Exploration of the optimal time to discontinue propranolol treatment in infantile hemangiomas: A prospective study.

BACKGROUND: Relapse of infantile hemangiomas after withdrawal from propranolol treatment is common. Early withdrawal is believed to increase the risk of relapse. OBJECTIVE: The objective of this study was to determine the optimal time to discontinue propranolol treatment for infantile hemangiomas. METHODS: A prospective study conducted at a tertiary referral center. RESULTS: Compared to withdrawal after 1-month maintenance treatment, withdrawal after 3-month maintenance, corresponding achieving maximum regression of infantile hemangiomas, was associated with a lower major relapse rate (P = .041). The relapse (P = .055) and adverse event rates (P = .154) between the 2 withdrawal modes were not statistically significant. Compared with direct withdrawal, the relapse (P = .396), major relapse (P = .963), and adverse event rates (P = .458) of gradual withdrawal were not statistically different. Patients with/without relapse could be best distinguished according to whether withdrawal followed a 3-month maintenance and age >13 months (area under the receiver operating characteristic curve = 0.603). Patients with/without major relapse could be best distinguished according to whether withdrawal was accompanied by 3-month maintenance (area under the receiver operating characteristic curve = 0.610). LIMITATIONS: The limitations of this study are nonrandomization and single-center design. CONCLUSIONS: The optimal propranolol withdrawal time to avoid relapse is when the patient is aged >13 months and the lesion has maintained for 3 months after reaching maximum regression, while the optimal time to prevent major relapse is after 3 months of maintenance.

KIAA1429 promotes infantile hemangioma regression by facilitating the stemness of hemangioma endothelial cells.

Infantile hemangiomas are common vascular tumors with a specific natural history. The proliferation and regression mechanism of infantile hemangiomas may be related to the multilineage differentiation ability of hemangioma stem cells, but the specific mechanism is not well elucidated. KIAA1429 is an N6 -methyladenosine methylation-related protein that can also exert its role in a methylation-independent manner. This study aims to explore the function of KIAA1429 in infantile hemangiomas. qRT-PCR, western blotting, and immunostaining were performed to verify the expression of KIAA1429. The endothelial and fibroblast-like phenotypes of hemangioma endothelial cells were detected after KIAA1429 knockdown and overexpression. The stemness properties of hemangioma endothelial cells and the underlying mechanism of KIAA1429 in hemangiomas were also investigated. Nude mouse models of infantile hemangiomas were conducted to ascertain the effects of KIAA1429 in vivo. The results showed that KIAA1429 was highly expressed in infantile hemangiomas, particularly in involuting hemangiomas. In vitro experiments confirmed that KIAA1429 inhibited the endothelial phenotype, enhanced the differentiation ability, and promoted the fibroblast-like phenotype of hemangioma endothelial cells by inducing endothelial cell transition to facultative stem cells. However, the effect of KIAA1429 on the potential target was shown to be independent of N6 -methyladenosine methylation modification. Mouse models further revealed that KIAA1429 could inhibit the proliferation and promote the regression of hemangiomas. In conclusion, this study found that KIAA1429 played an important role in the regression of infantile hemangiomas by enhancing the stemness of hemangioma endothelial cells and could be a potential treatment target for infantile hemangiomas.

Giant dorsal lipofibromatosis in an infant: a case report.

BACKGROUND: Lipofibromatosis is a rare, benign, soft tissue tumor that usually presents in children. Low incidence and lack of specificity in clinical presentation make its diagnosis difficult. CASE PRESENTATION: This is a case report of a patient with a giant lipofibromatosis on the back that resembles an infantile hemangioma, which posed great difficulty in diagnosis due to atypical clinical manifestations. After the postoperative pathological and immunohistochemical examination and fluorescence in situ hybridization, the patient was finally diagnosed with lipofibromatosis. CONCLUSIONS: The incidence of fibromatosis was low. This case presents an atypical clinical manifestation since the tumor growth was on the back, and this can easily cause misdiagnosis. This case suggests that the diagnosis of lipofibromatosis depends on the pathology and fluorescence in situ hybridization.

Propranolol suppresses HUVEC viability, migration, VEGF expression, and promotes apoptosis by downregulation of miR-4295.

