Diabetic foot ulcer (DFU) remains a serious chronic diabetic complication that can lead to disability. CircRNA‐itchy E3 ubiquitin protein ligase (circ‐ITCH) was observed to be down‐regulated in diabetic retinopathy and diabetic nephropathy, and overexpression of circ‐ITCH could inhibit the processes of these diseases. However, the detailed physiological and pathological functions of circ‐ITCH in wound healing of DFU remain undetermined.

Bone marrow stromal cell‐derived exosomal circular RNA improves diabetic foot ulcer wound healing by activating the nuclear factor erythroid 2‐related factor 2 pathway and inhibiting ferroptosis

Abstract Wound healing is a dynamic and highly sequential process involving a series of overlapping spatial and temporal phases, including hemostasis, inflammation, proliferation, and tissue remodeling. Mesenchymal stem cells (MSCs) are multipotent stem cells with self-renewal, multidirectional differentiation potential, and paracrine regulation. Exosomes are subcellular vesicular components 30–150 nm in size and are novel carriers of intercellular communication in regulating the biological behaviors of skin cells. Compared to MSCs, MSC-derived exosomes (MSC-exos) possess lower immunogenicity, easy storage, and highly effective biological activity. MSC-exos, mainly derived from adipose-derived stem cells (ADSCs), bone marrow-derived MSCs (BMSCs), human umbilical cord MSCs (hUC-MSCs), and other stem cell types, play a role in shaping the activity of fibroblasts, keratinocytes, immune cells, and endothelial cells in diabetic wounds, inflammatory wound repair, and even wound-related keloid formation. Therefore, this study focuses on the specific roles and mechanisms of different MSC-exos in wound healing, as well as the current limitations and various perspectives. Deciphering the biological properties of MSC-exos is crucial to providing a promising cell-free therapeutic tool for wound healing and cutaneous regeneration. Graphical Abstract 

Stem cell-derived exosomes: emerging therapeutic opportunities for wound healing

Abstract Skin wounds are characterized by injury to the skin due to trauma, tearing, cuts, or contusions. As such injuries are common to all human groups, they may at times represent a serious socioeconomic burden. Currently, increasing numbers of studies have focused on the role of mesenchymal stem cell (MSC)-derived extracellular vesicles (EVs) in skin wound repair. As a cell-free therapy, MSC-derived EVs have shown significant application potential in the field of wound repair as a more stable and safer option than conventional cell therapy. Treatment based on MSC-derived EVs can significantly promote the repair of damaged substructures, including the regeneration of vessels, nerves, and hair follicles. In addition, MSC-derived EVs can inhibit scar formation by affecting angiogenesis-related and antifibrotic pathways in promoting macrophage polarization, wound angiogenesis, cell proliferation, and cell migration, and by inhibiting excessive extracellular matrix production. Additionally, these structures can serve as a scaffold for components used in wound repair, and they can be developed into bioengineered EVs to support trauma repair. Through the formulation of standardized culture, isolation, purification, and drug delivery strategies, exploration of the detailed mechanism of EVs will allow them to be used as clinical treatments for wound repair. In conclusion, MSC-derived EVs-based therapies have important application prospects in wound repair. Here we provide a comprehensive overview of their current status, application potential, and associated drawbacks. 

Mesenchymal stem cell-derived extracellular vesicles in skin wound healing: roles, opportunities and challenges

Diabetes mellitus (DM) is among the chronic metabolic disorders that its incidence rate has shown an increase in developed and wealthy countries due to lifestyle and obesity. The treatment of DM has always been of interest, and significant effort has been made in this field. Exosomes belong to extracellular vesicles with nanosized features (30-150 nm) that are involved in cell-to-cell communication and preserving homeostasis. The function of exosomes is different based on their cargo, and they may contain lipids, proteins, and nucleic acids. The present review focuses on the application of exosomes in the treatment of DM; both glucose and lipid levels are significantly affected by exosomes, and these nanostructures enhance lipid metabolism and decrease its deposition. Furthermore, exosomes promote glucose metabolism and affect the level of glycolytic enzymes and glucose transporters in DM. Type I DM results from the destruction of β cells in the pancreas, and exosomes can be employed to ameliorate apoptosis and endoplasmic reticulum (ER) stress in these cells. The exosomes have dual functions in mediating insulin resistance/sensitivity, and M1 macrophage-derived exosomes inhibit insulin secretion. The exosomes may contain miRNAs, and by transferring among cells, they can regulate various molecular pathways such as AMPK, PI3K/Akt, and β-catenin to affect DM progression. Noteworthy, exosomes are present in different body fluids such as blood circulation, and they can be employed as biomarkers for the diagnosis of diabetic patients. Future studies should focus on engineering exosomes derived from sources such as mesenchymal stem cells to treat DM as a novel strategy. 

