. The generally held concepts that keloids and HSs represent "aberrant wound healing" or that they are "characterized by hyalinized collagen bundles" have done little to promote their accurate clinicopathological classification or to stimulate research into the specific causes of these scars and effective preventative therapies. To overcome this barrier, we review here the most recent findings regarding the pathology and pathogenesis of keloids and HSs. The aberrations of HSs and keloids in terms of the inflammation, proliferation, and remodeling phases of the wound healing process are described. In particular, the significant roles that the extracellular matrix and the epidermal and dermal layers of skin play in scar pathogenesis are examined. Finally, the current hypotheses of pathological scar etiology that should be tested by basic and clinical investigators are detailed. Therapies that have been found to be effective are described, including several that evolved directly from the aforementioned etiology hypotheses. A better understanding of pathological scar etiology and manifestations will improve the clinical and histopathological classification and treatment of these important lesions.

| S-EPMC4173836 | biostudies-literature

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data