Ferroptosis contributing to cardiomyocyte injury induced by silica nanoparticles via miR-125b-2-3p/HO-1 signaling.

BACKGROUND: Amorphous silica nanoparticles (SiNPs) have been gradually proven to threaten cardiac health, but pathogenesis has not been fully elucidated. Ferroptosis is a newly defined form of programmed cell death that is implicated in myocardial diseases. Nevertheless, its role in the adverse cardiac effects of SiNPs has not been described. RESULTS: We first reported the induction of cardiomyocyte ferroptosis by SiNPs in both in vivo and in vitro. The sub-chronic exposure to SiNPs through intratracheal instillation aroused myocardial injury, characterized by significant inflammatory infiltration and collagen hyperplasia, accompanied by elevated CK-MB and cTnT activities in serum. Meanwhile, the activation of myocardial ferroptosis by SiNPs was certified by the extensive iron overload, declined FTH1 and FTL, and lipid peroxidation. The correlation analysis among detected indexes hinted ferroptosis was responsible for the SiNPs-aroused myocardial injury. Further, in vitro tests, SiNPs triggered iron overload and lipid peroxidation in cardiomyocytes. Concomitantly, altered expressions of TfR, DMT1, FTH1, and FTL indicated dysregulated iron metabolism of cardiomyocytes upon SiNP stimuli. Also, shrinking mitochondria with ridge fracture and ruptured outer membrane were noticed. To note, the ferroptosis inhibitor Ferrostatin-1 could effectively alleviate SiNPs-induced iron overload, lipid peroxidation, and myocardial cytotoxicity. More importantly, the mechanistic investigations revealed miR-125b-2-3p-targeted HO-1 as a key player in the induction of ferroptosis by SiNPs, probably through regulating the intracellular iron metabolism to mediate iron overload and ensuing lipid peroxidation. CONCLUSIONS: Our findings firstly underscored the fact that ferroptosis mediated by miR-125b-2-3p/HO-1 signaling was a contributor to SiNPs-induced myocardial injury, which could be of importance to elucidate the toxicity and provide new insights into the future safety applications of SiNPs-related nano products.

Clinical guideline on the third generation minimally invasive surgery for hallux valgus.

Minimally invasive surgery for hallux valgus correction, has been attracting great interests in the recent decades, due to the potential benefits of less pain, decreased recovery times, smaller scars with better cosmesis, and improved early post-operative range of motion. The most recent developments in minimally invasive surgery have evolved into the third generation with modifications of the chevron-type osteotomy. This evidence-based clinical guideline of the third generation minimally invasive surgery for hallux valgus is initiated and developed collectively by the Foot and Ankle Committee of Orthopedic Branch of Chinese Medical Doctor Association, Foot and Ankle Committee of Sports Medicine Branch of Chinese Medical Doctor Association, and Foot and Ankle Expert Committee of Orthopedic Branch of the Chinese Association of the Integrative Medicine. This clinical guideline provides recommendations for indications, contraindications, operative planning and techniques, post-operative management, management of complications, and prognosis of the third generation minimally invasive surgery for hallux valgus. The Translational Potential of this Article This comprehensive guideline aims to establish standardized recommendations for the indications, contraindications, operative techniques, and post-operative management of the third generation minimally invasive surgery for hallux valgus. By adhering to this guideline, the success rate of the procedure could be maximized. This comprehensive guideline serves as a valuable reference for practitioners interested in or preparing to perform minimally invasive surgery for hallux valgus.

Surgical management of chronic Achilles tendon rupture: evidence-based guidelines.

