Exosomes from circ-Astn1-modified adipose-derived mesenchymal stem cells enhance wound healing through miR-138-5p/SIRT1/FOXO1 axis regulation

BACKGROUND Wound healing impairment is a dysfunction induced by hyperglycemia and its effect on endothelial precursor cells(EPCs)in type 2 diabetes mellitus.There is increasing evidence showing that exosomes(Exos)derived from adipose-derived mesenchymal stem cells(ADSCs)exhibit the potential to improve endothelial cell function along with wound healing.However,the potential therapeutic mechanism by which ADSC Exos contribute to wound healing in diabetic mice remains unclear.AIM To reveal the potential therapeutic mechanism of ADSC Exos in wound healing in diabetic mice.METHODS Exos from ADSCs and fibroblasts were used for high-throughput RNA sequencing(RNA-Seq).ADSC-Exo-mediated healing of full-thickness skin wounds in a diabetic mouse model was investigated.We employed EPCs to investigate the therapeutic function of Exos in cell damage and dysfunction caused by high glucose(HG).We utilized a luciferase reporter(LR)assay to analyze interactions among circular RNA astrotactin 1(circ-Astn1),sirtuin(SIRT)and miR-138-5p.A diabetic mouse model was used to verify the therapeutic effect of circ-Astn1 on Exo-mediated wound healing.RESULTS High-throughput RNA-Seq analysis showed that circ-Astn1 expression was increased in ADSC Exos compared with Exos from fibroblasts.Exos containing high concentrations of circ-Astn1 had enhanced therapeutic effects in restoring EPC function under HG conditions by promoting SIRT1 expression.Circ-Astn1 expression enhanced SIRT1 expression through miR-138-5p adsorption,which was validated by the LR assay along with bioinformatics analyses.Exos containing high concentrations of circ-Astn1 had better therapeutic effects on wound healing in vivo compared to wild-type ADSC Exos.Immunofluorescence and immunohistochemical investigations suggested that circ-Astn1 enhanced angiopoiesis through Exo treatment of wounded skin as well as by suppressing apoptosis through promotion of SIRT1 and decreased forkhead box O1 expression.CONCLUSION Circ-Astn1 promotes the therapeutic effect of ADSC-Exos and thus improves wound healing in diabetes via miR-138-5p absorption and SIRT1 upregulation.Based on our data,we advocate targeting the circ-Astn1/miR-138-5p/SIRT1 axis as a potential therapeutic option for the treatment of diabetic ulcers.

Therapy-induced senescent tumor cells in cancer relapse

Cellular senescence is characterized by a generally irreversible cell cycle arrest and the secretion of bioactive factors known as the senescence-associated secretory phenotype(SASP).In an oncogenic context,senescence is considered a tumor suppressive mechanism as it prevents cell proliferation and inhibits the progression from pre-malignant to malignant disease.However,recent studies have demonstrated that senescent tumor cells,which could spontaneously exist within cancer tissues or arise in response to various cancer interventions(the so-called therapy-induced senescence,TIS),can acquire pro-tumorigenic properties and are capable of driving local and metastatic relapse.This highlights the complex and multifaceted nature of cellular senescence in cancer biology.Here,we summarize the current knowledge of the pathological function of therapy-induced senescent tumor cells and discuss possible mechanisms by which tumor cell senescence contributes to cancer relapse.We also discuss implications for future studies toward targeting these less appreciated cells.

Hyperbaric oxygen therapy improves the effect of keloid surgery and radiotherapy by reducing the recurrence rate

Objective： Keloids are exuberant cutaneous scars that form due to abnormal growth of fibrous tissue fol- lowing an injury. The primary aim of this study was to assess the efficacy and mechanism of hyperbaric oxygen therapy （HBOT） to reduce the keloid recurrence rate after surgical excision and radiotherapy. Methods： （1） A total of 240 patients were randomly divided into two groups. Patients in the HBOT group （O group） received HBOT after surgical excision and radiotherapy. Patients in the other group were treated with only surgical excision and radiotherapy （K group）. （2） Scar tissue from recurrent patients was collected after a second operation. Hematoxylin and eosin （H＆E） staining was used to observe keloid morphology. Certain inflammatory factors （interleukin-6 （IL-6）, hypoxia-inducible factor-1α （HIF-1α）, tumor necrosis factor-α （TNF-α）, nuclear factor KB （NF-κB）, and vascular endothelial growth factor （VEGF）） were measured using immunohistochemical staining. Results： （1） The recurrence rate of the O group （5.97%） was significantly lower than that of the K group （14.15%）, P〈0.05. Moreover, patients in the O group reported greater satisfaction than those in the K group （P〈0.05）. （2） Compared with the recurrent scar tissue of the K group, the expression levels of the inflammatory factors were lower in the recurrent scar tissue of the O group. Conclusions： Adjunctive HBOT effectively reduces the keloid recurrence rate after surgical excision and radiotherapy by improving the oxygen level of the tissue and alleviating the inflammatory process.

