Capsiate ameliorates secondary hyperparathyroidism by improving insulin sensitivity and inhibiting angiogenesis.

Secondary hyperparathyroidism has a significant impact on the overall well-being of the body. Capsiates, known for their antioxidant and metabolic properties, have emerged as a promising alternative treatment for secondary hyperparathyroidism. This study aims to evaluate the effects and mechanisms of capsiates in the treatment of secondary hyperparathyroidism. To achieve our research objectives, we conducted a study on patients' serum and examined changes in metabolic markers using serum metabolomics. We induced secondary hyperparathyroidism in rat through dietary intervention and divided them into four groups. The first group, referred to as the Parathyroid Hormone (PTH) group, received a low-calcium and high-phosphate diet (0.2% calcium, 1.2% phosphorus). The second group served as the control group, receiving a standard phosphate and calcium diet (0.6% calcium, 0.6% phosphorus). The third group, called the capsiates group, consisted of rat from the control group treated with capsiates (intraperitoneal injection of 2 mg/kg capsiates for 2 weeks after 2 weeks of dietary intervention). The fourth group was the capsiates-treated PTH group. Subsequently, we conducted ribose nucleic acid (RNA) sequencing on parathyroid gland cells and evaluated serum thyroxine levels, oxidative stress, expression of proteins associated with vascular neogenesis, measurement of SOD, GSH and 3-nitrotyrosine, micro-CT and histological staining. The serum metabolomic data revealed a significant decrease in capsiate levels in the secondary hyperparathyroidism group. Administration of capsiates to PTH rat resulted in increased calcium levels compared to the PTH group. Additionally, the PTH + Capsiates group showed significantly lower levels of PTH and phosphate compared to the PTH group. The PTH group exhibited a notable increase in the quantity and size of mitochondria compared to the control group. Following capsiates administration to the PTH group, there was a significant reduction in the number of mitochondria and length of microvilli, but an increase in the size of mitochondria compared to the PTH group. Sequencing analysis revealed that vascular endothelial growth factor (VEGF) and Vascular Endothelial Growth Factor Receptor 1 (VEGFR1) play crucial roles in this process. Vascular-related variables and downstream signalling were significantly elevated in hyperthyroidism and were alleviated with capsaicin treatment. Finally, combining capsiates with the PTH group improved bone mineral density, Tb.N, BV.TV, Cs.Th, Tt.Ar, OPG, Ob.TV and Oc.TV, as well as the mineral apposition rate, but significantly decreased Tb.Sp and Receptor Activator for Nuclear Factor-κ B Ligand (RANKL) compared to the PTH group. The findings suggest that capsiates can improve secondary hyperparathyroidism and ameliorated osteoporosis outcomes by inhibiting angiogenesis and reducing oxidative stress.

Astragaloside IV promotes exosome secretion of endothelial progenitor cells to regulate PI3KR2/SPRED1 signaling and inhibit pyroptosis of diabetic endothelial cells.

BACKGROUND AIMS: Treating chronic non-healing diabetic wounds and achieving complete skin regeneration has always been a critical clinical challenge. METHODS: In order to address this issue, researchers conducted a study aiming to investigate the role of miR-126-3p in regulating the downstream gene PIK3R2 and promoting diabetic wound repair in endothelial progenitor cell (EPC)-derived extracellular vesicles. The study involved culturing EPCs with astragaloside IV, transfecting them with miR-126-3p inhibitor or mock plasmid, interfering with high glucose-induced damage in human umbilical vein endothelial cells (HUVECs) and treating diabetic skin wounds in rats. RESULTS: The healing of rat skin wounds was observed through histological staining. The results revealed that treatment with miR-126-3p-overexpressing EPC-derived extracellular vesicles accelerated the healing of rat skin wounds and resulted in better tissue repair with slower scar formation. In addition, the transfer of EPC-derived extracellular vesicles with high expression of miR-126-3p to high glucose-damaged HUVECs increased their proliferation and invasion, reduced necrotic and apoptotic cell numbers and improved tube formation. In this process, the expression of angiogenic factors vascular endothelial growth factor (VEGF)A, VEGFB, VEGFC, basic fibroblast growth factor and Ang-1 significantly increased, whereas the expression of caspase-1, NRLP3, interleukin-1ß, inteleukin-18, PIK3R2 and SPRED1 was suppressed. Furthermore, miR-126-3p was able to target and inhibit the expression of the PIK3R2 gene, thereby restoring the proliferation and migration ability of high glucose-damaged HUVEC. CONCLUSIONS: In summary, these research findings demonstrate the important role of miR-126-3p in regulating downstream genes and promoting diabetic wound repair, providing a new approach for treating chronic non-healing diabetic wounds.