BACKGROUND: Chronic Achilles tendon ruptures (CATR) often require surgical intervention to restore function. Despite numerous treatment modalities available, the optimal management strategy remains controversial given the limited high-quality evidence available. This article aims to provide evidence-based guidelines for the surgical management of CATR through a comprehensive systematic review of the available data. The consensus reached by synthesizing the findings will assist clinicians in making informed decisions and improving patient outcomes. METHODS: A group of 9 foot surgeons in three continents was consulted to gather their expertise on guidelines regarding the surgical management of CATR. Following the proposal of 9 clinical topics, a thorough and comprehensive search of relevant literature published since 1980 was conducted for each topic using electronic databases, including PubMed, MEDLINE, and Cochrane Library, to identify relevant studies published until 1 October 2023. All authors collaborated in drafting, discussing, and finalizing the recommendations and statements. The recommendations were then categorized into two grades: grade a (strong) and grade b (weak), following the GRADE (Grading of Recommendations Assessment, Development, and Evaluation) concept. Additionally, feedback from 21 external specialists, who were independent from the authors, was taken into account to further refine and finalize the clinical guidelines. RESULTS: Nine statements and guidelines were completed regarding surgical indications, surgical strategies, and postoperative rehabilitation protocol. CONCLUSION: Based on the findings of the systematic review, this guideline provides recommendations for the surgical management of CATR. We are confident that this guideline will serve as a valuable resource for physicians when making decisions regarding the surgical treatment of patients with CATR.

The naringin/carboxymethyl chitosan/sodium hyaluronate/silk fibroin scaffold facilitates the healing of diabetic wounds by restoring the ROS-related dysfunction of vascularization and macrophage polarization.

Chronic diabetic wounds remain a globally recognized clinical challenge, which occurs mainly due to the disturbances of wound microenvironmental induced by high concentrations of reactive oxygen species (ROS). Impairments in angiogenesis and inflammation in the wound microenvironment ultimately impede the normal healing process. Therefore, targeting macrophage and vascular endothelial cell dysfunction is a promising therapeutic strategy. In our study, we fabricated artificial composite scaffolds composed of naringin/carboxymethyl chitosan/sodium hyaluronate/silk fibroin (NG/CMCS/HA/SF) to promote wound healing. The NG/CMCS/HA/SF scaffold demonstrated favorable anti-inflammatory, anti-oxidative, and pro-angiogenic properties in both in vitro and in vivo experiments, effectively promoting the healing of diabetic wounds. The positive therapeutic effects observed indicate that the composite scaffolds have great potential in clinical wound healing applications.

Reprogramming Macrophage Polarization, Depleting ROS by Astaxanthin and Thioketal-Containing Polymers Delivering Rapamycin for Osteoarthritis Treatment.

Osteoarthritis (OA) is a chronic joint disease characterized by synovitis and joint cartilage destruction. The severity of OA is highly associated with the imbalance between M1 and M2 synovial macrophages. In this study, a novel strategy is designed to modulate macrophage polarization by reducing intracellular reactive oxygen species (ROS) levels and regulating mitochondrial function. A ROS-responsive polymer is synthesized to self-assemble with astaxanthin and autophagy activator rapamycin to form nanoparticles (NP@PolyRHAPM ). In vitro experiments show that NP@PolyRHAPM significantly reduced intracellular ROS levels. Furthermore, NP@PolyRHAPM restored mitochondrial membrane potential, increased glutathione (GSH) levels, and promoted intracellular autophagy, hence successfully repolarizing M1 macrophages into the M2 phenotype. This repolarization enhanced chondrocyte proliferation and vitality while inhibiting apoptosis. In vivo experiments utilizing an anterior cruciate ligament transection (ACLT)-induced OA mouse model revealed the anti-inflammatory and cartilage-protective effects of NP@PolyRHAPM , effectively mitigating OA progression. Consequently, the findings suggest that intra-articular delivery of ROS-responsive nanocarrier systems holds significant promise as a potential and effective therapeutic strategy for OA treatment.

Neutrophil peptide 1 accelerates the clearance of degenerative axons during Wallerian degeneration by activating macrophages after peripheral nerve crush injury.

