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Melatonin inhibits fibroblast cell functions and hypertrophic scar formation by enhancing autophagy through the MT2 receptor-inhibited PI3K/Akt /mTOR signaling

ABSTRACT: Hypertrophic scar (HS) is a fibrotic skin condition and characterized by abnormal proliferation of myofibroblasts and accumulation of extracellular matrix. Melatonin, an endogenous hormone, can alleviate fibrosis in multiple models of diseases. This study examined the effect of melatonin on fibrosis in primary fibroblasts from human HS (HSFs) and a rabbit ear model and potential mechanisms. Melatonin treatment significantly decreased the migration and contraction capacity, collagen and α-smooth muscle actin (α-SMA) production in HSFs. RNA-sequencing and bioinformatic analyses indicated that melatonin modulated the expression of genes involved in autophagy and oxidative stress. Mechanistically, melatonin treatment attenuated the AKT/mTOR activation through affecting the binding of MT2 receptor with PI3K to enhance autophagy, decreasing fibrogenic factor production in HSFs. Moreover, melatonin treatment inhibited HS formation in rabbit ears by enhancing autophagy. The anti-fibrotic effects of melatonin were abrogated by treatment with an autophagy inhibitor (3-methyladenine, 3-MA), an Akt activator (SC79), or an MT2 selective antagonist (4-phenyl-2propionamidotetralin, 4-P-PDOT). Therefore, melatonin may be a potential drug for prevention and treatment of HS.

ORGANISM(S): Homo sapiens

PROVIDER: GSE190135 | GEO | 2022/06/03

REPOSITORIES: GEO

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Melatonin inhibits fibroblast cell functions and hypertrophic scar formation by enhancing autophagy through the MT2 receptor-inhibited PI3K/Akt /mTOR signaling

Project description:Melatonin inhibits fibroblast cell functions and hypertrophic scar formation by enhancing autophagy through the MT2 receptor-inhibited PI3K/Akt /mTOR signaling

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The genomic response of human granulosa cells (KGN) to melatonin and specific agonists/antagonists to the melatonin receptors

Project description:Melatonin is a known modulator of follicle development, it acts through several molecular cascades via binding to its two high-affinity, G-protein coupled receptors MT1 and MT2. Even though it is believed that melatonin can modulate granulosa cell (GC) functions, there is still limited knowledge of how it can act in human GC through MT1 and MT2 and which one is the major receptor implicated in the effects of melatonin on the metabolic processes in the dominant follicle. To better characterize the roles of the MT1 and MT2 receptors on the effects of melatonin on follicular atresia and the regulation of proliferation and differentiation of granulosa cells during the antral stage, human granulosa-like tumor cells (KGN) were treated with specific melatonin receptor agonists and antagonists, and gene expression was analyzed with RNA-seq technology. Following appropriate normalization and the application of a fold change cut-off of 1.5 (FC 1.5, p ≤ 0.05) for each treatment, lists of the principal differentially expressed genes (DEGs) are generated. Analysis of major upstream regulators suggested that the MT1 receptor may be involved in the melatonin antiproliferative effect by reprogramming the metabolism of human GC by activating the PKB signaling pathway. Our data suggest that melatonin may act complementary through both MT1 and MT2 receptors to modulate human GC steroidogenesis, proliferation, and differentiation. However, MT2 receptors may be the ones implicated in transducing the effects of melatonin on the prevention of GC luteinization and follicle atresia at the antral follicular stage through stimulating the PKA pathway.

