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[en] Highlights: • LncRNA COL1A2-AS1 is upregulated in hypertrophic scar tissue and fibroblasts. • LncRNA COL1A2-AS1 suppresses fibroblasts proliferation by promoting Smad7 expression. • miR-21 is involved in lncRNA COL1A2-AS1-induced expression of Smad7. • Overexpression of miR-21 attenuates COL1A2-AS1–mediated proliferation suppression of hypertrophic scar fibroblasts. lncRNA COL1A2-AS1 (COL1A2 antisense RNA 1), a lncRNA overexpressed in hypertrophic scar, has been demonstrated to be involved in the hypertrophic scar formation. However, the mechanisms of lncRNA COL1A2-AS1 inhibiting the scar fibroblasts proliferation remains not well understood. In this study, we demonstrated that lncRNA COL1A2-AS1 was upregulated in hypertrophic scar tissue and fibroblasts, and suppressed fibroblasts proliferation by promoting Smad7 expression. Furthermore, we found that miR-21 was involved in lncRNA COL1A2-AS1-induced expression of Smad7, by which COL1A2-AS1 acted as endogenous sponge to adsorb miR-21 and in turn regulated Smad7 and a cascade of molecular to play a protective role in hypertrophic scar. In addition, overexpression of miR-21 attenuated COL1A2-AS1-mediated proliferation suppression of hypertrophic scar fibroblasts. In conclusion, our study demonstrated that COL1A2-AS1/miR-21/Smad pathway plays an important role in inhibiting hypertrophic scar formation, and suggested this novel pathway may be a new target for hypertrophic scar treatment.
[en] Functional biopolymer scaffolds are in high demand for tissue regeneration. In this study, we incorporated functionalized CNT in collagen or silk protein solution to generate biocomposite fibers by electrospinning. The addition of CNT reinforced the strength of the scaffolds and rendered the fibers electrical conductivity to not only facilitate the E-spun fiber formation but also grant the fibers an additional functionality that can be utilized for cell stimulation. Considering fiber dimension, alignment, mechanical strength, electrical conductivity and biocompatibility, silk-CNT fibers containing a minute amount of CNT (0.05%) outperformed other fiber types. The modulation effect of these fibers was examined by their application in inducing polarization and activation of fibroblasts with cellular deficit. While the fibroblasts on both collagen-CNT and silk-CNT fibers synthesized a substantially higher level of collagen type III (COLIII) than cells on pure protein fibers to reduce the abnormally high COLI/COLIII ratio, electrical stimulation boosted the collagen productivity by 20 folds in cells on silk-CNT than on collagen-CNT due to silk-CNT's high electrical conductivity. The developed approach can be potentially utilized to remedy the dysfunctional fibroblasts for therapeutic treatment of diseases and health conditions associated with collagen disorder.
[en] Production of type I collagen declines is a main characteristic during photoaging, but the mechanism is still not fully understood. Circular RNAs (circRNAs) are a class of newly identified non-coding RNAs with regulatory potency by sequestering miRNAs like a sponge. It's more stable than linear RNAs, and would be a useful tool for regulation of gene expression. However, the role of circRNAs in collagen expression during photoaging is still unclear. Here we performed deep sequencing of RNA generated from UVA irradiated and no irradiated human dermal fibroblasts (HDFs) and identified 29 significantly differentially expressed circRNAs (fold change ≥ 1.5, P < 0.05), 12 circRNAs were up-regulated and 17 circRNAs were down-regulated.3 most differentially expressed circRNAs were verified by qRT-PCR and the down-regulated circCOL3A1-859267 exhibited the most significantly altered in photoaged HDFs. Overexpression of circCOL3A1-859267 inhibited UVA-induced decrease of type I collagen expression and silencing of it reduced type I collagen intensity. Via a bioinformatic method, 44 miRNAs were predicted to binding with circCOL3A1-859267, 5 of them have been confirmed or predicted to interact with type I collagen. This study show that circCOL3A1-859267 regulate type I collagen expression in photoaged HDFs, suggesting it may be a novel target for interfering photoaging.