JOURNAL/nrgr/04.03/01300535-202408000-00036/figure1/v/2023-12-16T180322Z/r/image-tiff Macrophages play an important role in peripheral nerve regeneration, but the specific mechanism of regeneration is still unclear. Our preliminary findings indicated that neutrophil peptide 1 is an innate immune peptide closely involved in peripheral nerve regeneration. However, the mechanism by which neutrophil peptide 1 enhances nerve regeneration remains unclear. This study was designed to investigate the relationship between neutrophil peptide 1 and macrophages in vivo and in vitro in peripheral nerve crush injury. The functions of RAW 264.7 cells were elucidated by Cell Counting Kit-8 assay, flow cytometry, migration assays, phagocytosis assays, immunohistochemistry and enzyme-linked immunosorbent assay. Axonal debris phagocytosis was observed using the CUBIC (Clear, Unobstructed Brain/Body Imaging Cocktails and Computational analysis) optical clearing technique during Wallerian degeneration. Macrophage inflammatory factor expression in different polarization states was detected using a protein chip. The results showed that neutrophil peptide 1 promoted the proliferation, migration and phagocytosis of macrophages, and CD206 expression on the surface of macrophages, indicating M2 polarization. The axonal debris clearance rate during Wallerian degeneration was enhanced after neutrophil peptide 1 intervention. Neutrophil peptide 1 also downregulated inflammatory factors interleukin-1α, -6, -12, and tumor necrosis factor-α in vivo and in vitro. Thus, the results suggest that neutrophil peptide 1 activates macrophages and accelerates Wallerian degeneration, which may be one mechanism by which neutrophil peptide 1 enhances peripheral nerve regeneration.

S-Nitrosylation-mediated coupling of DJ-1 with PTEN induces PI3K/AKT/mTOR pathway-dependent keloid formation.

Background: Keloids are aberrant dermal wound healing characterized by invasive growth, extracellular matrix deposition, cytokine overexpression and easy recurrence. Many factors have been implicated as pathological causes of keloids, particularly hyperactive inflammation, tension alignment and genetic predisposition. S-Nitrosylation (SNO), a unique form of protein modification, is associated with the local inflammatory response but its function in excessive fibrosis and keloid formation remains unknown. We aimed to discover the association between protein SNO and keloid formation. Methods: Normal and keloid fibroblasts were isolated from collected normal skin and keloid tissues. The obtained fibroblasts were cultured in DMEM supplemented with 10% fetal bovine serum and 1% penicillin/streptomycin. The effects of DJ-1 on cell proliferation, apoptosis, migration and invasion, and on the expression of proteins were assayed. TurboID-based proximity labelling and liquid chromatography-mass spectrometry were conducted to explore the potential targets of DJ-1. Biotin-switch assays and transnitrosylation reactions were used to detect protein SNO. Quantitative data were compared by two-tailed Student's t test. Results: We found that DJ-1 served as an essential positive modulator to facilitate keloid cell proliferation, migration and invasion. A higher S-nitrosylated DJ-1 (SNO-DJ-1) level was observed in keloids, and the effect of DJ-1 on keloids was dependent on SNO of the Cys106 residue of the DJ-1 protein. SNO-DJ-1 was found to increase the level of phosphatase and tensin homolog (PTEN) S-nitrosylated at its Cys136 residue via transnitrosylation in keloids, thus diminishing the phosphatase activity of PTEN and activating the PI3K/AKT/mTOR pathway. Furthermore, Cys106-mutant DJ-1 is refractory to SNO and abrogates DJ-1-PTEN coupling and the SNO of the PTEN protein, thus repressing the PI3K/AKT/mTOR pathway and alleviating keloid formation. Importantly, the biological effect of DJ-1 in keloids is dependent on the SNO-DJ-1/SNO-PTEN/PI3K/AKT/mTOR axis. Conclusions: For the first time, this study demonstrated the effect of transnitrosylation from DJ-1 to PTEN on promoting keloid formation via the PI3K/AKT/mTOR signaling pathway, suggesting that SNO of DJ-1 may be a novel therapeutic target for keloid treatment.

Analysis of Risk Factors for in-hospital Death in Elderly Patients with TEXAS Stage 3 and 4 Diabetic Foot Ulcers after Tibial Transverse Translation: A Case-Control Study.