2022-10-26 | GSE201943 | GEO

HP1 wa191.D.mel 3rd Instar Larvae Nuclei mt2 Mutant

Project description:modENCODE_submission_3703 This submission comes from a modENCODE project of Gary Karpen. For full list of modENCODE projects, see http://www.genome.gov/26524648 Project Goal: We aim to determine the locations of 125 chromosomal proteins across the Drosophila melanogaster genome. The proteins under study are involved in basic chromosomal functions such as DNA replication, gene expression, gene silencing, and inheritance. We will perform Chromatin ImmunoPrecipitation (ChIP) using genomic tiling arrays. We will initially assay localizations using chromatin from three cell lines and two embryonic stages, and will then extend the analysis of a subset of proteins to four additional animal tissues/stages For data usage terms and conditions, please refer to http://www.genome.gov/27528022 and http://www.genome.gov/Pages/Research/ENCODE/ENCODEDataReleasePolicyFinal2008.pdf EXPERIMENT TYPE: CHIP-chip. BIOLOGICAL SOURCE: Strain: mt2 mutant(official name : MT2 [149] mutant genotype : Mt2 [149]/Mt2 [149] outcross : unknown tags : Transposon description : Mobilization of the progenitor insertion P{EP}GE15695. 59bp of 5' P{EP} sequence are present at the transcriptional start site description : along with a 4bp duplication of coding sequences. The mutation results in a frameshift. Developmental Stage: 3rd Instar Larvae; Genotype: Mt2 [149]/Mt2 [149]; NUMBER OF REPLICATES: 4; EXPERIMENTAL FACTORS: Strain mt2 mutant(official name : MT2 [149] mutant genotype : Mt2 [149]/Mt2 [149] outcross : unknown tags : Transposon description : Mobilization of the progenitor insertion P{EP}GE15695. 59bp of 5' P{EP} sequence are present at the transcriptional start site description : along with a 4bp duplication of coding sequences. The mutation results in a frameshift. Antibody HP1 wa191 (target is HP1a); Developmental Stage 3rd Instar Larvae

2013-02-22 | E-GEOD-44477 | biostudies-arrayexpress

H3K9me2-Ab2 (new lot).D.mel 3rd Instar Larvae Nuclei mt2 Mutant

Project description:modENCODE_submission_3693 This submission comes from a modENCODE project of Gary Karpen. For full list of modENCODE projects, see http://www.genome.gov/26524648 Project Goal: We aim to determine the locations of the major histone modifications across the Drosophila melanogaster genome. The modifications under study are involved in basic chromosomal functions such as DNA replication, gene expression, gene silencing, and inheritance. We will perform Chromatin ImmunoPrecipitation (ChIP) using genomic tiling arrays. We will initially assay localizations using chromatin from three cell lines and two embryonic stages, and will then extend the analysis of a subset of proteins to four additional animal tissues/stages. For data usage terms and conditions, please refer to http://www.genome.gov/27528022 and http://www.genome.gov/Pages/Research/ENCODE/ENCODEDataReleasePolicyFinal2008.pdf EXPERIMENT TYPE: CHIP-chip. BIOLOGICAL SOURCE: Strain: mt2 mutant(official name : MT2 [149] mutant genotype : Mt2 [149]/Mt2 [149] outcross : unknown tags : Transposon description : Mobilization of the progenitor insertion P{EP}GE15695. 59bp of 5' P{EP} sequence are present at the transcriptional start site description : along with a 4bp duplication of coding sequences. The mutation results in a frameshift. Developmental Stage: 3rd Instar Larvae; Genotype: Mt2 [149]/Mt2 [149]; NUMBER OF REPLICATES: 4; EXPERIMENTAL FACTORS: Strain mt2 mutant(official name : MT2 [149] mutant genotype : Mt2 [149]/Mt2 [149] outcross : unknown tags : Transposon description : Mobilization of the progenitor insertion P{EP}GE15695. 59bp of 5' P{EP} sequence are present at the transcriptional start site description : along with a 4bp duplication of coding sequences. The mutation results in a frameshift. Antibody H3K9me2-Ab2 (new lot) (target is H3K9me2); Developmental Stage 3rd Instar Larvae

2013-02-22 | E-GEOD-44470 | biostudies-arrayexpress

Expression array of early postnatal Mt2-mmp-targeted mammary glands

Project description:Mammary gland branching morphogenesis is thought to depend on the mobilization of the membrane-anchored matrix metalloproteinases, MT1-MMP and MT2-MMP, that drive epithelial cell invasion by remodeling the extracellular matrix and triggering associated signaling cascades. However, the roles that these proteinases play during mammary gland development in vivo remains undefined. A mammary gland branching program that occurs during the first 10 days of early postnatal development was used to characterize the impact of global Mt1-mmp or Mt2-mmp targeting on mammary gland morphogenesis. Transcriptome profiling of ductal networks and associated stroma was used to investigate the functional roles of MT2-MMP in the early postnatal mammary gland in an unbiased fashion.