Infantile hemangioma (IH) is a common benign tumor. Human umbilical vein endothelial cells (HUVECs) have the potential of stem cells, which has been widely used in vascular endothelial cell experiments. Oral propranolol was first reported to treat hemangioma in 2008. However, the role of propranolol in IH remains unclear. Therefore, in this study, we investigated the effects of propranolol on HUVECs in vitro, to explore the underlying mechanism of propranolol in IH. HUVECs were treated with 0.15, 1.5, and 15 µM of propranolol, and transfected with microRNA-4295 (miR-4295) mimic. Cell viability, migration, and apoptosis were examined using Cell Counting Kit-8, transwell assay, and flow cytometry analysis, respectively. In addition, the expressions and concentrations of miR-4295, vascular endothelial growth factor (VEGF), VEGF-A, FLT1, FLT2, and FOXF1 were assessed using real-time polymerase chain reaction, Western blot assay, and enzyme-linked immunosorbent assay. We found that 15 µM of propranolol decreased HUVEC viability the most. Then, cell migration and the concentrations of VEGF and VEGF-A were reduced, and apoptosis was increased when treated with propranolol. Meanwhile, the expressions of VEGF, VEGF-A, FLT1, FLT2, and FOXF1 were downregulated by propranolol exposure. Further study showed that miR-4295 expression was upregulated in IH tissues, and propranolol treatment downregulated miR-4295 expression in HUVECs. MiR-4295 overexpression alleviated the reductions of viability, migration, and factors expression, as well as the increase of apoptosis. Propranolol suppressed HUVEC viability, migration, the expression of VEGF, VEGF-A, FLT1/2, FOXF1, and promoted apoptosis via downregulation of miR-4295. This study lays a foundation for further study of the effect of propranolol on IH.

Long noncoding RNA expression profile of infantile hemangioma identified by microarray analysis.

Infantile hemangioma (IH) is one of the most common vascular tumors of childhood. Long noncoding RNAs (lncRNAs) play a critical role in angiogenesis, but their involvement in hemangioma remains unknown. This study aimed to assess the expression profiles of lncRNAs in IH and adjacent normal tissue samples, exploring the biological functions of lncRNAs as well as their involvement in IH pathogenesis. The lncRNA expression profiles were determined by lncRNA microarrays. A total of 1259 and 857 lncRNAs were upregulated and downregulated in IH, respectively, at a fold change cutoff of 2.0 (p < 0.05); in addition, 1469 and 1184 messenger RNAs (mRNAs) were upregulated and downregulated, respectively (fold change cutoff of 2.0; p < 0.05). A total of 292 differentially expressed mRNAs were targeted by the lncRNAs with altered expression in hemangioma, including 228 and 64 upregulated and downregulated, respectively (cutoff of 2.0, p < 0.05). Gene ontology (GO) analyses revealed several angiogenesis-related pathways. An lncRNA-mRNA co-expression network for differentially expressed lncRNAs revealed significant associations of the lncRNAs MEG3, MEG8, FENDRR, and Linc00152 with their related mRNAs. The validation results of nine differentially expressed lncRNAs (MALAT1, MEG3, MEG8, p29066, p33867, FENDRR, Linc00152, p44557_v4, p8683) as well as two mRNAs (FOXF1, EGFL7) indicated that the microarray data correlated well with the QPCR results. Interestingly, MALAT1 knockdown induced apoptosis and S-phase cell cycle arrest in human umbilical vein endothelial cells (HUVECs). Overall, this study revealed the lncRNA expression profile of IH and that lncRNAs likely regulate several genes with important roles in angiogenesis.

Comprehensive Treatment and Gene Analysis of a Male Patient with Follicular Occlusion Tetrad with Fordyce Granules.

Follicular occlusion tetrad (FOT) is a chronic inflammatory skin disease that seriously affects patients' quality of life. At present, there is no standard treatment plan for FOT. We report the case of a 50-year-old male patient diagnosed as having FOT with Fordyce granules and type 2 diabetes mellitus. During hospitalization, the patient received comprehensive and systematic treatment. The patient healed well after surgery and the 10-month follow-up revealed no recurrence. We found eight gene mutations by whole-exome sequencing (WES) of the patient's peripheral blood.

