Adipose-derived stem cells transplantation improves survival and alleviates contraction of skin grafts via promoting macrophages M2 polarization.

BACKGROUND: Full-thickness skin grafts are widely used in plastic and reconstructive surgery. The main limitation of skin grafting is the poor textural durability and associated contracture, which often needs further corrective surgery. Excessive inflammation is the main reason for skin graft contractions, which involve overactivation of myofibroblasts. These problems have prompted the development of new therapeutic approaches, including macrophage polarization modulation and stem cell-based therapies. Currently, adipose-derived stem cells (ASCs) have shown promise in promoting skin grafts survival and regulating macrophage phenotypes. However, the roles of ASCs on macrophages in decreasing skin grafts contraction remain unknown. MATERIALS AND METHODS: Rat adipose-derived stem cells (rASCs) were isolated from rat inguinal adipose tissues. Full-thickness skin graft model was constructed on male rats divided into control group and rASCs treatment group. Skin graft was assessed for concentration, elasticity modulus and stiffness. Rat bone marrow-derived macrophages (rBMDMs) were isolated from rat femurs, and subsequent RT-qPCR and coculture assays were carried out to explore the cellular mechanisms. Immunohistochemical and immunofluorescence staining were used to verify mechanisms in vivo. RESULTS: In vivo results showed that after injection of ASCs, improved texture, increased survival and inhibited contraction of skin grafts were seen. Vascularization was also improved as illustrated by laser perfusion image and vascular endothelial growth factor (VEGF) concentration. Histological analysis revealed that ASCs injection significantly reduced expression of pro-inflammatory cytokines (TNF-a, IL-1ß) and increased expression of anti-inflammatory (IL-10) and pro-healing cytokines (IGF-1). At cellular level, after co-culturing with rASCs, rat bone marrow derived macrophages (rBMDMs) favored M2 polarization even under inflammatory stimulus. CONCLUSION: ASCs treatment enhanced vascularization via angiogenic cytokines secretion and alleviated inflammatory environment in skin grafts by driving M2 macrophages polarization, which improved survival and decreased skin grafts contraction. Our work showed that ASCs transplantation can be harnessed to enhance therapeutic efficacy of skin grafting in cutaneous defects treatment.

LncRNA-PVT1 Inhibits Ferroptosis through Activating STAT3/GPX4 Axis to Promote Osteosarcoma Progression.

BACKGROUND: Osteosarcoma (OS) is a primary malignant bone tumor in the pediatric and adolescent populations. Long non-coding RNAs (LncRNAs), such as plasma-cytoma variant translocation 1 (PVT1), have emerged as significant regulators of OS metastasis. Recent studies have indicated that activation of signal transducer and activator of transcription 3 (STAT3) signaling, which might be controlled by PVT1, inhibits ferroptosis to promote the malignant progression of cancer. Therefore, the present study aimed to determine the role of PVT1 in OS pathogenesis and investigate whether PVT1 affects OS progression by regulating STAT3/GPX4 pathway-mediated ferroptosis. METHODS: The human OS cell line MG63 were transfected with sh-PVT1 plasmid to inhibit PVT1 expression, with or without co-transfection with a STAT3 overexpression plasmid. The expression of PVT1 was determined by real-time quantitative polymerase chain reaction (RT-qPCR). The proliferation, migration, invasion, and apoptosis of MG63 cells were determined using the cell counting kit-8 (CCK8), Transwell assay, and flow cytometry. The levels of malondialdehyde (MDA), Fe2+, and glutathione (GSH) were determined by ELISA kits, whereas reactive oxygen species (ROS) level was determined by immunofluorescence. The protein expression levels of STAT3, p-STAT3, and glutathione peroxidase 4 (GPX4) were detected by western blot (WB). RESULTS: PVT1 expression was significantly increased in MG63 cells. When knocking down PVT1 with sh-PVT1 plasmid, the proliferation, migration, and invasion of MG63 cells were markedly inhibited, while the rate of apoptosis was upregulated. Further investigation revealed that MG63 cells with PVT1 knockdown exhibited elevated levels of MDA, Fe2+, and ROS. In addition, the inhibition of PVT1 expression resulted in decreased levels of GSH and inhibited expression of p-STAT3 and GPX4. When sh-PVT1 was co-transfected with STAT3 overexpression plasmid in MG63 cells, the increased levels of MDA, Fe2+, and ROS were downregulated, and the decreased expressions of GSH, p-STAT3, and GPX4 were upregulated. CONCLUSION: PVT1 promotes OS metastasis by activating the STAT3/GPX4 pathway to inhibit ferroptosis. Targeting PVT1 might be a novel therapeutic strategy for OS treatment.