OBJECTIVE: Chinese physicians developed the Tibial Transverse Transport (TTT) technique to treat diabetic foot ulcers with more than 90% effective rate. But this method still could not avoid the in-hospital death of patients. This study adopted a case-control study to explore the risk factors of in-hospital death in elderly patients with chronic ischemic diabetic foot after receiving TTT treatment. METHODS: A total of 54 patients were included in the study from January 1, 2017 to April 30, 2021, by being paired with the cases in case group with their demographic data and results of blood routine, liver and kidney function. There were nine patients in case group with six male and three male. Forty-five patients were selected in control group according to gender and diabetes type with 30 male and 15 female. Single factor logics regression analysis was used to explore the risk factors and odd ratios (OR) of in-hospital death in patients. The nomogram and decision curve analysis (DCA) had been done by R Studio software. RESULTS: The study found that age, course of diabetic foot, small dense low-density Lipoprotein (smLDL), homocysteine (Hcy), superoxide dismutase (SOD), and prealbumin (PA) were risk factors for in-hospital death of patients. The smLDL had the highest risk. The nomogram showed that PA accounted for the largest proportion in the death risk factors. The results of DCA proved that above six risk factors were the risk factors for patients with TEXAS Stage 3 and 4 diabetic foot ulcers. CONCLUSION: In the future diagnosis and TTT treatment for diabetic foot ulcers, doctors need to pay close attention to age, course of diabetic foot, smLDL, Hcy, SOD, and PA.

Epidermal Stem Cell Derived Exosomes Alleviate Excessive Autophagy Induced Endothelial Cell Apoptosis by Delivering miR200b-3p to Diabetic Wounds.

The dysfunction of endothelial cells caused by hyperglycemia is observed as a decrease in neovascularization in diabetic wound healing. Studies have found that epidermal stem cells (EpiSCs) can promote the angiogenesis of full-thickness wounds. To further explain the therapeutic effect of EpiSCs, EpiSC-derived exosomes (EpiSC-EXOs) are considered the main substance contributing to stem cell effectivity. In our study, EpiSCs and EpiSC-EXOs were supplied to the dorsal wounds of db/db mice. Results showed that EpiSCs could colonize in the wound area and both EpiSCs and EpiSC-EXOs could accelerate diabetic wound healing by promoting angiogenesis. In vitro, persistent high glucose led to the malfunction and apoptosis of endothelial cells. The apoptosis induced by high glucose is due to excessive autophagy and was alleviated by EpiSC-EXOs. RNA sequencing of EpiSC-EXOs showed that miR200b-3p was enriched in EpiSC-EXOs and alleviated the apoptosis of endothelial cells. Synapse defective rho GTPase homolog 1 was identified the target of miR200b-3p and affected the phosphorylation of ERK to regulate intracellular autophagy and apoptosis. Furthermore, animal experiments validated the angiogenic effect of miR200b-3p. Collectively, our results verified the effect of EpiSC-EXOs on apoptosis caused by hyperglycemia in endothelial cells through the miR200b-3p/synapse defective rho GTPase homolog 1 /RAS/ERK/autophagy pathway, providing a theoretical basis for EpiSC in treating diabetic wounds.

Morphological analysis and classification of posterior malleolar fractures based on CT scans.

OBJECTIVES: The aim of the study was to propose a classification system of posterior malleolar fractures by fracture lines with the use of CT scans, including 3D CT reconstruction, which can better understand morphological characteristics, analyze the mechanism and guide the surgeon to choose the optimal approach and fixation. METHODS: Patients with OTA/AO type 44 fractures involving the posterior malleolus and preoperative CT scans were included. We retrospectively analyzed 128 consecutive patients with posterior malleolar fractures from January 2013 to December 2019 at our institution. CT data were loaded into Mimics software (V20.0, Materialize), in which 3D CT reconstruction, morphological analysis and data measurements were made. RESULTS: Based on the number of fracture lines in 128 consecutive patients, posterior malleolar fractures were classified into three types: type 1 with a single fracture line, type 2 with double fracture lines and type 3 with multiple fracture lines. According to the distribution of the fracture line, type 1 was divided into types 1A, 1B and 1C, and type 2 was divided into types 2A, 2B and 2C. The fracture line from the fibular notch to the posterior rim of the distal tibia was defined as type 1A, and the fracture line to the medial malleolus was defined as type 1B. Type 1C was a small fragment in the posterior rim of the distal tibia. Type 2A was regarded as type 1A with type 1C. It was considered type 2B because another fracture line started from the fracture line of type 1A and extended to the medial malleolus. In type 2C, we could see that the double fracture lines were all from the fibular notch to the posterior rim of the distal tibia and did not cross. Type 3 fractures were comminuted fractures with multiple fracture lines. CONCLUSION: The morphology of posterior malleolar fractures, involvement of the fibular notch, or the medial malleolus can be obviously assessed by our classification system. We found the relation of the injury mechanism between type 1 and type 2 by comparing the area of the fragment. We have indicated that each type of fracture corresponds to its associated injury mechanism and which surgical approach and fixation can be chosen.