Bioactive Wound Healing 3D Structure Based on Chitosan Hydrogel Loaded with Naringin/Cyclodextrin Inclusion Nanocomplex.

The current assay aimed to fabricate and analyze a potent wound healing structure based on a naringin (Nar)/ß-cyclodextrin (ß-CD)-loaded chitosan hydrogel. Using the simulation studies, we assessed the interactions among the Nar, ß-CD, and the formation of the inclusion complex. Then, the formation of the hydrogel nanocomplex was simulated and evaluated using the in silico methods. The results showed that after optimization of the structures by DMol3 based on DFT-D, the total energies of Nar, GP, CD, and ß-CD were calculated at -2100.159, -912.192, -3778.370, and -4273.078 Ha, respectively. The encapsulation energy of Nar on ß-CD in the solvent phase was calculated at -93.626 kcal/mol, and the Nar structure was located inside ß-CD in solution. The negative interaction energy value for the encapsulation of Nar on ß-CD suggests the exothermic adsorption process and a stable structure between Nar and ß-CD. Monte Carlo method was applied to obtain adsorption of CS/GP on Nar/ß-CD. Its value of the obtained interaction energy was calculated at -1.423 × 103 kcal/mol. The characterization confirmed the formation of a Nar/ß-CD inclusion complex. The Zeta potential of the pristine ß-CD changed from -4.60 ± 1.1 to -17.60 ± 2.34 mV after interaction with Nar, and the heightened surface negativity can be attributed to the existence of electron-rich naringin molecules, as well as the orientation of the hydroxyl (OH) group of the ß-CD toward the surface in an aqueous solution. The porosity of the fabricated hydrogels was in the range of 70-90% and during 14 days around 47.0 ± 3.1% of the pure hydrogel and around 56.4 ± 5.1 of hydrogel nanocomposite was degraded. The MTT assay showed that the hydrogels were biocompatible, and the wound contraction measurement (in an animal model) showed that the closure of the induced wound in the hydrogel nanocomposite treatment was faster than that of the control group (wound without treatment). The results of this study indicate that the developed bioactive wound healing 3D structure, which is composed of a chitosan hydrogel containing a Nar/ß-CD inclusion nanocomplex, has potential as an effective material for wound dressing applications.

Osteomodulin contributes to keloid development by regulating p38 MAPK signaling.

A keloid is a classic fibrotic skin disease characterized by excessive deposition of extracellular matrix (ECM). Osteomodulin (OMD) is a heterologous protein that is a part of osteoadherin and plays a role in modulating ECM deposition. In this study, we investigated the effects of OMD on ECM synthesis and the tumor-like phenotype of keloid fibroblasts. We enrolled 10 patients with keloids and 10 age- and sex-matched healthy individuals, whose keloid or normal skin tissues were collected during surgery. Real-time quantitative polymerase chain reaction (qRT-PCR), western blotting, and immunohistochemical staining were performed to analyze OMD expression in skin tissues. Cell transfection, CCK-8 assay, EdU staining, Transwell assay, qRT-PCR, western blotting, and immunofluorescence were performed to study the effects of OMD on primary keloid-derived fibroblasts (KFs). OMD exhibited greater expression in human keloid specimens than in normal skin tissues. Consistently, higher expression of OMD was observed in KFs, compared to that in normal fibroblasts. Silencing OMD expression in transforming growth factor (TGF)-ß1-treated KFs inhibited cell proliferation and migration, as well as collagen and fibronectin expression; however, overexpression of OMD had the opposite effect. p38 mitogen-activated protein kinase (MAPK) was activated in keloid tissues but not in normal skin. OMD was positively correlated with p38 MAPK activation. Adding SB203580, p38 MAPK inhibitor, significantly reversed the effects of OMD on the regulation of KF phenotype. The high expression of OMD may contribute to hyperproliferation of KFs, their migration, and excess ECM synthesis in KFs via regulation of the p38 MAPK signaling pathway.

A Rare Case Report of Neonatal Neurofibromatosis Type 1 Presented with Giant Faciocervical Mass and Complicated with HIE.