Development of pro-angiogenic skin substitutes for wound healing.

Wounds pose significant challenges to public health, primarily due to the loss of the mechanical integrity and barrier function of the skin and impaired angiogenesis, causing physical morbidities and psychological trauma to affect patients. Reconstructing the vasculature of the wound bed is crucial for promoting wound healing, reducing scar formation and enhancing the quality of life for patients. The development of pro-angiogenic skin substitutes has emerged as a promising strategy to facilitate vascularization and expedite the healing process of burn wounds. This review provides an overview of the various types of skin substitutes employed in wound healing, explicitly emphasising those designed to enhance angiogenesis. Synthetic scaffolds, biological matrices and tissue-engineered constructs incorporating stem cells and primary cells, cell-derived extracellular vesicles (EVs), pro-angiogenic growth factors and peptides, as well as gene therapy-based skin substitutes are thoroughly examined. The review summarises the existing challenges, future directions and potential innovations in pro-angiogenic dressing for skin substitutes. It highlights the need for continued research to develop new technologies and combine multiple strategies and factors, and to overcome obstacles and advance the field, ultimately leading to improved outcomes for wound patients.

Identification of CRKL as an oncogenic biomarker for prognosis and immunotherapy in melanoma, and its potential molecular mechanism.

CRKL (CRK Like Proto-Oncogene) belongs to the Crk family and is a 39-kDa adapter protein that encodes SH2 and SH3 (src homologs) domains. To identify its oncogenic role in malignant melanoma, we investigated the association between CRKL and mutation, prognosis, tumor mutation burden, immune cell infiltration of melanoma, and explored the associations between CRKL and immunotherapy response. Our results showed that abnormal CRKL expression is associated with poor prognosis in melanoma and is significantly correlated with immune-activated pathways and processes, immune cell infiltrations, and expression of immunoregulators. Importantly, we found that CRKL expression is a predictive biomarker for anti-PD1 therapy response in melanoma patients. Furthermore, inhibiting CRKL expression in melanoma cell lines suppressed their proliferation and metastasis, as well as activated the pyroptosis-related pathway. Our study provides potential mechanisms of melanoma pathogenesis, which may suggest new avenues for targeted therapy in this disease.

The Usage of Mesh and Relevant Prognosis in Implant Breast Reconstruction Surgery: A Meta-analysis.

BACKGROUND: Although mesh-based implant breast reconstruction surgery is emerging as the primary surgical procedure for breast reconstruction, mesh use remains controversial in implant breast reconstruction surgery, especially in terms of how to select the ideal mesh. Our aim is to elaborate relevant prognosis in the mesh-based implant breast reconstruction surgery. METHODS: Relevant studies were identified from PubMed, Web of Science, EMBASE, and Cochrane library searches. Extracted data included study type, basic characteristics, mesh information, complications, etc. We analyzed the included cohort studies and randomized controlled trials that reported mesh-related implant breast reconstruction complications and breast quality scale scores. RESULTS: A total of 32 studies including 7475 subjects were included. The results showed that the overall complication rate was 2.07 times higher in the biological mesh group than in the synthetic mesh group (risk ratio [RR]: 2.07, 95% CI 1.14-3.78). The risk of seroma was 4.50 times higher in the biological mesh group than in the synthetic mesh group (RR: 4.50, 95% CI 2.27-8.95). In terms of comparing breast quality scale scores, the mesh group had scores that were 1.49 (95% CI 0.19-2.78) higher than the non-mesh group for "physical well-being" and 2.05 (95% CI 0.08-4.02) higher for "sexual well-being." CONCLUSIONS: Our study found that the risk of total complications was higher with biological mesh than with synthetic mesh in implant breast reconstruction surgery. Based on short-term cost, healthcare burden, and healthcare benefits, synthetic meshes are superior to biological meshes. LEVEL OF EVIDENCE III: This journal requires that authors assign a level of evidence to each article. 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 .