Talar coverage of the tibia plays a role in anterior ankle impingement: a retrospective cohort study.

PURPOSE: Ankle impingement is generally characterised by limited range of motion and pain due to pathological contact between structures. Anterior ankle impingement is usually diagnosed by clinical examination and radiographic evidence of tibiotalar osteophytes. In addition to osteophytes, radiographs may show a correlation between the tibia and talus, which may further aid in the diagnosis of anterior ankle impingement. The purpose of this study is to investigate the relationship between the tibia and talus in anterior ankle impingement. METHODS: In this retrospective cohort study, the tibial coverage of 22 patients with anterior ankle impingement was compared with that of 67 healthy subjects. RESULTS: The percentage of tibial coverage was 0.674 ± 0.043 in the anterior ankle impingement group and 0.580 ± 0.032 in the control group. The difference between groups was statistically significant (P < 0.05). CONCLUSIONS: In addition to existing criteria, the percentage of tibial coverage may provide valuable information for the diagnosis of anterior ankle impingement.

Targeting phenylpyruvate restrains excessive NLRP3 inflammasome activation and pathological inflammation in diabetic wound healing.

Moderate inflammation is essential for standard wound healing. In pathological conditions, such as diabetes, protracted and refractory wounds are associated with excessive inflammation, manifested by persistent proinflammatory macrophage states. However, the mechanisms are still unclear. Herein, we perform a metabolomic profile and find a significant phenylpyruvate accumulation in diabetic foot ulcers. Increased phenylpyruvate impairs wound healing and augments inflammatory responses, whereas reducing phenylpyruvate via dietary phenylalanine restriction relieves uncontrolled inflammation and benefits diabetic wounds. Mechanistically, phenylpyruvate is ingested into macrophages in a scavenger receptor CD36-dependent manner, binds to PPT1, and inhibits depalmitoylase activity, thus increasing palmitoylation of the NLRP3 protein. Increased NLRP3 palmitoylation is found to enhance NLRP3 protein stability, decrease lysosome degradation, and promote NLRP3 inflammasome activation and the release of inflammatory factors, such as interleukin (IL)-1ß, finally triggering the proinflammatory macrophage phenotype. Our study suggests a potential strategy of targeting phenylpyruvate to prevent excessive inflammation in diabetic wounds.

The Reliability and Accuracy of the Medial Malleolar Fracture Classification Based on 3D CT Reconstruction.

OBJECTIVE: There is a new medial malleolar fracture classification based on 3D CT reconstruction. However, there is no study assessing the reliability and accuracy of the new classification system and comparison between the new and the classic classification. This study aimed to compare the reliability and accuracy of the medial malleolar fracture classification based on 3D CT reconstruction and the Herscovici classification system. METHODS: We retrospectively analyzed the consecutive ankle fractures in our hospital from January 2013 to September 2020. Five inexperienced and five experienced orthopedic surgeons were included as observers to assess 68 cases with medial malleolar fractures. Ten evaluators classified the cases according to the two classification systems. The reference results of each case were made by the consensus of three senior trauma surgeons. The interobserver reliability, intraobserver reliability, and accuracy were evaluated at an interval of 6 weeks using Fleiss's kappa (κ) statistics. RESULTS: We found substantial interobserver and intraobserver reliability and 81.4% accuracy for the new classification, which was statistically superior to the Herscovici classification (P < 0.05). The reliability and accuracy of both classifications were similar in inexperienced and experienced groups, except for type III in the new classification. The interobserver reliability of type II was the best (P < 0.05), and the intraobserver reliability of IVc ranked the worst (P < 0.05) in the new classification. CONCLUSION: The reliability and accuracy of the new classification are superior to the Herscovici classification. Clinical experiences will not affect the assessment of both classification systems in most instances.