Corrigendum: Editorial: Recent innovations to inhibit scar formation for better skin regeneration.

[This corrects the article DOI: 10.3389/fsurg.2023.1325832.].

Obesity, Glycemic Traits, Lifestyle Factors, and Risk of Facial Aging: A Mendelian Randomization Study in 423,999 Participants.

BACKGROUND: Several recent observational studies have associated obesity, lifestyle factors (smoking, sleep duration, and alcohol drinking), and glycemic traits with facial aging. However, whether this relationship is causal due to confounding and reverse causation is yet to be substantiated. AIMS: We aimed to assess these relationships using Mendelian randomization (MR). METHODS: For the instrumental variables, this paper selected independent single nucleotide polymorphisms (SNPs) linked to the exposures at a genome-wide state (P < 5 × 10-8) in equivalent genome-wide association studies (GWAS). Using the UK Biobank, we obtained summary-level data for facial aging on 423,999 individuals. The primary assessments were performed through the combination of complementing techniques (simple method approaches, weighted model, MR-Egger, and weighted median) and the inverse-variance-weighted method. Along with that, we examined the heterogeneity and horizontal pleiotropy through different types of sensitivity analyses. RESULTS: The correlations were (a) facial aging for body mass index (BMI, OR = 1.054, 95% CI 1.044-1.64), (b) waist/hip ratio (OR = 1.056, 95% CI 1.023-1.091), and (c) smoking (OR = 1.023, 95% CI 1.007-1.039). Equally important, the correlations for waist/hip ratio remained robust after adjusting for the genetically predicted BMI (OR = 1.028, 95% CI 1.003-1.054). However, no causal effects of alcoholic drinking, glycemic traits, and sleep duration on facial aging were observed. CONCLUSIONS: The outcomes shed light on the potential correlation of obesity and cigarette smoking with facial aging while putting forward a more comprehensive and credible foundation for the optimization of facial aging strategies. NO LEVEL ASSIGNED: This journal requires that authors assign a level of evidence to each submission to which Evidence-Based Medicine rankings are applicable. This excludes Review Articles, Book Reviews, and manuscripts that concern Basic Science, Animal Studies, Cadaver Studies, and Experimental Studies. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

Alcohol drinking, smoking, and cutaneous melanoma risk: Mendelian randomization analysis.

OBJECTIVE: To investigate the causal relationship between poor lifestyle habits, such as smoking and drinking, and cutaneous malignant melanoma. METHOD: In the present study, alcohol consumption and smoking were used as exposure factors, and single nucleotide polymorphisms closely associated with alcohol consumption and smoking were used as instrumental variables, while cutaneous melanoma was set as an outcome variable. Two-sample Mendelian randomization analyses were run between alcohol consumption and melanoma and smoking and melanoma to investigate their causal associations, respectively. RESULTS: We found a positive and statistically significant causal effect of alcohol intake on the risk of cutaneous malignant melanoma (OR: 2.23; 95%CI: 1.11-4.47; p=0.02). The present study showed no significant causal relationship between cigarettes per day and cutaneous melanoma (OR: 0.85; 95%CI: 0.54-1.35; p=0.50) or smoking initiation and cutaneous melanoma (OR: 1.02; 95%CI: 0.74-1.39; p=0.88). CONCLUSIONS: This study provides Mendelian randomization evidence supporting alcohol consumption as a risk factor for cutaneous malignant melanoma. And the causal relationship between smoking and cutaneous malignant melanoma still needs to be further investigated.

Wetland vegetation cover changes and its response to climate changes across Heilongjiang-Amur River Basin.