A bibliometric study: Relevant studies on scar laser therapy since the 21st century.

To summarise research studies on scar laser therapy since the 21st century using bibliometric methods, and to speculate on the possible development in the future. The literature about scar laser therapy in Web of Science database was searched. CiteSpace and VOSviewer were used to analyse main countries, institutions, journals，subject hotspots and trends, etc. A total of 884 papers have been published since the 21st century. These publications were written by 653 authors from 515 institutions in 58 countries. The United States published 287 papers in this field and ranks first. Laser in Surgery and Medicine is the most widely published journal, with Shumaker as the core author. The main keyword clustering includes terms such as combination therapy, wound healing, fractional photothermolysis, experience, scar formation, etc. CiteSpace and VOSviewer were used to sort out and summarise the countries, institutions, authors, journals, research hotspots and frontier topics of related literature about scar laser therapy since the 21st century. The current situation of its application and basic scientific research in clinical treatments were summarised briefly. This provides a new idea for the development and research of scar laser therapy in the future.

Progress in copper-based materials for wound healing.

Chronic wounds have become the leading cause of death, particularly among diabetic patients. Chronic wounds affect ~6.5 million patients each year, according to statistics, and wound care and management incur significant financial costs. The rising prevalence of chronic wounds, combined with the limitations of current treatments, necessitates the development of new and innovative approaches to accelerate wound healing. Copper has been extensively studied for its antibacterial and anti-inflammatory activities. Copper in its nanoparticle form could have better biological properties and many applications in health care.

Attitudes toward depression among rural primary healthcare providers in hunan areas, China: a cross sectional study.

BACKGROUND: Mental health services are not sufficient for depression patients in rural areas of China, training in mental health knowledge for primary healthcare providers has been encouraged, but the effect of this encouragement has rarely been reported. METHODS: A cross-sectional survey was conducted in primary healthcare facilities that sought to include all the primary healthcare providers (registered physicians and nurses) in two cities in Hunan province, China by administering questionnaires that covered depression symptoms, typical depression cases, and the Revised Depression Attitude Questionnaire. RESULTS: In total, 315 primary healthcare providers agreed to participate in the study and finished the questionnaires, of which 12.1% had training in depression. In addition, 62.9% of the rural primary healthcare providers were able to recognize most general depression symptoms, and 8.3% were able to recognize all general depression symptoms. The primary healthcare providers in the survey held a neutral to slightly negative attitude towards depression as indicated by their professional confidence (mean scores 16.51 ± 4.30), therapeutic optimism/pessimism (mean scores 29.02 ± 5.98), and general perspective (mean scores 18.12 ± 3.12) scores. Fewer rural primary healthcare providers knew (28.3%) or applied (2.9%) psychological intervention in the clinic. CONCLUSIONS: Our study indicated that primary healthcare providers knew about general depression symptoms, but lacked psychological intervention skills and held low confidence in and pessimistic attitudes toward depression care. We therefore speculate that existing psychological training for primary healthcare providers is insufficient in quantity and quality, making the need to explore more effective types of training urgently.

Prognostic Analysis of Skin Scar Loosening and Tissue-Expansive Autologous Skin Grafting in the Treatment of Skin Postburn Scars.