Mid-term follow-up evaluation of a new arthroscopic Broström procedure for chronic lateral ankle instability.

BACKGROUND: Chronic lateral ankle instability (CLAI) usually progresses from a previous lateral ankle sprain that was not treated properly. Several procedures have been introduced to address these patients, including open or arthroscopic techniques, the most common of which is the Broström procedure. Here, we describe a new outside-in arthroscopic Broström procedure and its results for treating patients with CLAI. METHODS: Thirty-nine patients (16 male and 23 female; mean age, 35 years [range, 16-60 years]) with CLAI were treated arthroscopically after failing non-operative management. All patients were symptomatic with a combination of recurrent ankle sprains, "giving way," and avoidance of sports and presented with a positive anterior drawer test upon the physical examination. All patients underwent arthroscopic lateral ligament reconstruction using the new technique. Patient characteristics and pre- and postoperative visual analog scale (VAS), American Orthopedic Foot and Ankle Society Ankle-Hindfoot Scale system (AOFAS), and Karlsson scores were recorded. RESULTS: The mean AOFAS score increased from 48 (mean 48, range 33-72) preoperatively to 91 (mean 91, range 75-98) at the final follow-up, Karlsson-Peterson and FAAM scores were also significantly improved. Two patients (5.13%) reported superficial peroneal nerve irritation symptoms postoperatively. Three patients (7.69%) complained of mild pain anteroinferior to the lateral ankle. CONCLUSIONS: The arthroscopic outside-in Broström procedure with a single suture anchor was a safe, effective, and reproducible technique for CLAI. Ankle stability resumed with a high clinical success rate. The main complication was injury to the superficial peroneal nerve, which crossed the area of repair.

Melatonin influences the biological characteristics of keloid fibroblasts through the Erk and Smad signalling pathways.

Background: Keloids are abnormal fibrous hyperplasias that are difficult to treat. Melatonin can be used to inhibit the development of certain fibrotic diseases but has never been used to treat keloids. We aimed to discover the effects and mechanisms of melatonin in keloid fibroblasts (KFs). Methods: Flow cytometry, CCK-8 assays, western blotting, wound-healing assays, transwell assays, collagen gel contraction assays and immunofluorescence assays were applied to demonstrate the effects and mechanisms of melatonin in fibroblasts derived from normal skin, hypertrophic scars and keloids. The therapeutic potential of the combination of melatonin and 5-fluorouracil (5-FU) was investigated in KFs. Results: Melatonin significantly promoted cell apoptosis and inhibited cell proliferation, migration and invasion, contractile capability and collagen production in KFs. Further mechanistic studies demonstrated that melatonin could inhibit the cAMP/PKA/Erk and Smad pathways through the membrane receptor MT2 to alter the biological characteristics of KFs. Moreover, the combination of melatonin and 5-FU remarkably promoted cell apoptosis and inhibited cell migration and invasion, contractile capability and collagen production in KFs. Furthermore, 5-FU suppressed the phosphorylation of Akt, mTOR, Smad3 and Erk, and melatonin in combination with 5-FU markedly suppressed the activation of the Akt, Erk and Smad pathways. Conclusions: Collectively, melatonin may inhibit the Erk and Smad pathways through the membrane receptor MT2 to alter the cell functions of KFs, while combination with 5-FU could exert even more inhibitory effects in KFs through simultaneous suppression of multiple signalling pathways.

Status and frontier analysis of indoor PM2.5-related health effects: a bibliometric analysis.