The Heilongjiang-Amur River Basin is one of the largest and most complex aquatic systems in Asia, comprising diverse wetland resources. The wetland vegetation in mid-high latitude areas has high natural value and is sensitive to climate changes. In this study, we investigated the wetland vegetation cover changes and associated responses to climate change in the Heilongjiang-Amur River Basin from 2000 to 2018 based on the growing season (May to September) climate and LAI data. Our results indicated that the wetland LAI increased at 0.014 m2·m-2/yr across Heilongjiang-Amur River Basin with the regional climate showed wetting and warming trends. On a regional scale, wetland vegetation in China and Russia had positive partial correlation with solar radiation and minimum air temperature, with precipitation showing a slight lag effect. In contrast, wetland vegetation in Mongolia had positive partial correlation with precipitation. These correlations were further investigated at different climate intervals. We found the precipitation is positively correlated with LAI in the warm regions while is negatively correlated with LAI in the wet regions, indicating an increase in precipitation is beneficial for the growth of wetland vegetation in heat sufficient areas, and when precipitation exceeds a certain threshold, it will hinder the growth of wetland vegetation. In the cold regions, we found solar radiation and minimum air temperature are positively correlated with LAI, suggesting SR and minimum air temperature instead of mean air temperature and maximum air temperature play more important roles in affecting the wetland vegetation growth in the heat limited areas. The LAI was found to be negatively correlated with maximum air temperature in the arid areas, indicating excessive temperature would inhibit the wetland vegetation growth when the water is limited. Our investigation can provide a scientific foundation for the trilateral region in wetland ecosystem protection and is beneficial for a more comprehensive understanding of the responses of wetlands in the middle and high latitudes to climate change.

Alcohol drinking, smoking, and cutaneous melanoma risk: Mendelian randomization analysis / Consumo de alcohol, tabaquismo y riesgo de melanoma cutáneo: análisis de aleatorización mendeliana

Objective: To investigate the causal relationship between poor lifestyle habits, such as smoking and drinking, and cutaneous malignant melanoma. Method: In the present study, alcohol consumption and smoking were used as exposure factors, and single nucleotide polymorphisms closely associated with alcohol consumption and smoking were used as instrumental variables, while cutaneous melanoma was set as an outcome variable. Two-sample Mendelian randomization analyses were run between alcohol consumption and melanoma and smoking and melanoma to investigate their causal associations, respectively. Results: We found a positive and statistically significant causal effect of alcohol intake on the risk of cutaneous malignant melanoma (OR: 2.23; 95%CI: 1.11-4.47; p = 0.02). The present study showed no significant causal relationship between cigarettes per day and cutaneous melanoma (OR: 0.85; 95%CI: 0.54-1.35; p = 0.50) or smoking initiation and cutaneous melanoma (OR: 1.02; 95%CI: 0.74-1.39; p = 0.88). Conclusions: This study provides Mendelian randomization evidence supporting alcohol consumption as a risk factor for cutaneous malignant melanoma. And the causal relationship between smoking and cutaneous malignant melanoma still needs to be further investigated.(AU)

Objetivo: Investigar la relación causal entre los malos hábitos de vida, como el tabaquismo y el consumo de alcohol, y el melanoma maligno cutáneo. Método: En el presente estudio, el consumo de alcohol y el tabaquismo se utilizaron como factores de exposición, y los polimorfismos de nucleótido único estrechamente asociados con el consumo de alcohol y el tabaquismo se utilizaron como variables instrumentales, mientras que el melanoma cutáneo se estableció como variable de resultado. Se realizaron análisis de aleatorización mendeliana de dos muestras entre el consumo de alcohol y el melanoma, y entre el tabaquismo y el melanoma, para investigar sus asociaciones causales, respectivamente. Resultados: Se encontró un efecto causal positivo y estadísticamente significativo del consumo de alcohol sobre el riesgo de melanoma maligno cutáneo (OR: 2,23; IC95%: 1,11-4,47; p = 0,02). El presente estudio no mostró una relación causal significativa entre cigarrillos por día y melanoma cutáneo (OR: 0,85; IC95%: 0,54-1,35; p = 0,50) ni entre inicio de fumar y melanoma cutáneo (OR: 1,02; IC95%: 0,74-1,39; p = 0,88). Conclusiones: Este estudio aporta pruebas de aleatorización mendeliana que apoyan el consumo de alcohol como factor de riesgo de melanoma maligno cutáneo. En cuanto a la relación causal entre el tabaquismo y el melanoma maligno cutáneo aún debe investigarse más a fondo.(AU)

An Online Prognostic Application for Melanoma Based on Machine Learning and Statistics.