[en] Highlights: • TFB2M have been known to critical in mitochondrial DNA gene expression. • We identified a variation of TFB2M gene sequence in Korean autism patients. • The variation caused increased mitochondrial DNA gene expression. • Increased mitochondrial biogenesis resulted in ROS production and damaged cells. • Structural changes of variant TFB2M seems to delay unloading of DNA from TFB2M. Mitochondrial dysfunction and subsequent enhanced oxidative stress is implicated in the pathogenesis of autism spectrum disorder (ASD). Mitochondrial transcription factor B2 (TFB2M) is an essential protein in mitochondrial gene expression. No reports have described TFB2M mutations and variations involved in any human diseases. We identified a rare homozygous c.790C>T (His264Tyr) variation in TFB2M gene in two Korean siblings with ASD by whole-exome sequencing. The roles of the TFB2M variation in the pathogenesis of ASD were investigated. Patient fibroblasts revealed increased transcription of mitochondrial genes and mitochondrial function in terms of ATP, membrane potential, oxygen consumption, and reactive oxygen species (ROS). Overexpression of the TFB2M variant in primary-cultured fibroblasts demonstrated significantly increased transcription of mitochondrial genes and mitochondrial function compared with overexpression of wild-type TFB2M. Molecular dynamics simulation of the TFB2M variant protein suggested an increase in the rigidity of the hinge region, which may cause alterations in loading and/or unloading of TFB2M on target DNA. Our results suggest that augmentation of mitochondrial gene expression and subsequent enhancement of mitochondrial function may be associated with the pathogenesis of ASD in Korean patients.
[en] Highlights: • LncRNA HAGLROS was higher expressed in patients with pneumonia. • LPS caused WI-38 cell injury and increased HAGLROS levels. • Downregulation of HAGLROS alleviated LPS-induced WI-38 cell injury by miR-100. • NFΚB3 was verified as a functional target of miR-100. • Knockdown of HAGLROS inhibited the activation of PI3K/AKT/NF-κB pathway. Pneumonia is a lower respiratory disease caused by pathogens or other factors. This study aimed to explore the roles and mechanism of long noncoding RNA HAGLROS in lipopolysaccharides (LPS)-induced inflammatory injury in pneumonia. The HAGLROS expression in serum of patients with acute stage pneumonia was detected. To induce pulmonary injury, WI-38 human lung fibroblasts were stimulated with lipopolysaccharides (LPS). The HAGLROS expressions in LPS-treated WI-38 cells and the effects of HAGLROS knockdown on the viability, apoptosis, and autophagy of LPS-induced cells were detected. Moreover, the regulatory relationship between HAGLROS and miR-100 was explored as well as the functional targets of miR-100 were identified. Furthermore, the regulatory relationship between miR-100 and PI3K/AKT/NF-κB pathway was elucidated. LncRNA HAGLROS was higher expressed in serum of patients with acute stage pneumonia compared with that in serum of healthy control. LPS caused WI-38 cell injury and increased HAGLROS levels. Downregulation of HAGLROS alleviated LPS-induced cell injury via increasing cell viability, and inhibiting apoptosis and autophagy. Moreover, there was a negative correlation between HAGLROS and miR-100, and the effects of HAGLROS downregulation on LPS-induced apoptosis and autophagy in WI-38 cells were by regulation of miR-100. Furthermore, NFΚB3 was verified as a functional target of miR-100 and effects of miR-100 inhibition on LPS-induced WI-38 cell injury were alleviated by knockdown of NFΚB3. Besides, Knockdown of HAGLROS inhibited the activation of PI3K/AKT/NF-κB pathway. Our findings reveal that downregulation of HAGLROS may alleviate LPS-induced inflammatory injury in WI-38 cells via modulating miR-100/NF-κB axis. HAGLROS/miR-100/NF-κB axis may provide a new strategy for treating acute stage of pneumonia.
[en] Highlights: • GDC-0084 is a novel small-molecule PI3K/mTOR dual inhibitor. • GDC-0084 inhibits cutaneous squamous cell carcinoma (cSCC) cell survival/proliferation. • GDC-0084 induces apoptosis activation in cSCC cells. • GDC-0084 blocks PI3K-Akt-mTOR and DNA-PKcs signaling activation in cSCC cells. • Gastric gavage of GDC-0084 inhibits A431 xenograft tumor growth in SCID mice. GDC-0084 is a novel and potent small-molecule PI3K-mTOR dual inhibitor. The present study examined its potential activity in cutaneous squamous cell carcinoma (cSCC) cells. Our results show that GDC-0084 treatment at nanomole concentrations potently inhibited survival and proliferation of established (A431, SCC-13 and SCL-1 lines) and primary human cSCC cells. GDC-0084 induced apoptosis activation and cell cycle arrest in the cSCC cells. It was more efficient than other known PI3K-Akt-mTOR inhibitors in killing cSCC cells, but was non-cytotoxic to the normal human skin fibroblasts/keratinocytes. In A431 cells and primary cSCC cells, GDC-0084 blocked phosphorylation of key PI3K-Akt-mTOR components, including p85, Akt, S6K1 and S6. GDC-0084 also inhibited DNA-PKcs activation in cSCC cells. Significantly, restoring DNA-PKcs activation by a constitutively active-DNA-PKcs (S2056D) partially inhibited GDC-0084-induced cell death and apoptosis in A431 cells. In vivo, GDC-0084 daily gavage potently inhibited A431 xenograft tumor growth in mice. In GDC-0084-treated tumor tissues PI3K-Akt-mTOR and DNA-PKcs activation were significantly inhibited. In summary, GDC-0084 inhibits human cSCC cell growth in vitro and in vivo through blocking PI3K-Akt-mTOR and DNA-PKcs signalings.