Epidemiological data indicate atmospheric particulate matter, especially fine particulate matter (PM2.5), has many negative effects on human health. Of note, people spend about 90% of their time indoors. More importantly, according to the World Health Organization (WHO) statistics, indoor air pollution causes nearly 1.6 million deaths each year, and it is considered as one of the major health risk factors. In order to obtain a deeper understanding of the harmful effects of indoor PM2.5 on human health, we used bibliometric software to summarize articles in this field. In conclusion, since 2000, the annual publication volume has increased year by year. America topped the list for the number of articles, and Professor Petros Koutrakis and Harvard University were the author and institution with the most published in this research area, respectively. Over the past decade, scholars gradually paid attention to molecular mechanisms, therefore, the toxicity can be better explored. Particularly, apart from timely intervention and treatment for adverse consequences, it is necessary to effectively reduce indoor PM2.5 through technologies. In addition, the trend and keywords analysis are favorable ways to find out future research hotspots. Hopefully, various countries and regions strengthen academic cooperation and integration of multi-disciplinary.

Single-stage transplantation combined with epidermal stem cells promotes the survival of tissue-engineered skin by inducing early angiogenesis.

BACKGROUND: The composite transplantation of a split-thickness skin graft (STSG) combined with an acellular dermal matrix (ADM) is a promising repair method for full-thickness skin defects. Due to delayed vascularization of the ADM, no currently available engineered skin tissue is able to permanently cover full-thickness skin defects via a single-stage procedure. Epidermal stem cells (EpSCs) have been found to promote angiogenesis in the wound bed. Whether EpSCs can induce early angiogenesis of dermal substitutes and promote the survival of single-stage tissue-engineered skin transplantation needs to be further studied. METHODS: In vitro, rat vascular endothelial cells (RVECs) were treated with the supernatant of EpSCs cultured in ADM and stimulated for 48 h. RVECs were analysed by RNA sequencing and tube formation assays. For the in vivo experiment, 75 rats were randomly divided into five groups: ADM, ADM + EpSCs (AE), STSG, ADM + STSG (AS), and ADM + STSG + EpSCs (ASE) groups. The quality of wound healing was estimated by general observation and H&E and Masson staining. The blood perfusion volume was evaluated using the LDPI system, and the expression of vascular markers was determined by immunohistochemistry (IHC). RESULTS: The active substances secreted by EpSCs cultured in ADM promoted angiogenesis, as shown by tube formation experiments and RNA-seq. EpSCs promoted epithelialization of the ADM and vascularization of the ADM implant. The ASE group showed significantly increased skin graft survival, reduced skin contraction, and an improved cosmetic appearance compared with the AS group and the STSG control group. CONCLUSIONS: In summary, our findings suggest that EpSCs promote the formation of new blood vessels in dermal substitutes and support one-step transplantation of tissue-engineered skin, and thereby provide new ideas for clinical application.

Analysis of miR-203a-3p/SOCS3-mediated induction of M2 macrophage polarization to promote diabetic wound healing based on epidermal stem cell-derived exosomes.

BACKGROUND: The development of therapeutic strategies to improve wound healing in individual diabetic patients remains challenging. Stem cell-derived exosomes represent a promising nanomaterial, and microRNAs (miRNAs) can be isolated from them. It is important to identify the potential therapeutic role of specific miRNAs, given that miRNAs can play a therapeutic role. METHODS: qPCR, flow cytometry, and western blotting were used to verify the effect of epidermal stem cell-derived exosomes (EpiSC-EXOs) on M2 macrophage polarization and SOCS3 expression. By screening key miRNAs targeting SOCS3 in EpiSC-EXOs by high-throughput sequencing, we verified the mechanism in vitro. Finally, an animal model was used to verify the effect of promoting healing. RESULTS: The use of EpiSC-EXOs reduced SOCS3 expression and promoted M2 macrophage polarization. The abundant miR-203a-3p present in the EpiSC-EXOs specifically bound to SOCS3 and activated the JAK2/STAT3 signaling pathway to induce M2 macrophage polarization. Treatment of the db/db mouse wound model with miR-203a-3p agomir exerted a pro-healing effect. CONCLUSIONS: Our results demonstrated that the abundant miR-203a-3p present in EpiSC-EXOs can promote M2 macrophage polarization by downregulating SOCS3 and suggested that diabetic wounds can obtain better healing effects through this mechanism.

Pre- and postnatal particulate matter exposure and blood pressure in children and adolescents: A systematic review and meta-analysis.