BACKGROUND: Melanoma is a common cancer that causes a severe socioeconomic burden. Patients usually turn to plastic surgeons to determine their prognosis after surgery. METHODS: Data from hundreds of thousands of real-world patients were downloaded from the Surveillance, Epidemiology, and End Results database. Nine mainstream machine learning models were applied to predict 5-year survival probability and three survival analysis models for overall survival prediction. Models that outperformed were deployed online. RESULTS: After manual review, 156,154 real-world patients were included. The deep learning model was chosen for predicting the probability of 5-year survival, based on its area under the receiver operating characteristic curve (0.915) and its accuracy (84.8%). The random survival forest model was chosen for predicting overall survival, with a concordance index of 0.894. These models were deployed at www.make-a-difference.top/melanoma.html as an online calculator with an interactive interface and an explicit outcome for everyone. CONCLUSIONS: Users should make decisions based on not only this online prognostic application but also multidimensional information and consult with multidiscipline specialists.

EIF3B stabilizes PTGS2 expression by counteracting MDM2-mediated ubiquitination to promote the development and progression of malignant melanoma.

Malignant melanoma (MM) is a neoplasm that develops from human melanocytes. It was reported that eukaryotic translation initiation factor 3 subunit B (EIF3B) is associated with multiple types of cancers, but its role in MM has not been reported. In the present study, we found that EIF3B was abundantly expressed in MM and was strongly related to lymphatic metastasis and pathological stage of MM patients. In addition, EIF3B depletion could block the progression of MM in vitro and in vivo. In contrast, EIF3B overexpression increased cell proliferation and migration in melanoma cells. More importantly, we identified that EIF3B's driver role in MM was mediated by PTGS2. In detail, we found that EIF3B stabilized PTGS2 expression by inhibiting PTGS2 ubiquitination, which is mediated by the E3 ligase MDM2. Moreover, like EIF3B, silencing PTGS2 could suppress MM development, and more interestingly, it could reverse the situation caused by overexpression of EIF3B in vitro and in vivo. Furthermore, the proliferation and migration inhibited by silencing of EIF3B were also partially recovered by overexpression of PTGS2. Overall, our findings revealed the potential of EIF3B as a therapeutic target for MM. Identification of EIF3B's function in MM may pave the way for future development of more specific and more effective targeted therapy strategies against MM.

Efficacy and Safety of Botulinum Toxin Type A in the Treatment of Benign Parotid Hypertrophy: A Prospective Study.

BACKGROUND: Benign parotid hypertrophy makes the earlobe area appear swollen and weakens the lateral facial contour and aesthetics. Efficacious treatment for benign parotid hypertrophy is not available. The authors evaluated the efficacy and safety of botulinum toxin type A for benign parotid hypertrophy treatment. METHODS: Thirty-six participants with benign parotid hypertrophy were enrolled and treated with botulinum toxin type A injection. After 6 months of follow-up, changes in the thickness and length of the superficial lobe of the parotid gland were assessed. Analyses of patient subgroups and image analyses were also undertaken to assess improvement. RESULTS: Thirty-three participants completed this study. Superficial lobe of the parotid gland thickness was reduced significantly after botulinum toxin type A injection, but the longitudinal diameter of the parotid gland was not changed significantly ( p < 0.001 and p = 0.146, respectively). Subgroup analyses showed that the degree of parotid gland hypertrophy affected treatment efficacy and degree of improvement, but age and sex did not ( p < 0.001, p = 0.137, and p = 0.138, respectively). Image analyses showed improvement in the facial contour ( p < 0.05). Serious adverse reactions or complications were not observed. CONCLUSION: Botulinum toxin type A can be used to treat benign parotid hypertrophy, reduce parotid gland volume, and improve the facial contour. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, IV.

Lasers and Intense Pulsed Light for the Treatment of Pathological Scars: A Network Meta-Analysis.