BACKGROUND: This study aims to observe and investigate the clinical value of scar loosening and tissue-expansive autologous skin grafting in the treatment of postburn scars and independent risk characteristics for surgery-related complications. METHODS: We retrospectively analyzed 94 cases with postburn scars, and all patients were treated with scar loosening and autologous skin grafting. Overall therapeutic effects were evaluated using the standard of cure and improvement of clinical diseases. Burn Specific Health Scale-brief was used to analyze patients' quality of life. The visual analog scale scores were used to analyze esthetic satisfaction. Surgery-related complications were recorded, and logistic regression model was used to analyze independent factors affecting surgery-related complications. RESULTS: As for overall efficacy evaluation, 50 cases were cured, 19 cases were markedly improved, 17 cases improved, and 8 cases were detected and tested, and the overall effective rate was 91.4%. The Burn Specific Health Scale-brief and visual analog scale score showed a trend of increasing gradually. It indicated that the patients were satisfied with the operation and their quality of life was improved. The logistic regression model showed that history of skin disease (OR=1.53 (1.08-2.16), P =0.02) and skin area (OR=2.50 (1.22-4.50), P <0.01) were significantly associated with surgery-related complications. CONCLUSIONS: Scar loosening and autologous skin grafting is a safe and effective treatment. The history of skin disease and skin area was the independent factors for surgery-related complications.

Current Status of Auricular Reconstruction Strategy Development.

Microtia has severe physical and psychological impacts on patients, and auricular reconstruction offers improved esthetics and function, alleviating psychological issues. Microtia is a congenital disease caused by a multifactorial interaction of environmental and genetic factors, with complex clinical manifestations. Classification assessment aids in determining treatment strategies. Auricular reconstruction is the primary treatment for severe microtia, focusing on the selection of auricular scaffold materials, the construction of auricular morphology, and skin and soft tissue scaffold coverage. Autologous rib cartilage and synthetic materials are both used as scaffold materials for auricular reconstruction, each with advantages and disadvantages. Methods for achieving skin and soft tissue scaffold coverage have been developed to include nonexpansion and expansion techniques. In recent years, the application of digital auxiliary technology such as finite element analysis has helped optimize surgical outcomes and reduce complications. Tissue-engineered cartilage scaffolds and 3-dimensional bioprinting technology have rapidly advanced in the field of ear reconstruction. This article discusses the prevalence and classification of microtia, the selection of auricular scaffolds, the evolution of surgical methods, and the current applications of digital auxiliary technology in ear reconstruction, with the aim of providing clinical physicians with a reference for individualized ear reconstruction surgery. The focus of this work is on the current applications and challenges of tissue engineering and 3-dimensional bioprinting technology in the field of ear reconstruction, as well as future prospects.

Biofilms in wound healing: A bibliometric and visualised study.

Bibliometric analyses are often used as a means of visualising the knowledge base and associated trends and patterns in a target scientific field based on a quantitative review of the corresponding literature. In this study, we explore the current status of research pertaining to biofilms in wound healing and elucidate trends in this research space. Through this process, we gain insight into findings from papers indexed in the Web of Science Core Collection. These references were then analysed and plotted using Microsoft Excel 2019, VOSviewer, and CiteSpace V. The results provide a fresh perspective regarding global trends and hotspots in biofilm-related wound healing research. These findings also offer a foundation that researchers can use to identify active hotspots of scientific interest to guide further research endeavours.

Angiogenesis and flap-related research: A bibliometric analysis.

Adequate blood supply, a prerequisite for flap survival after grafting, makes angiogenesis of the flap the biggest problem to be solved. Researches have been conducted around vascularisation in correlation with flap grafting. However, bibliometric analyses systematically examining this research field are lacking. As such, we herein sought to conduct comprehensive comparative analyses of the contributions of different researchers, institutions, and countries to this research space in an effort to identify trends and hotspots in angiogenesis and vascularisation in the context of flap grafting. Publications pertaining to angiogenesis and vascularisation in the context of flap grafting were retrieved from the Web of Science Core Collection. References were then analysed and plotted using Microsoft Excel 2019, VOSviewer, and CiteSpace V. In total, 2234 papers that were cited 40 048 times (17.63 citations/paper) were included in this analysis. The greatest number of studies were from the United States, with these studies exhibiting both the highest number of citations (13 577) and the greatest overall H-index (60). For The institutions that published the greatest number of studies were WENZHOU MEDICAL UNIVERSITY (681), while UNIVERSITY OF ERLANGEN NUREMBERG has the highest number of citations (1458), and SHANGHAI JIAO TONG UNIVERSITY holds the greatest overall H-index (20). The greatest number of studies in this research space were published by Gao WY, while Horch RE was the most commonly cited researcher in the field. The VOS viewer software clustered relevant keywords into three clusters, with clusters 1, 2, 3, and 4 corresponding to studies in which the keywords 'anatomy', 'survival', 'transplantation', 'therapy' most frequently appeared. The most promising research hotspot-related terms in this field included 'autophagy', 'oxidative stress', 'ischemia/reperfusion injury', which exhibited a most recent average appearing year (AAY) of 2017 and after. Generally speaking, the results of this analysis indicate that the number of articles exploring angiogenesis and flap-related research has risen steadily, with the United States and China being the two countries publishing the greatest proportion of studies in this field. The overall focus of these studies has shifted away from 'infratest and tissue engineering' towards 'mechanisms'. In the future, particular attention should be paid to emerging research hotspots, which include 'ischemia/reperfusion injury' and treatments for promoting vascularization, such as 'platelet-rich plasma'. In light of these findings, funding agencies should continue increasing their investment in the exploration of the concrete mechanisms and interventional therapeutic relevance of angiogenesis during flap transplantation.