A newborn with giant faciocervical mass and presented with asphyxia during birth was admitted to the hospital. After stabilizing her vital sign, we provided the patient with image examinations and whole-exome sequencing, which revealed a heterozygous variation of neurofibromatosis type 1 (NF1). The final diagnosis of the patient was NF1 complicated with neonatal hypoxic-ischemic encephalopathy (NHIE). During hospitalization, the patient received comprehensive and systematic care. There was no reports of similar cases in the literature. So, this report aimed to elucidate the special clinical manifestations, diagnosis, treatment and prognosis of NF1 complicated with NHIE by analyzing the clinical data of the patient and her family and reviewing relevant literature.

Delayed Inflammatory Reactions After Hyaluronic Acid Filling of Neck Lines: A Case Report.

The incidence of adverse events after hyaluronic acid filling is gradually increasing. In addition to acute reactions in the early postoperative period, there have been some cases of delayed inflammatory reactions. However, such events are rarely reported in Asia, which may be due to atypical symptoms, long intervals, and misidentification of the product quality. Herein, we present a case in which erythema of the neck appeared three weeks after hyaluronic acid injection into the neck lines and a delayed inflammatory reaction was diagnosed. Watchful waiting was performed, and the erythema subsided spontaneously after two weeks. This case suggests that in patients with a history of hyaluronic acid injections who develop allergic and inflammatory reactions after an interval, it is important to consider whether the reaction is a delayed inflammatory reaction, and if aggressive intervention is necessary.

Does autologous fat grafting serve the need for reconstructive surgery in oral cancer patients? A prospective evaluation in cosmetic surgery patients.

BACKGROUND: The prevalence of cancer is growing daily. Oral cancer, which is primarily triggered by tobacco use, can have detrimental effects on facial appearance. Despite significant advances in the molecular underpinnings of cancer, surgery, chemotherapy and radiotherapy have become standard cancer treatment methods. These treatments remove the tumor but can significantly alter patient's appearance, which can impact their physical and mental wellbeing. The soft tissue augmentation technique of autologous fat grafting (AFG), commonly referred to as lipofilling, is frequently used in cosmetic and reconstructive surgery to promote facial rejuvenation and body form remodeling. The advantages of AFG include its biocompatibility, low immunogenicity and allergenicity, as well as its capability to heal wounds. OBJECTIVES: To explore the advantages of and patient satisfaction with the AFG technique as a potential facial restoration procedure in oral cancer patients. MATERIAL AND METHODS: We examined the effects of facial AFG in cosmetic surgery patients and investigated the prevalence of postoperative problems. Patient satisfaction and potential complications after autologous fat filling in different areas of the facial space were investigated using clinical evaluations, patient-reported outcomes and photographic assessments. RESULTS: All of the patients were satisfied with the results in terms of improved facial shape, skin glossiness, skin elasticity, ptosis, and facial expressions. More than 80% of the patients and surgeons reported overall satisfaction. CONCLUSIONS: Based on these findings, we hypothesize that the AFG approach may be beneficial as a reconstructive therapy for patients with oral cancer following treatment. This technique will improve the patient's physical appearance, confidence and mental wellbeing.

M2 Macrophage-Derived Exosomal lncRNA MIR4435-2HG Promotes Progression of Infantile Hemangiomas by Targeting HNRNPA1.

Purpose: Infantile hemangiomas (IHs) are commonly observed benign tumors that can cause serious complications. M2-polarized macrophages in IHs promote disease progression. In this study, we investigated the role of M2 macrophage-derived exosomal lncRNA MIR4435-2HG in IHs. Patients and Methods: Exosomes derived from M2 polarized macrophages were extracted. Next, using cell co-culture or transfection, we investigated whether M2 polarized macrophage-derived exosomes (M2-exos) can transport MIR4435-2HG to regulate the proliferation, migration, invasion, and angiogenesis of hemangioma-derived endothelial cells (HemECs). RNA-seq and RNA pull-down assays were performed to identify targets and regulatory pathways of MIR4435-2HG. We explored the possible mechanisms through which MIR4435-2HG regulates the biological function of HemECs. Results: M2-exos significantly enhanced the proliferation, migration, invasion, and angiogenesis of HemECs. Thus, HemECs uptake M2-exos and promote biological functions through the inclusion of MIR4435-2HG. RNA-seq and RNA pull-down experiments confirmed that MIR4435-2HG regulates of HNRNPA1 expression and directly binds to HNRNPA1, consequently affecting the NF-κB signal pathway. Conclusion: MIR4435-2HG of M2-exos promotes the progression of IHs and enhances the proliferation, migration, invasion, and angiogenesis of HemECs by directly binding to HNRNPA1. This study not only reveals the mechanism of interaction between M2 macrophages and HemECs, but also provides a promising therapeutic target for IHs.