BACKGROUND: Laser and intense pulsed light (IPL) therapies have shown promising effects on pathological scars, but the comparative effectiveness of laser and IPL therapies has not yet been studied. OBJECTIVES: The aim of this study was to compare and rank the efficacy of laser and IPL therapies to determine the most effective treatment method for pathological scars. METHODS: Relevant studies published up to February 2022 were identified by searching PubMed, Web of Science, Cochrane Library, CNKI, and Wanfang databases. We defined Vancouver Scar Scale score as the primary outcome. Both frequentist and Bayesian approaches were used to perform a network meta-analysis. RESULTS: We included 25 trials with a total of 1688 participants. The rankings based on the surface under the cumulative ranking curve for the Vancouver Scar Scale score based on the Bayesian approach suggested IPL + CO2 (96.43%) > pulsed dye laser (PDL) + 1064-nm Nd:YAG (yttrium aluminum garnet) laser (86.21%) > PDL + CO2 (82.15%) > CO2 (58.97%) > 1064-nm Nd:YAG (57.03%) > PDL (52%) > 532-nm Nd:YAG (33.28%) > Er:YAG + IPL (28.38%) > Er:YAG (26.56%) > IPL (15.03%) > control (13.97%). The ranking results based on the frequentist approach were basically consistent with those based on the Bayesian approach. CONCLUSIONS: The results of the network meta-analysis showed that the combination of IPL and CO2 laser has the highest probability of being the most effective intervention. However, our conclusions must be interpreted with caution due to the relatively few evaluation indicators included in our study. Future well-designed randomized controlled trials with large sample sizes are required to confirm our conclusions.

Thermal and moisture response to land surface changes across different ecosystems over Heilong-Amur River Basin.

The Heilong-Amur River Basin (HARB) in Northeast Asia has experienced distinct land surface changes during the past 40 years due to extensive ecological restoration programs, agricultural management, and grassland grazing in different ecosystems. However, the regional climate impact caused by the long-term spatially heterogeneous land surface changes in this mid-high latitude region is not well documented. Therefore, this study used multi-source satellite measurements records and a high-resolution land-atmosphere coupled regional climate model (WRF) to investigate the land surface changes and their associated thermal and moisture impacts across three main ecosystems over the Heilong-Amur River basin from 1982 to 2018. Firstly, satellite observations indicated an overall greening in HARB, with variations across ecosystems. The significant summer farmland greening is the most representative, with the farmland green vegetation fraction (GVF) remarkably increasing by 7.78% in summer. The forest greening magnitude is stronger in spring (3.42%) than in summer (2.85%), while the grassland vegetation showed some local browning signals in summer. Secondly, our simulated results showed the summer farmland greening accelerated evapotranspiration (ET) by 0.161 mm/d and significantly cools the surface temperature by 0.508 °C averaged at the ecosystem scale, which was highly correlated with the satellite observations but with lower cooling magnitude. The forest greening brought less surface cooling in spring than summer due to the stronger albedo feedback, despite with greater increase in GVF and ET. While with the opposite process, the local grassland browning leads to consistent warming effects, which can be detected from both satellite observations and our simulation results. Finally, our results also found that rainfall increasing averagely at the ecosystem scale can't fully compensate the water emission from enhanced ET due to the surface greening, contributing to soil moisture decline in both farmland and relative dry forests.

Identification and functional analysis of a three-miRNA ceRNA network in hypertrophic scars.