https://www.dovepress.com/getfile.php?fileID=79225

Exosomes as Promising Nanostructures in Diabetes Mellitus: From Insulin Sensitivity to Ameliorating Diabetic Complications

Exosomes, as therapeutically relevant cell-secreted extracellular vesicles, have attracted enormous interest because they participate in intercellular communication and facilitate wound healing. Stem cell-derived exosomes exhibit similar biological effects to source cells with the exception of low immunogenicity and no tumorigenicity, as well as superior efficacy in promoting wound healing. Exosomes accelerate wound healing by promoting angiogenesis and cell proliferation, as well as balancing inflammatory responses. Particularly, when exosomes are genetically modified or used in combination with materials, they can exhibit better comprehensive therapeutic properties, such as enriching active ingredients, targeted delivery, and physiological barrier to penetration, which are not available in traditional single products. Besides, exosomes have also been considered for diagnostic and therapeutic uses related to wounds, such as repairing complex wounds, enhancing graft success, treating related complications, and serving as diagnostic biomarkers. However, their clinical applications still face challenges, as reliable commercial products are not yet available. This review will focus on recent research advances that describe the characteristics and isolation of exosomes, introduce the sources of exosomes suitable for wound repair and related complications, illustrate the value of engineered exosomes and their development directions in the future, and provide evidence for the potential therapeutic application of exosomes in wound healing, as well as discuss potential risks, challenges, and solutions for future applications.

Exosomes and Their Bioengineering Strategies in the Cutaneous Wound Healing and Related Complications: Current Knowledge and Future Perspectives

Exosomes from linc00511-overexpressing ADSCs accelerates angiogenesis in diabetic foot ulcers healing by suppressing PAQR3-induced Twist1 degradation.

Objective: This study was determined to investigate the impact of intranasal dexmedetomidine (DEX) on postoperative sleep quality in older patients (age over 65) with chronic insomnia during their hospitalization after surgery.Design: A randomized double-blind controlled trial was conducted to compare the effects of intranasal dexmedetomidine spray with a placebo group.Setting and Participants: The study was carried out at Xiangya Hospital, Central South University. 110 participants with chronic insomnia were analyzed.Methods: This trial enrolled older patients who underwent total hip/knee arthroplasty and randomized them to receive intranasal dexmedetomidine (2.0 μg/kg) or saline daily at around 9 p.m. after surgery until discharge. The primary outcomes were subjective sleep quality assessed with the Leeds Sleep Evaluation Questionnaire (LSEQ). The secondary outcomes included the objective sleep quality measured with the Acti-graph, the Pittsburgh Sleep Quality Index (PSQI), the Insomnia Severity Index (ISI). The other outcomes included the incidence of delirium, levels of inflammatory factors, visual analog scale (VAS) pain scores, postoperative opioid consumption, and treatment-related adverse events.Results: 174 patients were screened for eligibility, and 110 were recruited and analyzed. The DEX group had significantly higher scores on both the LSEQ-Getting to sleep and LSEQ-Quality of Sleep at each time point compared to the placebo (p < 0.0001), The least squares (LS) mean difference in LSEQ-GTS score at T0 between placebo group and DEX group was 2 (95% CI, −1–6), p = 0.4071 and at T5 was −14 (95% CI, −17 to −10), p < 0.0001; The LS mean difference in the LSEQ-QOS score at T0 was −1 (95% CI, −4 to 1), p = 0.4821 and at T5 was −16 (95% CI, −21 to −10), p < 0.0001. The DEX group exhibited significant improvement in Total Sleep Time (TST), Sleep Onset Latency (SOL), and Sleep Efficiency (SE), at each time point after treatment compared to the placebo group (p < 0.0001). The PSQI and ISI scores in the DEX group were reduced after treatment (p < 0.001). No significant adverse events were reported with the use of dexmedetomidine.Conclusion and Implications: This study demonstrates that intranasal administration of dexmedetomidine improves postoperative sleep quality in older patients with chronic insomnia who undergo surgery, without increasing the incidence of adverse effects.Clinical Trial Registration:http://www.chictr.org.cn/, identifier ChiCTR2200057133

