Hypertrophic scar (HS) is a common fibroproliferative disorders with no fully effective treatments. The conversion of fibroblasts to myofibroblasts is known to play a critical role in HS formation, making it essential to identify molecules that promote myofibroblast dedifferentiation and to elucidate their underlying mechanisms. In this study, we used comparative transcriptomics and single-cell sequencing to identify key molecules and pathways that mediate fibrosis and myofibroblast transdifferentiation. Epidermal stem cell-derived extracellular vesicles (EpiSC-EVs) were isolated via ultracentrifugation and filtration, followed by miRNA sequencing to identify miRNAs targeting key molecules. After in vitro and in vivo treatment with EpiSC-EVs, we assessed antifibrotic effects through scratch assays, collagen contraction assays, Western blotting, and immunofluorescence. Transcriptomic sequencing and rescue experiments were used to investigate the molecular mechanism by which miR-203a-3p in EpiSC-EVs induces myofibroblast dedifferentiation. Our results indicate that PIK3CA is overexpressed in HS tissues and positively correlates with fibrosis. EpiSC-EVs were absorbed by scar-derived fibroblasts, promoting dedifferentiation from myofibroblasts to quiescent fibroblasts. Mechanistically, miR-203a-3p in EpiSC-EVs plays an essential role in inhibiting PIK3CA expression and PI3K/AKT/mTOR pathway hyperactivation, thereby reducing scar formation. In vivo studies confirmed that EpiSC-EVs attenuate excessive scarring through the miR-203a-3p/PIK3CA axis, suggesting EpiSC-EVs as a promising therapeutic approach for HS.
Purpose: This study aims to investigate the in vitro antiviral effects of the aqueous solution of Changyanning (CYN) tablets on Enterovirus 71 (EV71), and to analyze its active components. Methods: The in vitro anti-EV71 effects of CYN solution and its herbal ingredients were assessed by testing the relative viral RNA (vRNA) expression level and the cell viability rates. Material basis analysis was performed using HPLC-Q-TOF-MS/MS detection. Potential targets and active components were identified by network pharmacology and molecular docking. The screened components were verified by in vitro antiviral experiments. Results: CYN solution exerted anti-EV71 activities as the vRNA is markedly reduced after treatment, with a half maximal inhibitory concentration (IC 50 ) of 996.85 μg/mL. Of its five herbal ingredients, aqueous extract of Mosla chinensis (AEMC) and leaves of Liquidambar formosana Hance (AELLF) significantly inhibited the intracellular replication of EV71, and the IC 50 was tested as 202.57 μg/mL and 174.77 μg/mL, respectively. Based on HPLC-Q-TOF-MS/MS results, as well as the comparison with the material basis of CYN solution, a total of 44 components were identified from AEMC and AELLF. Through network pharmacology, AKT1, ALB, and SRC were identified as core targets. Molecular docking performed between core targets and the components indicated that 21 components may have anti-EV71 effects. Of these, nine were selected for in vitro pharmacodynamic verification, and only rosmarinic acid manifested in vitro anti-EV71 activity, with an IC 50 of 11.90 μg/mL. Moreover, rosmarinic acid can stably bind with three core targets by forming hydrogen bonds. Conclusion: CYN solution has inhibitory effects on EV71 replication in vitro, and its active component was identified as rosmarinic acid. Our study provides a new approach for screening and confirmation of the effective components in Chinese herbal preparation. Keywords: antiviral effects, material basis analysis, component-target-pathway-disease network, protein–protein interaction network, core targets, rosmarinic acid
Vascular endothelial growth factor (VEGF) and placental growth factor (PlGF) are key angiogenic stimulators during normal development and wound healing, as well as in a variety of pathological conditions. Recent studies have demonstrated a synergistic effect of VEGF and PlGF in pathological angiogenesis and suggest a role for PlGF in amplifying VEGF action in endothelial cells. We show here in the mouse model of oxygen‐induced retinopathy that VEGF is significantly increased ( P < 0.01) in the retina at both the mRNA and protein levels. In this mouse model, PlGF was significantly upregulated in the retina at the protein level ( P < 0.01) without a corresponding change in mRNA levels. In cultured human retinal and umbilical vein endothelial cells, VEGF induced the production of PlGF protein by over 10‐fold ( P < 0.01) in a dose‐dependent manner through a post‐transcriptional mechanism. The increased PlGF expression upon VEGF treatment was significantly reduced by inhibition of the protein kinase C (PKC) and MEK signaling pathways, as well as by treatment with the calcium ionophore A23187. Taken together, our findings demonstrate that VEGF can amplify its effects on endothelial cells by inducing the production of PlGF via a post‐transcriptional mechanism in a PKC‐dependent manner, and provide a potential link between PKC inhibition and amelioration of vascular complications in the development of angiogenic diseases.