BACKGROUND: Hypertrophic scar (HTS) is a fibrotic disorder of skins and may have repercussions on the appearance as well as functions of patients. Recent studies related have shown that competitive endogenous RNA (ceRNA) networks centering around miRNAs may play an influential role in HTS formation. This study aimed to construct and validate a three-miRNA (miR-422a, miR-2116-3p, and miR-3187-3p) ceRNA network, and explore its potential functions. METHODS: Quantitative real­time PCR (qRT­PCR) was used to compare expression levels of miRNAs, lncRNAs, and genes between HTS and normal skin. Target lncRNAs and genes of each miRNA were predicted using starBase as well as TargetScan database to construct a distinct ceRNA network; overlapping target lncRNAs and genes of the three miRNAs were utilized to develop a three-miRNA ceRNA network. For every network, protein-protein interaction (PPI) network analysis was performed to identify its hub genes. For each network and its hub genes, Gene Oncology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis were conducted to explore their possible functions. RESULTS: MiR-422a, miR-2116-3p, and miR-3187-3p were all downregulated in HTS tissues and fibroblasts. MiR-422a-based ceRNA network consisted of 101 lncRNAs with 133 genes; miR-2116-3p-centered ceRNA network comprised 85 lncRNAs and 978 genes; miR-3187-3p-derived ceRNA network encompassed 84 lncRNAs as well as 1128 genes. The three-miRNA ceRNA network included 2 lncRNAs with 9 genes, where MAPK1, FOSL2, ABI2, KPNA6, CBL, lncRNA-KCNQ1OT1, and lncRNA-EBLN3P were upregulated. According to GO and KEGG analysis, these networks were consistently related to ubiquitination. Three ubiquitination-related genes (CBL, SMURF2, and USP4) were upregulated and negatively correlated with the expression levels of the three miRNAs in HTS tissues. CONCLUSIONS: This study identified a three-miRNA ceRNA network, which might take part in HTS formation and correlate with ubiquitination.

The effect of botulinum toxin injection dose on the appearance of surgical scar.

Early postoperative injection of botulinum toxin type A (BTxA) can reduce surgical scar hypertrophy. BTxA injection at different time points is associated with different levels of efficacy, but the efficacy of different doses of BTxA for scar management has not investigated. The purpose of this study was to investigate the effect of different doses of BTxA administered early after surgery on scar improvement through a split-scar experiment. The study included 22 patients who underwent surgery between September 2019 and October 2020. High- and low-dose BTxA was randomly administered into each half of the surgical wound closure immediately after surgery. One half of the incision was injected with a low dose (4 U) of BTxA, and the other half was injected with a high dose (8 U). The scars were then evaluated at postoperative 6 months using the modified Stony Brook Scar Evaluation Scale (mSBSES), and patient satisfaction was evaluated using the Visual Analogue Scale (VAS). The occurrence of complications or adverse events was also recorded. Twenty patients completed the study and were analyzed. Compared with the low-dose sides, the high-dose sides had significantly better mSBSES scores and significantly higher VAS scores (p < 0.01, respectively). No serious adverse reactions or post-injection complications were observed. Immediately after the operation, high-dose BTxA (that is within the therapeutic range) injection improved the appearance of postoperative scar more than low-dose injection.

Circ_PRKDC knockdown promotes skin wound healing by enhancing keratinocyte migration via miR-31/FBN1 axis.

Circular RNA protein kinase, DNA-activated, catalytic subunit (circ_PRKDC) has been found to impede wound healing in diabetic foot ulcers via regulating keratinocyte proliferation and migration. However, the mechanisms underlying circ_PRKDC in skin wound healing remain unclear. The expression of circ_PRKDC, microRNA (miR)-31 and fibrillin 1 (FBN1) was detected using quantitative reverse transcription-polymerase chain reaction and Western blot assays. The migration ability and the changes of matrix metallopeptidase 9 (MMP-9) and MMP2 levels were determined using wound healing, transwell and Western blot assays. The interaction between miR-31 and circ_PRKDC or FBN1 was verified by dual-luciferase reporter assay. The expression of circ_PRKDC was gradually down-regulated in wound edge at 1 and 7 days after injury relative to the unwounded skin. In human epidermal keratinocytes (HEKa), knockdown of circ_PRKDC promoted cell migration partly through up-regulating MMP-2 and MMP9, while circ_PRKDC overexpression showed opposite effects. In a mechanical study, we confirmed that miR-31 was a target of circ_PRKDC, and inhibition of miR-31 reversed the promotive effect of circ_PRKDC knockdown on HEKa migration. Besides that, miR-31 was verified to target FBN1, and ectopic overexpression of miR-31 accelerated HEKa migration via FBN1. Importantly, we also demonstrated that FBN1 overexpression attenuated the effects of circ_PRKDC knockdown on HEKa migration. In all, circ_PRKDC knockdown promoted HEKa migration during wound healing through miR-31/FBN1 axis, suggesting the therapeutic potential for circ_PRKDC on skin wound healing.