Exosomes from human adipose-derived mesenchymal stem cells inhibit production of extracellular matrix in keloid fibroblasts via downregulating transforming growth factor-ß2 and Notch-1 expression.

Keloids are an excessive tissue response to dermal damage, characterized by uncontrolled growth and a high recurrence rate after various treatments. Abnormalities with the extracellular matrix (ECM) are one of the most important contributing factors to the formation of keloids. Although exosomes from human adipose-derived mesenchymal stem cells (adMSC-Exos) have been shown to promote repair and regeneration in wounds, they have seldom been studied for the treatment of keloids. In this study, we aimed to investigate the effects of adMSC-Exos on ECM remodeling in keloids using both in vitro and ex vivo models. The results showed that adMSC-Exos inhibited gene and protein expression of collagen I (COL-1), collagen III (COL-3), fibronectin (FN), and α-smooth muscle actin (α-SMA) in keloid fibroblasts (KFs). Furthermore, using an ex vivo tissue explant model, we found that adMSC-Exos significantly suppressed COL production and disrupted the microvessel stucture. We also demonstrated that adMSC-Exos inhibited the protein expression of Smad3 and Notch-1, and the expression of transforming growth factor ß2 (TGF-ß2) in KFs, and promoted the expression of TGF-ß3. These findings largely explain the mechanisms underlying the inhibition of ECM production in keloids by adMSC-Exos. In conclusion, our results revealed that adMSC-Exos effectively inhibited the production of ECM in keloids, which provides a new potential alternative for the systemic treatment of keloids.

Sclerotherapy in Lymphatic Malformations with Intralesional Hemorrhage: A Retrospective Comparison with Non-Hemorrhagic Lymphatic Malformations.

Purpose: To compare the outcomes of sclerotherapy with bleomycin and lauromacrogol between lymphatic malformations (LM) with and without intralesional hemorrhage and identify the factors affecting the outcomes of LM with hemorrhage. Patients and Methods: This retrospective study examined patients with LM who underwent sclerotherapy with bleomycin and lauromacrogol between January 2019 and December 2021. Regression models were used to analyze the factors associated with the outcomes of LM with hemorrhage. Results: 52 patients were included in the study, including 26 with intralesional hemorrhage. Masses with bluish skin (p = 0.026) and pain (p = 0.001) were more common in LM with hemorrhage. With similar outcomes, the average number of sessions was 2.9 in LM with hemorrhage and 2 in LM without hemorrhage (p = 0.028). The efficacies of the macrocystic and mixed types (93.3% and 83.3%, respectively) were higher than that of the microcystic type (40%) (p = 0.036). As the number of sessions increased, the relapse rate decreased (p = 0.018). Conclusion: Sclerotherapy with bleomycin and lauromacrogol is effective and safe for LM with hemorrhage. An increased number of injections for patients with hemorrhage was associated with similar efficacy for those without hemorrhage and similar relapse rates.

Skin Wound Tension Reduction Device Combined with Ablative Fractional Carbon Dioxide Laser to Reduce Scar Formation After Excision of Pediatric Facial Skin Lesions: A Prospective Cohort Study.

PURPOSE: To investigate the efficacy of skin wound tension reduction device (SWTRD) combined with ablative fractional carbon dioxide laser (CO2-AFL) for the prevention of scar formation following the excision of facial cutaneous lesions in children. METHODS: Patients undergoing surgical excision of facial cutaneous lesions in our hospital between May 2019 and April 2021 were enrolled. After the excision of facial cutaneous lesions and based on the personal intents and conditions, patients were assigned to undergo SWTRD combined with CO2-AFL. Outcome evaluations were as follows: defect size, incision width, scar width, the Vancouver Scar Scale (VSS) and University of North Carolina 4P Scar Scale (UNC4P). RESULTS: A total of 25 pediatric patients (mean age, 9.88 years) were enrolled in the study. Following the treatment of SWTRD+CO2-AFL, scar widths were relatively narrow and the appearance of the incision scars was significantly improved. A significant reduction in the patient-reported UNC4P scores at 6 months (3, 1-4) was observed when compared with that at 2 months (0, 0-1) after surgery (p<0.001). A similar reduction in the VSS scar scale was also evident (6 months: 1, 0.75-2.5 vs 2 months: 6.5-8.5; p<0.001). CONCLUSION: Combined SWTRD and CO2-AFL treatment effectively modulates the scar formation after the incision is healed and resulting in preventing scar widening, leading to the improvement of scar appearance, reduction in wound pain and pruritus and its overall prognosis.