BACKGROUND: Early life is a susceptible period of air pollution-related adverse health effects. Hypertension in children might be life-threatening without prevention or treatment. Nevertheless, the causative association between environmental factors and childhood hypertension was limited. In the light of particulate matter (PM) as an environmental risk factor for cardiovascular diseases, this study investigated the association of pre- and postnatal PM exposure with blood pressure (BP) and hypertension among children and adolescents. METHOD: Four electronic databases were searched for related epidemiological studies published up to September 13, 2022. Stata 14.0 was applied to examine the heterogeneity among the studies and evaluate the combined effect sizes per 10 µg/m3 increase of PM by selecting the corresponding models. Besides, subgroup analysis, sensitivity analysis, and publication bias test were also conducted. RESULTS: Prenatal PM2.5 exposure was correlated with increased diastolic blood pressure (DBP) in offspring [1.14 mmHg (95% CI: 0.12, 2.17)]. For short-term postnatal exposure effects, PM2.5 (7-day average) was significantly associated with systolic blood pressure (SBP) [0.20 mmHg (95% CI: 0.16, 0.23)] and DBP [0.49 mmHg (95% CI: 0.45, 0.53)]; and also, PM10 (7-day average) was significantly associated with SBP [0.14 mmHg (95% CI: 0.12, 0.16)]. For long-term postnatal exposure effects, positive associations were manifested in SBP with PM2.5 [ß = 0.44, 95% CI: 0.40, 0.48] and PM10 [ß = 0.35, 95% CI: 0.19, 0.51]; DBP with PM1 [ß = 0.45, 95% CI: 0.42, 0.49], PM2.5 [ß = 0.31, 95% CI: 0.27, 0.35] and PM10 [ß = 0.32, 95% CI: 0.19, 0.45]; and hypertension with PM1 [OR = 1.43, 95% CI: 1.40, 1.46], PM2.5 [OR = 1.65, 95% CI: 1.29, 2.11] and PM10 [OR = 1.26, 95% CI: 1.09, 1.45]. CONCLUSION: Both prenatal and postnatal exposure to PM can increase BP, contributing to a higher prevalence of hypertension in children and adolescents.

Posterior malleolus fracture: a mid-term follow-up.

BACKGROUND: The treatment of posterior malleolar fractures is changing rapidly, and the evidence base is still catching up. This study aimed to assess the mid-term prognosis of posterior malleolar fractures based on different morphological types and provides evidence for the treatment of posterior malleolar fractures. METHODS: We retrospectively analyzed the data of inpatients with posterior malleolar fractures from 1 January 2012 to 31 December 2019 at one high-volume tertiary trauma center. Fracture morphology was classified into small-shell fragment, single-fragment (small-fragment and large-fragment) and multifragment (double-fragment and compressive-fragment) by computed tomography according to our previous study. All patients were followed up at an average of 5.06 (range, 2.21-8.70) years. The Olerud-Molander Ankle Score (OMAS), EuroQol-5 Dimensions (EQ-5D) and American Orthopedic Foot and Ankle Society (AOFAS) score were recorded. RESULTS: Seventy-nine patients were included, and 7 patients were classified into the small-shell group, 52 patients into the single-fragment group and 20 patients into the multifragment group. Of all the patients, the average OMAS, EQ-5D and AOFAS scores were 85.9, 82.8 and 92.5, respectively. In the single-fragment group, patients who underwent surgical fixation in the posterior malleolus had significantly better scores (P = 0.037, 0.033 and 0.027). Among the patients with small fragments, the surgical fixation group also had higher OMAS (93.1 ± 7.5 vs. 83.5 ± 19.5, P = 0.042) and AOFAS scores (98.1 ± 3.1 vs. 91.0 ± 14.1, P = 0.028). The mean OMAS, EQ-5D and AOFAS scores were 85.5, 85.7 and 91.7, respectively, in patients with multiple fragments who underwent surgical fixation. CONCLUSION: This study shows that in fractures with a single fragment, surgical fixation of the posterior malleolar fragment led to a better prognosis in the midterm. All single fragments should be fixed regardless of size. Fixation of the posterior region in all single- and multi-fragments in posterior malleolar fractures led to satisfactory outcomes. LEVEL OF EVIDENCE: Level III, follow-up study.