Tumour lineage plasticity is an emerging hallmark of aggressive tumours. Tumour cells usually hijack developmental signalling pathways to gain cellular plasticity and evade therapeutic targeting. In the present study, the secreted protein growth and differentiation factor 1 (GDF1) is found to be closely associated with poor tumour differentiation. Overexpression of GDF1 suppresses cell proliferation but strongly enhances tumour dissemination and metastasis. Ectopic expression of GDF1 can induce the dedifferentiation of hepatocellular carcinoma (HCC) cells into their ancestral lineages and reactivate a broad panel of cancer testis antigens (CTAs), which further stimulate the immunogenicity of HCC cells to immune-based therapies. Mechanistic studies reveal that GDF1 functions through the Activin receptor-like kinase 7 (ALK7)-Mothers against decapentaplegic homolog 2/3 (SMAD2/3) signalling cascade and suppresses the epigenetic regulator Lysine specific demethylase 1 (LSD1) to boost CTA expression. GDF1-induced tumour lineage plasticity might be an Achilles heel for HCC immunotherapy. Inhibition of LSD1 based on GDF1 biomarker prescreening might widen the therapeutic window for immune checkpoint inhibitors in the clinic.
Introduction Soil erosion plays a crucial role in soil and water conservation management, as well as in ecological construction planning. This study focuses on the slopes of three planting patterns (uniform distribution, aggregation distribution, and random distribution), along with bare slopes, in the Baojiagou watershed of the Pisha Sandstone area, based on soil erosion intensity grade maps after rainfall from 2021 to 2023. Methods A method combining Multi-Criteria Evaluation (MCE) and the CA-Markov model is used to analyze the spatial variation of soil erosion intensity types on different slopes. This approach integrates multiple influencing factors and generates a suitability map for the conversion of soil erosion intensity types. Ultimately, the dynamic characteristics of soil erosion in 2023 are simulated under various slope conditions. Results Results indicated: (1) The spatial distribution of simulated soil erosion intensity grade maps for different slopes largely aligned with actual maps, and regions with soil erosion depth greater than 3 cm were resistant to transitioning to lower erosion zones. (2) The Kappa coefficients for simulated soil erosion intensity in uniform distribution, random distribution, aggregate distribution, and bare control slopes were 65.24%, 73.62%, 75.88%, and 69.06%, respectively, confirming the feasibility of the CA-Markov model for simulating soil erosion dynamics. (3) The simulation of soil erosion intensity on different slopes in 2023 revealed that erosion intensity on uniformly distributed, aggregated, and bare control slopes remained predominantly in the erosion zone with a depth of 1–2 cm, while randomly distributed slopes experienced a shift from mild erosion area to slight erosion area. Discussion This study improves the understanding of soil erosion across different vegetation patterns and demonstrates the applicability of the CA-Markov model for simulating dynamic erosion on slopes. The findings contribute to the development of broader ecological models and offer insights into vegetation management and erosion control strategies for similar landscapes.
Robot welding technology includes independent planning, welding seam position detection, automatic welding seam tracking, etc. Welding seam recognition is a very important link. Traditional algorithms are far inferior to artificial intelligence algorithms in the welding seam recognition. This paper proposes a novel multi-path neural network algorithm, which performs well in the self-collected welding seam recognition data set called WL_HIST. The accuracy of welding seam recognition is as high as 95.3%, which is much higher than 65.3% of the traditional HOG manual feature extraction algorithm. The results show that the deep learning algorithm has a significant and outstanding performance in the welding robot recognition technology.
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