Circular RNA expression profiles in the plasma of patients with infantile hemangioma determined using microarray analysis.

Circular RNAs (circRNAs) are noncoding RNAs that have important roles in tumor progression. Previous studies have examined the circRNAs involved in infantile hemangioma (IH) tumors. The present study compared the circRNA levels in plasma samples from patients with IH and control individuals. The circRNA expression profiles were determined using microarray in three pairs of plasma samples from patients with proliferative IH and healthy control subjects. Expression of the identified differentially expressed circRNAs was verified using reverse transcription-quantitative PCR (RT-qPCR) and a bioinformatics analysis was performed to predict the microRNAs targeted by the validated circRNAs. From the circRNA expression profiles in the plasma of patients with IHs, 128 differentially expressed circRNAs were identified, of which 72 were upregulated and 56 were downregulated. The downregulated expression of three circRNAs [Homo sapiens (hsa)_circRNA_101566, hsa_circRNA_103546 and hsa_circRNA_103573] was verified using RT-qPCR. Gene Ontology term and Kyoto Encyclopedia of Genes and Genomes pathway analyses indicated that all identified networks participated in angiogenesis and tumor formation and progression. It was determined that hsa_circRNA_101566, which is able to regulate the mTOR signaling pathway, may be an important regulatory molecule in IH development and that targeting of hsa_miR_520c is able to indirectly regulate the vascular endothelial growth factor signaling pathway. Further studies are required to clarify these effects and the underlying mechanisms.

Oral propranolol therapy in parotid hemangiomas: A retrospective comparison with other infantile hemangiomas.

BACKGROUND: The outcomes of propranolol treatment remain controversial for parotid hemangiomas, which may be inferior to outcomes for infantile hemangiomas (IHs) at other sites. METHODS: Patients with IHs treated with oral propranolol were retrospectively reviewed. Outcomes of propranolol therapy for parotid hemangiomas and other IHs were examined. Regression models were conducted to analyze the factors associated with the outcomes for parotid hemangiomas. RESULTS: Longer treatment duration was needed for parotid hemangiomas (p = 0.012) at a comparable efficacy and relapse rate as those of IHs at other sites. The higher efficacy was associated with early intervention before 4 months of age (OR = 5.2, p = 0.011), while, the lower relapse rate was associated with adequate treatment duration over 6 months (OR = 9.2, p = 0.010). CONCLUSIONS: With a longer propranolol treatment duration, parotid hemangiomas could achieve a comparable efficacy and relapse rate as other IHs. Early treatment initiation and adequate treatment duration benefited the outcomes.

Identification of ACTA2 as a Key Contributor to Venous Malformation.