Bacillus subtilis WB800N alleviates diabetic wounds in mice by regulating gut microbiota homeostasis and TLR2.

OBJECTIVE: This study aims to investigate the effect of Bacillus subtilis WB800N on diabetic wounds. METHODS: Haematoxylin & eosin (H&E) staining was used to observe the healing of skin wounds. Collagen deposition was assessed by Masson staining. Western blotting and qRT-PCR were used to detect vascular endothelial-related factors (VWF), CD31, TLR2, NLRP3, ASC and Caspase-1 expression. 16S rDNA sequencing detected microbiota distribution. The concentrations of IL-1ß and IL-37 were measured by ELISA. Apoptosis was measured by the TUNEL assay. RESULTS: Compared with the control group, wound healing was delayed in diabetic mice. The wound area in the Bacillus subtilis group decreased more significantly than the diabetic wound group. H&E staining showed that Bacillus subtilis WB800N promoted wound healing and increased re-epithelialization. Masson staining showed that Bacillus subtilis WB800N increased collagen deposition in mice with diabetic wounds. Bacillus subtilis WB800N upregulated VWF and CD31 protein expression in diabetic wounds mice. The 16S rDNA results showed that Bacillus subtilis WB800N reduced the diversity of the gut microbiota of diabetic wounds mice and regulated the microbial composition. At the genus level, Bacillus subtilis WB800N reduced the relative abundance of Muribaculaceae and CG - 005 in diabetic wounds mice, whilst increasing the relative abundance of Lactobacillus. Bacillus subtilis WB800N increased the expression of TLR2, NLRP3, ASC and Caspase-1. Bacillus subtilis WB800N increased the concentrations of IL-1ß and IL-37 in serum. Bacillus subtilis WB800N upregulated cell apoptosis. The TLR2 antagonist Sparstolonin B (SsnB) reduced the expression of TLR2, NLRP3, ASC, Caspase-1, IL-1ß and IL-37 and the apoptosis in diabetic wounds mice, whilst the combined intervention of Bacillus subtilis and SsnB reversed the effect of SsnB treatment alone. CONCLUSION: Bacillus subtilis WB800N alleviated diabetic wound healing by regulating gut microbiota homeostasis and TLR2. SIGNIFICANCE AND IMPACT OF RESEARCH: Our findings might provide potential therapeutic targets for diabetic wounds.

Inhibition of xCT suppresses the efficacy of anti-PD-1/L1 melanoma treatment through exosomal PD-L1-induced macrophage M2 polarization.

Tumor cells increase glutamate release through the cystine/glutamate transporter cystine-glutamate exchange (xCT) to balance oxidative homeostasis in tumor cells and promote tumor progression. Although clinical studies have shown the potential of targeting programmed cell death 1 (PD-1)/programmed death ligand 1 (PD-L1) signaling in melanoma, response rates are low. However, it remains unclear how glutamate metabolism affects anti-PD-1/PD-L1 treatment efficacy in melanoma. Here, we demonstrated that although inhibition of xCT either by pharmacological inhibitor (sulfasalazine [SAS]), approved by US Food and Drug Administration (FDA) for inflammatory diseases, or genetic knockdown induced reactive oxygen species (ROS)-related death in melanoma cells, inhibition of xCT significantly reduced the efficacy of anti-PD-1/PD-L1 immune checkpoint blockade through upregulating PD-L1 expression via the transcription factors IRF4/EGR1, as a consequence, exosomes carrying relatively large amounts of PD-L1 secreted from melanoma cells resulted in M2 macrophage polarization and reduced the efficacy of anti-PD-1/PD-L1 therapy in melanoma. Taken together, our results reveal that inhibition of xCT by SAS is a promising therapeutic strategy for melanoma; on the other hand, SAS treatment blunted the efficacy of anti-PD-1/PD-L1 via exosomal PD-L1-induced macrophage M2 polarization and eventually induced anti-PD-1/PD-L1 therapy resistance.