Intranasal dexmedetomidine improves postoperative sleep quality in older patients with chronic insomnia: a randomized double-blind controlled trial

Background: Exosomes from ADSCs (adipose-derived stem cells) possess various therapeutic effects, but their roles in diabetic foot ulcers are poorly understood. We aimed to investigate the role of ADSCs-derived exosomes on regulating angiogenesis in diabetic foot ulcers healing.

Methods: EPCs (endothelial progenitor cells) from human peripheral blood were applied as in vitro model of angiogenesis. Exosomes isolated from ADSCs culture medium were characterized by electron microscopy, size distribution and biomarker expression. Cell proliferation, migration, apoptosis and angiogenesis were detected by CCK-8 and EdU staining, wound healing, flow cytometry and tube formation assays, respectively. Expression of inflammatory factors and related genes in serum and cell culture or tissues were detected by ELISA, IF, qRT-PCR and western blotting as appropriate. The PAQR3-BTRC-Twist1 interaction was verified using Co-immunoprecipitation. Rat diabetic foot model was further constructed for the evaluation of wound healing and histological alterations.

Findings: EPCs from diabetes showed suppressed proliferation, migration and angiogenesis and decreased Twist1 protein. Similarly, high glucose repressed the proliferation, migration and angiogenesis of EPCs, which also elevated PAQR3 and suppressed Twist1 expression. However, these impaired EPCs biological functions were recovered by the application of exosomes from linc00511-overexpressing ADSCs, along with increased Twist1 and decreased PAQR3. Mechanistically, PAQR3 overexpression reduced Twist1 protein level in EPCs by enhancing BTRC-mediated Twist1 ubiquitin degradation. Exosomes from linc00511-overexpressing ADSCs alleviated rat diabetic foot ulcers by inhibiting Twist1 ubiquitination to promote angiogenesis.

Interpretation: Exosomes from linc00511-overexpressing ADSCs promotes diabetic foot ulcers healing by accelerating angiogenesis via suppressing PAQR3-induced Twist1 ubiquitin degradation.

Funding Statement: None.

Declaration of Interests: The authors declare that there is no conflict of interest.

Ethics Approval Statement: The study with human blood samples were approved by the Ethics Committee of Central South University (Changsha, China). Written informed consents were obtained from all DM patients and volunteers before blood sample collection. Above animal operations were approved by the Research Animal Ethics Committee of Central South University and carried out following the Guide for the Care and Use of Laboratory Animals (NIH).

Exosomes from linc00511-Overexpressing ADSCs Accelerates Angiogenesis in Diabetic Foot Ulcers Healing by Suppressing of PAQR3-Induced Twist1 Degradation

In China, dezocine is commonly employed as a partial agonist of mu/kappa opioid receptors during anesthesia induction for surgical patients, yet evidence supporting its causal association with emergence delirium is limited. The objective of this investigation was to evaluate the impact of intravenous dezocine administered during anesthesia induction on emergence delirium. The retrospective studied existing data containing medical records of patients undergoing an elective laparoscopy procedure and the study was conducted with ethics-board approval. The primary outcome was the incidence of emergence delirium. Secondary outcomes included the VAS in the PACU and 24 h after surgery, the RASS score in the PACU, postoperative MMSE, hospital stay, and ICU stay. A total of 681 patients were analyzed, after being propensity score-matched, the dezocine and non-dezocine group each had 245 patients. Emergence delirium occurred in 26/245 (10.6%) of patients who received dezocine and 41/245 (16.7%) of patients did not receive dezocine. Patients on whom dezocine was used were associated with a significantly lower incidence of emergence delirium (absolute risk difference, −6.1%, 95% CI, −12% to −0.2%; relative risk [RR], 0.63; 95% CI, 0.18–0.74). All secondary outcome measures and adverse outcomes were not significantly different. The use of dezocine during anesthesia induction was associated with a decreased incidence of emergence delirium after elective laparoscopic surgeries.