[en] Highlights: • Normal human fibroblasts show intrinsic and directed migration for a long duration. • NMIIA controls protrusion formation in the anterior region to steer migration. • NMIIB prevents protrusions in the posterior region to maintain front-rear polarity. • NMIIA and NMIIB differentially contribute to intrinsic and directed migration. Nonmuscle myosin II (NMII) plays an essential role in directional cell migration. In this study, we investigated the roles of NMII isoforms (NMIIA and NMIIB) in the migration of human embryonic lung fibroblasts, which exhibit directionally persistent migration in an intrinsic manner. NMIIA-knockdown (KD) cells migrated unsteadily, but their direction of migration was approximately maintained. By contrast, NMIIB-KD cells occasionally reversed their direction of migration. Lamellipodium-like protrusions formed in the posterior region of NMIIB-KD cells prior to reversal of the migration direction. Moreover, NMIIB KD led to elongation of the posterior region in migrating cells, probably due to the lack of load-bearing stress fibers in this area. These results suggest that NMIIA plays a role in steering migration by maintaining stable protrusions in the anterior region, whereas NMIIB plays a role in maintenance of front-rear polarity by preventing aberrant protrusion formation in the posterior region. These distinct functions of NMIIA and NMIIB might promote intrinsic and directed migration of normal human fibroblasts.
[en] A colony-forming assay of human skin fibroblast radiosensitivity was established in our laboratory and applied to primary skin biopsies from 12 women belonging to an unselected group of patients who received postmastectomy radiotherapy 10-12 years prior to this study. The aim was to investigate the relationship between in vitro radiosensitivity and the occurrence of subcutaneous fibrosis after radiotherapy. Early generations of normal skin fibroblasts in exponential growth were irradiated at room temperature at a high dose-rate to estimate the surviving fraction of colony-forming cells after single doses ranging from 1 to 8 Gy. A linear-quadratic cell survival curve was fitted to the data and from these fits the surviving fraction at 3.5 Gy (SF3.5) was estimated. Replicate experiments of different cell generations were made to validate the assay, and the between-patients variability was significantly larger than the assay variability for both SF2(p=0.002) and SF3.5(p=0.04). Patients were treated in the period 1978-1982 with a dose per fraction between 2.7 and 3.9 Gy, a total of 12 fractions at two fractions per week. They were evaluated with respect to the occurence of marked subcutaneous fibrosis in a total of 36 independent treatment fields. In each treatment field the total dose and dose per fraction at the relevant dosimetric reference depth as well as the length of follow-up were recorded. (Author)
[en] Highlights: • HOTTIP is required for activation of distal HOXA genes but its role is restricted by CTCF boundary. • HOTTIP and CTCF coordinate to specify the pattern of histone modifications on HOXA genes in foreskin fibroblasts. • HOTTIP RNA acts as a new interaction partner of CTCF. The spatiotemporal control of HOX gene expression is dependent on positional identity and often correlated to their genomic location within each loci. Maintenance of HOX expression patterns is under complex transcriptional and epigenetic regulation, which is not well understood. Here we demonstrate that HOTTIP, a lincRNA transcribed from the 5′ edge of the HOXA locus, physically associates with the CCCTC-binding factor (CTCF) that serves as an insulator by organizing HOXA cluster into disjoint domains, to cooperatively maintain the chromatin modifications of HOXA genes and thus coordinate the transcriptional activation of distal HOXA genes in human foreskin fibroblasts. Our results reveal the functional connection of HOTTIP and CTCF, and shed light on lincRNAs in gene activation and CTCF mediated chromatin organization.