Assessment of an Artificial Intelligence Mandibular Osteotomy Design System: A Retrospective Study.

BACKGROUND: In this study, an AI osteotomy software was developed to design the presurgical plan of mandibular angle osteotomy, which is followed by the comparison between the software-designed presurgical plan and the traditional manual presurgical plan, thus assessing the practicability of applying the AI osteotomy software in clinical practices. METHODS: (1) Develop an AI osteotomy software: design an algorithm based on convolutional neural networks capable of learning feature point and processing clustering segmentation; then, select 2296 cases of successful 3D mandibular angle osteotomy presurgical plans, followed by using those 2296 cases to train the deep learning algorithm; (2) compare the osteotomy presurgical plan of AI osteotomy software and that of manual: first step: randomly selecting 80 cases of typical female head 3D CTs, and designing those 80 cases by means of AI osteotomy software designing (group A) and manually designing (group B), respectively; second step: comparing several indexes of group A and those of group B, including the efficiency index (time from input original CT data to osteotomy presurgical plan output), the safety index (the minimum distance from the osteotomy plane to the mandibular canal), the symmetry indexes (bilateral difference of mandibular angle, mandibular ramus height and mandibular valgus angle) and aesthetic indexes (width ratio between middle and lower faces (M/L), mandibular angle and mandibular valgus angle). RESULTS: The efficiency index: the design time of group A is 1.768 ± 0.768 min and that of group B is 26.108 ± 1.137 min, with P = 0.000; the safety index: The minimum distances from the osteotomy plane to the mandibular canal are 3.908 ± 0.361mm and 3.651 ± 0.437mm, p = 0.117 in groups A and B, respectively; The symmetry indexes: Bilateral differences of mandibular angle are 1.824 ± 1.834° and 1.567 ± 1.059° in groups A and B, respectively, with P = 0.278; bilateral differences of mandibular ramus height are 2.083 ± 1.263 and 2.965 ± 1.433, respectively, with P = 0.119 in groups A and B; Aesthetic indexes: M/L in groups A and B is 1.364 ± 0.074 and 1.371 ± 0.067, respectively, with P = 0.793; mandibular angles in groups A and B are 127.724 ± 5.800° and 127.242 ± 5.545°, respectively, with P = 0.681; Valgus angles in groups A and B are 11.474 ± 5.380 and 9.743 ± 4.620, respectively, with P = 0.273. CONCLUSIONS: With high efficiency, as well as safety, symmetry and aesthetics equivalent to those of a manual design, the AI osteotomy software designing can be used as an alternative method for manual osteotomy designing. LEVEL OF EVIDENCE IV: This journal requires that authors assign a level of evidence to each article. 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.

Aspirin inhibits the growth of hypertrophic scar in rabbit ears via regulating Wnt/ß-catenin signal pathway. / 阿司匹林通过调控Wnt/ß-cateninä¿¡å·é€šè·¯æŠ‘åˆ¶å ”è€³å¢žç”Ÿæ€§ç˜¢ç—•çš„ç”Ÿé•¿.