Hyperbaric oxygen treatment on keloid tumor immune gene expression

Background:Hyperbaric oxygen treatment(HBOT)has been demonstrated to influence the keloid recurrence rate after surgery and to relieve keloid symptoms and other pathological processes in keloids.To explore the mechanism of the effect of HBOT on keloids,tumor immune gene expression and immune cell infiltration were studied in this work.Methods:From February 2021 to April 2021,HBOT was carried out on keloid patients four times before surgery.Keloid tissue samples were collected and divided into an HBOT group(keloid with HBOT before surgery[HK]group,n=6)and a non-HBOT group(K group,n=6).Tumor gene expression was analyzed with an Oncomine Immune Response Research Assay kit.Data were mined with R package.The differentially expressed genes between the groups were compared.Hub genes between the groups were determined and verified with Quantitative Real-time PCR.Immune cell infiltration was analyzed based on CIBERSORT deconvolution algorithm analysis of gene expression and verified with immunohistochemistry(IHC).Results:Inflammatory cell infiltration was reduced in the HK group.There were 178 upregulated genes and 217 downregulated genes.Ten hub genes were identified,including Integrin Subunit Alpha M(ITGAM),interleukin(IL)-4,IL-6,IL-2,Protein Tyrosine Phosphatase Receptor Type C(PTPRC),CD86,transforming growth factor(TGF),CD80,CTLA4,and IL-10.CD80,ITGAM,IL-4,and PTPRC with significantly downregulated expression were identified.IL-10 and IL-2 were upregulated in the HK group but without a significant difference.Infiltration differences of CD8 lymphocyte T cells,CD4 lymphocyte T-activated memory cells,and dendritic resting cells were identified with gene CIBERSORT deconvolution algorithm analysis.Infiltration levels of CD4 lymphocyte T cell in the HK group were significantly higher than those of the K group in IHC verification.Conclusion:HBOT affected tumor gene expression and immune cell infiltration in keloids.CD4 lymphocyte T cell,especially activated memory CD4+T,might be the key regulatory immune cell,and its related gene expression needs further study.

Inflatable pressure garment device for pressure therapy after chest wall keloid operation and radiotherapy

Aim: Keloids often occur on the chest wall, with high recurrence rates despite surgery and radiotherapy. Garment pressure therapy is commonly used to treat hypertrophic scars and keloids. Irregularity of the chest wall surface can inhibit the effects of the garment pressure therapy. This clinical study is to determine the effect of inflatable pressure garment in preventing keloid recurrence after keloid operation and radiotherapy. Methods: Chest wall keloid was removed and radiotherapy was administered at the surgical sites on the 1st and 7th postoperative days in 61 patients. An inflatable pressure garment device was designed and its pressure effect was confirmed by comparing it with the general pressure garment at the sites of the right and left infraclavicular area, manubrium and sternal area between breasts. The keloid patients were treated with inflatable pressure garment device 1 month after the operation. The clinical results were observed. Results: The detected pressures were 0.26 ± 0.21, 0.49 ± 0.16, 0.53 ± 0.10 and 0.91 ± 0.17 kPa at the sites of the right infraclavicular area, the manubrium area, the left infraclavicular area and sternal area between breasts with the general pressure garment. These were obvious lower (P < 0.05) than that generated with the inflatable pressure garment device of which the average pressures were 7.26 ± 0.41, 7.6 ± 0.32, 9.02 ± 0.54 and 10.31 ± 0.14 kPa at the corresponding sites.Sixty-one patients were treated with this device after keloid surgical excision and radiotherapy. Satisfactory results were observed. Conclusion: Appropriate and effective pressure can be generated with inflatable pressure garment on the chest wall. This device may be useful in preventing chest wall keloid recurrence after keloid operation and radiotherapy.

Reconstruction of a large defect of the female chest following keloid excision with use of the rectus abdominis myocutaneous flap

Aim: This study aimed to investigate the efficacy of the myocutaneous flap of the rectus abdominis in the surgical treatment of a large defect on the female chest following keloid excision.Methods: According to the location and size of the keloid on the chest, a myocutaneous flap based on the left or right rectus abdominis muscle was designed and transferred for repair of a chest defect following keloid resection. Radiotherapy was performed in the surgical area on the first and seventh postoperative days.Results: From January 2015 to March 2016, rectus abdominis myocutaneous flap coverage and early radiotherapy were used to treat 7 cases of keloids on the female chest. A postoperative follow-up of 10-14 months (average 12 months) was conducted. All the flaps survived well without evidence of keloid recurrence, and all patients achieved an improved chest shape.Conclusion:The rectus abdominis myocutaneous flap is a viablemethod for wound closure following resection of large keloids on the female chest.