Objectives: Proteomics and high connotation functional gene screening (HCS) were used to screen key functional genes that play important roles in the pathogenesis of venous malformation. Furthermore, this study was conducted to analyze and explore their possible functions, establish a gene mutation zebrafish model, and perform a preliminary study to explore their possible pathogenic mechanisms in venous malformation. Methods: Pathological and normal tissues from patients with disseminated venous malformation were selected for Tandem Mass Tag (TMT) proteomics analysis to identify proteins that were differentially expressed. Based on bioinformatics analysis, 20 proteins with significant differential expression were selected for HCS to find key driver genes and characterize the expression of these genes in patients with venous malformations. In vitro experiments were then performed using human microvascular endothelial cells (HMEC-1). A gene mutant zebrafish model was also constructed for in vivo experiments to explore gene functions and pathogenic mechanisms. Results: The TMT results showed a total of 71 proteins that were differentially expressed as required, with five of them upregulated and 66 downregulated. Based on bioinformatics and proteomics results, five highly expressed genes and 15 poorly expressed genes were selected for functional screening by RNAi technology. HCS screening identified ACTA2 as the driver gene. Quantitative polymerase chain reaction (qPCR) and western blot were used to detect the expression of ACTA2 in the pathological tissues of patients with venous malformations and in control tissues, and the experimental results showed a significantly lower expression of ACTA2 in venous malformation tissues (P < 0.05). Cell assays on the human microvascular endothelial cells (HMEC-1) model showed that cell proliferation, migration, invasion, and angiogenic ability were all significantly increased in the ACTA2 over-expression group (P < 0.05), and that overexpression of ACTA2 could improve the inhibitory effect on vascular endothelial cell proliferation. We constructed an ACTA2-knockdown zebrafish model and found that the knockdown of ACTA2 resulted in defective vascular development, disruption of vascular integrity, and malformation of micro vein development in zebrafish. Further qPCR assays revealed that the knockdown of ACTA2 inhibited the Dll4/notch1 signaling pathway, Ephrin-B2 signaling pathway, and vascular integrity-related molecules and activated the Hedgehog signaling pathway. Conclusion: This study revealed that ACTA2 deficiency is an important factor in the pathogenesis of venous malformation, resulting in the disruption of vascular integrity and malformed vascular development. ACTA2 can be used as a potential biomarker for the treatment and prognosis of venous malformations.

CXCL2 Impairs Functions of Bone Marrow Mesenchymal Stem Cells and Can Serve as a Serum Marker in High-Fat Diet-Fed Rats.

In modern society excessive consumption of a high-fat diet (HFD) is a significant risk factor for many diseases such as diabetes, osteoarthritis and certain cancers. Resolving cellular and molecular mechanisms underlying HFD-associated disorders is of great importance to human health. Mesenchymal stem cells (MSCs) are key players in tissue homeostasis and adversely affected by prolonged HFD feeding. Low-grade systemic inflammation induced by HFD is characterized by increased levels of pro-inflammatory cytokines and alters homeostasis in many organs. However, whether, which and how HFD associated inflammatory cytokines impair MSCs remain unclear. Here we demonstrated that HFD induced serum cytokines disturbances, especially a continuous elevation of serum CXCL2 level in rats. Coincidentally, the differentially expressed genes (DEGs) of bone marrow MSCs (BMSCs) which functions were impaired in HFD rats were enriched in cytokine signaling. Further mechanism analysis revealed that CXCL2 treatment in vitro suppresses the adipogenic potential of BMSCs via Rac1 activation, and promoted BMSC migration and senescence by inducing over-production of ELMO1 and reactive oxygen species (ROS) respectively. Moreover, we found that although glycolipid metabolism indicators can be corrected, the CXCL2 elevation and BMSC dysfunctions cannot be fully rescued by diet correction and anti-inflammatory aspirin treatment, indicating the long-lasting deleterious effects of HFD on serum CXCL2 levels and BMSC functions. Altogether, our findings identify CXCL2 as an important regulator in BMSCs functions and may serve as a serum marker to indicate the BMSC dysfunctions induced by HFD. In addition, our findings underscore the intricate link among high-fat intake, chronic inflammation and BMSC dysfunction which may facilitate development of protective strategies for HFD associated diseases.

Characterization of epigenetic and transcriptional landscape in infantile hemangiomas with ATAC-seq and RNA-seq.

Aim: This study was conducted to reveal epigenetic landscape in infantile hemangiomas (IHs) and identify transcription factors (TFs) and their downstream genes active in IHs. Materials & methods: We performed Assay for Transposase Accessible Chromatin (ATAC-seq) with RNA-seq in three pairs of IHs and their adjacent normal tissues. Functions of candidate TFs were investigated in human umbilical vein endothelial cells (HUVECs). Results: Chromatin of IH tissues is less compact. Some candidate genes and TFs were identified. In HUVECs, SPDEF inhibited cell viability and tube formation, and promoted apoptosis; SOX4 exerted the opposite effect. SPDEF may act through EPHA5, ZBTB46 and SASH1; SOX4 may act through MMP12 and HIVEP3. Conclusion: Epigenetics plays a role in IHs. SPDEF and SOX4 may act in IHs.