OBJECTIVES: Steroidal anti-inflammatory drugs have certain side effects in the treatment of hypertrophic scar, and the scar recurrence is easy after withdrawal of steroid anti-inflammatory drugs. Finding reliable alternative drugs is an effective means to improve this defect. Aspirin, a traditional non-steroidal anti-inflammatory drug, is safe for topical use and has anti-inflammatory effects similar to those of steroidal anti-inflammatory drugs, which may have similar effects on the treatment of hypertrophic scar. This study aims to investigate the inhibitory effect of aspirin on the proliferation of hypertrophic scar in rabbit ears and the underlying mechanism. METHODS: The rabbit ear hypertrophic scar models were prepared. The rabbits were randomly divided into a normal skin group (group A), a blank control group (group B), a 0.9% NaCl group (group C), a 0.2% aspirin group (group D), a 0.5% aspirin group (group E), a 2% aspirin group (group F), and a triamcinolone acetonide group (group G). Macroscopic observation of hyperplasia was performed 8 weeks after local injection of the scar, followed by collecting the scar tissue samples for HE staining, Masson staining, and immunohistochemistry, respectively to assess the proliferation of fibroblasts and collagen fibers, and calculate the hypertrophic index, microvessel density, and immunohistochemical score. RESULTS: All rabbit ear hypertrophic scar models were successfully constructed. In groups B and C, the hypertrophic scar edge was irregular, with reddish protruding epidermis, significant contracture and hard touch. In group D, E, and F, with the increase of aspirin administration concentration, the scar became thinner and gradually flat, the proliferation of fibrocytes and collagen fibers was weakened, and the hypertrophic index was gradually decreased (P<0.05). Immunohistochemistry showed that the expression of ß-catenin was decreased in the group D, E and F in turn, and the immunohistochemical score was gradually decreased (P<0.05). There was no significant difference in hypertrophic index, microvessel density, and immunohistochemical score (all P>0.05). CONCLUSIONS: Local injection of aspirin can reduce the generation of hypertrophic scar in a dose-dependent manner within a certain concentration range; aspirin inhibits the growth of hypertrophic scar in rabbit ears by inhibiting Wnt/ß-catenin signal pathway; 2% aspirin and 40 mg/mL triamcinolone acetonide have similar curative efficacy on hypertrophic scar.

Prognostic signature and immune efficacy of m1 A-, m5 C- and m6 A-related regulators in cutaneous melanoma.

Cutaneous melanoma (CM) is an aggressive cancer; given that initial and specific signs are lacking, diagnosis is often late and the prognosis is poor. RNA modification has been widely studied in tumour progression. Nevertheless, little progress has been made in the signature of N1 -methyladenosine (m1 A), 5-methylcytosine (m5 C), N6 -methyladenosine (m6 A)-related regulators and the tumour microenvironment (TME) cell infiltration in CM. Our study identified the characteristics of m1 A-, m5 C- and m6 A-related regulators based on 468 CM samples from the public database. Using univariate, multivariate and LASSO Cox regression analysis, a risk model of regulators was established and validated by a nomogram on independent prognostic factors. The gene set variation analysis (GSVA) and the Kyoto Encyclopedia of Genes and Genomes (KEGG) clarified the involved functional pathways. A combined single-sample gene set enrichment analysis (ssGSEA) and CIBERSORT approach revealed TME of regulator-related prognostic signature. The nine-gene signature stratified the patients into distinct risk subgroups for personalized prognostic assessment. Additionally, functional enrichment, immune infiltration and immunotherapy response analysis indicated that the high-risk group was correlated with T-cell suppression, while the low-risk group was more sensitive to immunotherapy. The findings presented here contribute to our understanding of the TME molecular heterogeneity in CM. Nine m1 A-, m5 C- and m6 A-related regulators may also be promising biomarkers for future research.

Resveratrol promotes skin wound healing by regulating the miR-212/CASP8 axis.