2016-10-05 | GSE77678 | GEO

Penicillium sp. MT2 MMC-2018

Project description:Penicillium sp. MT2 MMC-2018 Genome sequencing and assembly

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Microarray profiling analysis of microRNAs expression in Hypertrophic scar

Project description:Excessive repair after burn or trauma will lead to the formation of pathological scar. TGF-β1 is a powerful growth factor after wound healing. It is considered to be a key regulator of HS and various fibrotic diseases. MicroRNAs (miRNAs) can widely participate in the pathophysiological processes of various diseases by participating in post transcriptional gene regulation. At present, there is no research report on miR-361 and hypertrophic scar. This study found that miR-361 in HS is down-regulated. MiR-361 can inhibit the proliferation of HS fibroblasts and promote their apoptosis by inhibiting TGF-β1. Moreover, miR-361 can inhibit the formation of rabbit ear scar by inhibiting the expression of TGF-β1.

2021-11-22 | GSE189134 | GEO

Inhibition of PIK3CA by miR-203a-3p reduces hypertrophic scar formation via PI3K/AKT/mTOR signaling pathway

Project description:Hypertrophic scar (HS) is a skin fibroproliferative disease currently having no truly effective therapy. PIK3CA is a catalytic subunit of PI3K able to promote collagen synthesis in benign fibrotic diseases and to regulate cell survival, proliferation, and adhesion in malignancies. To explore PIK3CA’s functions in HS formation, we performed transcriptome sequencing and experimental validation. PIK3CA were overexpressed in HS tissues, and positively correlated with fibrosis. We then screened out miR-203a-3p as the most suitable endogenous inhibitor of PIK3CA through bioinformatics. Intriguingly, miR-203a-3p suppressed the proliferation, migration, collagen synthesis, and contractility, as well as trans-differentiation of fibroblasts into myofibroblasts in vitro, improved the morphology and histology of HS in vivo. Mechanistically, miR-203a-3p attenuated fibrosis by inactivating PI3K/AKT/mTOR pathway via directly targeting PIK3CA. In conclusion, Our findings identified that PIK3CA and PI3K/AKT/mTOR pathway were actively involved in HS formation and demonstrated that miR-203a-3p might serve as a potential strategy for HS therapy through targeting PIK3CA and inactivating PI3K/AKT/mTOR pathway.

2023-07-15 | GSE236983 | GEO

Comparison of gene expression in mouse placentas with different combination of MT1-MMP and MT2-MMP alleles

Project description:MT1-MMP and MT2-MMP double deficiency in mice leads to development of a placental defect resulting in embryonic death after E10.5. The protein substrate for these two proteases in placenta is unknown, which poses an obstacle in uncovering of molecular mechanism behind the observed placental defect. In search for a potential substrate for these two proteases in placenta we have employed whole genome microarray expression profiling as a discovery platform to identify genes, expression of which might be affected by double MMP deficiency. Fetal parts of mouse placentas were isolated from E10.5 placentas of different genotypes for MT1- and MT2-MMP.

2010-03-09 | E-GEOD-18604 | biostudies-arrayexpress

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Project description:Heat shock proteins (Hsps) are molecular chaperones primarily involved in maintenance of protein homeostasis. Their function has been best characterized in heat stress (HS) response during which Hsps are transcriptionally controlled by heat stress transcription factors (Hsfs). The role of Hsfs and Hsps in HS-response in tomato was initially examined by transcriptome analysis using the Massive Analysis of cDNA Ends (MACE) method. Approximately 9.6% of all genes expressed in leaves are enhanced in response to HS, including a subset of Hsfs and Hsps. The underlying Hsp-Hsf networks with potential functions in stress responses or developmental processes were further explored by meta-analysis of existing microarray datasets. We identified clusters with differential transcript profiles with respect to abiotic stresses, plant organs and developmental stages. The composition of two clusters points toward two major chaperone networks. One cluster consisted of constitutively expressed plastidial chaperones and other genes involved in chloroplast protein homeostasis. The second cluster represents genes strongly induced by heat, drought and salinity stress, including HsfA2 and many stress-inducible chaperones, but also potential targets of HsfA2 not related to protein homeostasis. This observation attributes a central regulatory role to HsfA2 in controlling different aspects of abiotic stress response and tolerance in tomato. 2 samples

2014-08-01 | E-GEOD-56611 | biostudies-arrayexpress

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