https://www.mdpi.com/2075-4426/13/4/590/pdf?version=1679982874

Effects of Dezocine on the Reduction of Emergence Delirium after Laparoscopic Surgery: A Retrospective Propensity Score-Matched Cohort Study

Objective: To investigate the relationship between intraoperative electroencephalogram burst suppression (BS) and emergence delirium (ED) in elderly patients undergoing elective laparoscopic surgery under total intravenous anesthesia (TIVA). Methods: From October 2017 to September 2019, a total of 358 elderly patients who underwent elective laparoscopic surgery under TIVA at Xiangya Hospital, Central South University, were included. Patients were divided into two groups based on the confusion assessment method for the intensive care unit (CAM-ICU) assessment conducted before leaving the post-anesthesia care unit (PACU): the ED group [n=63, 46 males, 17 females, average age of (70.8±0.6) years] and the non-ED group [n=295, 220 males, 75 females, average age of (69.7±0.2) years]. Preoperative general information, intraoperative conditions, and intraoperative electroencephalogram BS status were collected. A multivariate logistic regression model was employed to identify risk factors associated with ED. Results: In the ED group, the duration of surgery, intraoperative blood loss, the burst suppression ratio (BSR)>10% lasting for more than 1 minute were (224.4±9.6) min, (240.8±33.9) ml, 36.5% (23/63), respectively, which were higher than those of the non-ED group [(204.7±3.6) min, (150.5±9.2) ml, 21.7% (64/295), all P<0.05]. Multivariate logistic regression analysis revealed that a longer duration of education was a protective factor for ED (OR=0.904, 95%CI: 0.833-0.982,P=0.016), whereas increased intraoperative blood loss (OR=1.002, 95%CI: 1.000-1.003, P=0.013) and BSR>10% lasting for more than 1 minute (OR=2.131, 95%CI: 1.004-4.524,P=0.049) were identified as risk factors for ED. Conclusion: In elderly patients undergoing laparoscopic surgery under TIVA, intraoperative electroencephalogram BS may be a risk factor for ED.目的： 探讨老年患者全凭静脉麻醉下择期腹腔镜术中脑电爆发抑制与苏醒期谵妄（ED）的相关性。 方法： 回顾性收集中南大学湘雅医院2017年10月至2019年9月行全凭静脉麻醉下择期腹腔镜手术治疗的老年患者358例。根据患者出麻醉后恢复室（PACU）前重症监护室意识模糊评估量表（CAM-ICU）结果将患者分为ED组［63例，男46例，女17例，年龄（70.8±0.6）岁］及非ED组［295例，男220例，女75例，年龄（69.7±0.2）岁］。采集患者术前一般情况、术中相关情况、术中脑电爆发抑制情况，采用多因素logistic回归模型分析患者发生ED的危险因素。 结果： ED组患者手术时间、术中失血量、术中脑电爆发抑制比（BSR）>10% 且持续1 min以上发生率分别为（224.4±9.6）min、（240.8±33.9）ml、36.5%（23/63），均高于非ED组的（204.7±3.6）min、（150.5±9.2）ml、21.7%（64/295）（均P<0.05）。多因素logistic回归分析显示，受教育年限长是ED的保护因素（OR=0.904，95%CI：0.833~0.982，P=0.016），术中失血量多（OR=1.002，95%CI：1.000~1.003，P=0.013）、BSR>10%且持续1 min以上（OR=2.131，95%CI：1.004~4.524，P=0.049）是ED的危险因素。 结论： 老年患者腹腔镜术中脑电爆发抑制可能是手术后ED的危险因素。. 

[The correlation between burst suppression on electroencephalogram during laparoscopic surgery and emergence delirium in elderly patients].

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