The wound-healing process is a natural response to burn injury. Resveratrol (RES) may have potential as a therapy for wound healing, but how and whether RES regulates skin repair remains poorly understood. Human epidermal keratinocyte (HaCaT) cells were treated with lipopolysaccharide (LPS), and a mouse skin wound-healing model was established. Cell viability and apoptosis were analyzed by 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide or flow cytometry. Cell proliferation was assessed by cell viability and colony-formation analyses. Cell migration was tested by wound-healing analysis. The microRNA-212 (miR-212) and caspase-8 (CASP8) levels were determined by quantitative reverse transcription polymerase chain reaction and western blotting. The correlation between miR-212 and CASP8 was analyzed by dual-luciferase reporter analysis. Skin wound healing in mice was assessed by measuring the wound area and gap after hematoxylin-eosin (HE) staining. RES reduced the LPS-induced reduction in viability and apoptosis in HaCaT cells. miR-212 expression was reduced by LPS and increased by exposure to RES. RES promoted cell proliferation and migration after LPS treatment by increasing miR-212 levels. CASP8 was a target of miR-212. CASP8 silencing promoted cell proliferation and migration, which was reversed by miR-212 knockdown in LPS-treated HaCaT cells. RES promoted skin wound healing in mice, which was reduced by miR-212 knockdown. Thus, RES facilitates cell proliferation and migration in LPS-treated HaCaT cells and promotes skin wound-healing in a mouse model by regulating the miR-212/CASP8 axis.

SIRT1 Regulates N6 -Methyladenosine RNA Modification in Hepatocarcinogenesis by Inducing RANBP2-Dependent FTO SUMOylation.

BACKGROUND AND AIMS: Hepatocellular carcinoma (HCC) is associated with high malignancy rates. Recently, a known deacetylase silent information regulator 1 (SIRT1) was discovered in HCC, and its presence is positively correlated with malignancy and metastasis. N6 -methyladenosine (m6 A) is the most prominent modification, but the exact mechanisms on how SIRT1 regulates m6 A modification to induce hepatocarcinogenesis remain unclear. APPROACH AND RESULTS: Here we demonstrate that SIRT1 exerts an oncogenic role by down-regulating fat mass and obesity-associated protein (FTO), which is an m6 A demethylase. A crucial component of small ubiquitin-related modifiers (SUMOs) E3 ligase, RANBP2, is activated by SIRT1, and it is indispensable for FTO SUMOylation at Lysine (K)-216 site that promotes FTO degradation. Moreover, Guanine nucleotide-binding protein G (o) subunit alpha (GNAO1) is identified as m6 A downstream targets of FTO and tumor suppressor in HCC, and depletion of FTO by SIRT1 improves m6 A+ GNAO1 and down-regulates its mRNA expression. CONCLUSIONS: We demonstrate an important mechanism whereby SIRT1 destabilizes FTO, steering the m6 A+ of downstream molecules and subsequent mRNA expression in HCC tumorigenesis. Our findings uncover a target of SIRT1 for therapeutic agents to treat HCC.

MiR-106a-5p modulates apoptosis and metabonomics changes by TGF-ß/Smad signaling pathway in cleft palate.

BACKGROUND: The molecular mechanisms of abnormal palatogenesis were investigated in this study. A key regulator, miR-106a-5p, and its target pathway were analyzed. OBJECTIVES: This research is trying to clarify the underlying mechanism of the modulation of miRNA transcription during the formation of cleft palate by 7T and 9.4T NMR metabolomic platforms. METHOD: Differentially expressed miRNAs and mRNAs were analyzed by microarray analysis and verified by qRT-PCR. The protein expression in TGFß signaling pathways were analyzed by Western Blotting. The relationship between miR-106a-5p and TGFß were analyzed by luciferase reporter assay. Cell apoptosis were analyzed by flow cytometer. And finally, the metabonomics were analyzed by NMR and multivariate data analysis models (MVDA). RESULTS: The expression of miR-106a-5p increased in cleft palatal tissue and negatively correlated with the protein level of Tgfbr2. The luciferase assay further proved that the tgfbr2 was a direct target of miR-106a-5p. In another aspect, miR-106a-5p increased apoptosis level in palatal mesenchymal cells, possibly because its inhibition of TGFß signaling pathway. Moreover, low cholesterol and choline levels with high citric acid and lipid levels were observed by 7T and 9.4T NMR metabonomic analysis, which inferred the disorder of cell membrane synthesis in cleft palate formation. Furthermore, transformation from choline to phosphatidylcholine regulated by miR-106a-5p was also disrupted, resulting in phosphatidic choline synthesis disorder and reduced cell membrane synthesis. CONCLUSIONS: The regulatory mechanism of cleft palate was studied at transcriptional and metabolomics levels, which may provide important information in understanding the primary cause of this abnormality.