Hydrogel Microneedle Patches Loaded with Stem Cell Mitochondria-Enriched Microvesicles Boost the Chronic Wound Healing.

Rescuing or compensating mitochondrial function represents a promising therapeutic avenue for radiation-induced chronic wounds. Adult stem cell efficacies are primarily dependent on the paracrine secretion of mitochondria-containing extracellular vesicles (EVs). However, effective therapeutic strategies addressing the quantity of mitochondria and mitochondria-delivery system are lacking. Thus, in this study, we aimed to design an effective hydrogel microneedle patch (MNP) loaded with stem cell-derived mitochondria-rich EVs to gradually release and deliver mitochondria into the wound tissues and boost wound healing. We, first, used metformin to enhance mitochondrial biogenesis and thereby increasing the secretion of mitochondria-containing EVs (termed "Met-EVs") in adipose-derived stem cells. To verify the therapeutic effects of Met-EVs, we established an in vitro and an in vivo model of X-ray-induced mitochondrial dysfunction. The Met-EVs ameliorated the mitochondrial dysfunction by rescuing mitochondrial membrane potential, increasing adenosine 5'-triphosphate levels, and decreasing reactive oxygen species production by transferring active mitochondria. To sustain the release of EVs into damaged tissues, we constructed a Met-EVs@Decellularized Adipose Matrix (DAM)/Hyaluronic Acid Methacrylic Acid (HAMA)-MNP. Met-EVs@DAM/HAMA-MNP can load and gradually release Met-EVs and their contained mitochondria into wound tissues to alleviate mitochondrial dysfunction. Moreover, we found Met-EVs@DAM/HAMA-MNP can markedly promote macrophage polarization toward the M2 subtype with anti-inflammatory and regenerative functions, which can, in turn, enhance the healing process in mice with skin wounds combined radiation injuries. Collectively, we successfully fabricated a delivery system for EVs, Met-EVs@DAM/HAMA-MNP, to effectively deliver stem cell-derived mitochondria-rich EVs. The effectiveness of this system has been demonstrated, holding great potential for chronic wound treatments in clinic.

MicroRNA-138 Aggravates Inflammatory Responses of Macrophages by Targeting SIRT1 and Regulating the NF-κB and AKT Pathways.

BACKGROUND/AIMS: With increased understanding of sepsis, mortality is decreasing. However, there is still a lack of effective therapeutic strategy. The inflammatory response of macrophages is critical during sepsis. METHODS: Macrophages were stimulated with LPS. Western blotting and qRT-PCR were used to detect inflammatory responses. Then, the inhibitor of microRNA-138 was transfected and Western blotting, qRT-PCR, H&E staining and ELISA were used to verify the role of microRNA-138 in inflammation. Then target gene prediction databases were used to predict the potential target of microRNA-138. Both animal and cell models under LPS challenges were established to verify the regulation of SIRT1 and microRNA-138 during inflammation. RESULTS: The present study showed that microRNA-138 was increased in macrophages stimulated with LPS. Additionally, the NF-κB and AKT pathways were both activated. The pre-treatment of microRNA-138 inhibitor decreased inflammatory factors, downregulated the NF-κB pathway, activated the AKT pathway and protected against organ damage in mice challenged with LPS. SIRT1 was demonstrated as a potential target of microRNA-138In macrophages stimulated with LPS, the inhibition effect of microRNA-138 inhibitor on inflammation was lost by SIRT1 siRNA pre-treatment. In the animal model, the protective effect of microRNA-138 antagomir disappeared in SIRT1 knockout mice. CONCLUSION: We demonstrated that miR-138 participated in the inflammatory process by inhibiting SIRT1 and activating the NF-κB pathway.

A Randomized, Placebo-Controlled, Double-Blind, Prospective Clinical Trial of Botulinum Toxin Type A in Prevention of Hypertrophic Scar Development in Median Sternotomy Wound.

BACKGROUND: Linear hypertrophic scar is a common surgical problem that can be difficult to manage, especially for the median sternotomy scar. Botulinum toxin type A (BTA) is widely used in cosmetic surgery and has been shown to improve scar quality recently. The aim of this study was to evaluate the efficacy of BTA injected in the early postoperative of median sternotomy on preventing scar formation. METHODS: In this prospective randomized controlled trial, 19 consecutive patients who underwent median sternotomy were enrolled. The median sternotomy wound in each patient was divided into the upper half and the lower half. Both halves of the wound were randomized to receive the treatment with either BTA or normal saline. At 6-month follow-up, scars were assessed using the Vancouver Scar Scale, scar widths were measured, and patients were asked to evaluate their overall satisfaction. RESULTS: Seventeen patients with median sternotomy wounds completed the entire study. At 6-month follow-up, the mean Vancouver Scar Scale score for the BTA-treated group was 3.44 ± 1.68 and for the normal saline control group was 6.29 ± 2.39, and there was a statistically significant difference between the two groups (P < 0.05). There were also significant improvements in scar width and patient satisfaction for the BTA-treated halves of the wounds (P < 0.05). CONCLUSIONS: The study demonstrates that early postoperative BTA injection can decrease scar formation and reduce scar width in median sternotomy wounds, and the overall appearance is more satisfactory. LEVEL OF EVIDENCE I: 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 .

Acute downregulation of miR-199a attenuates sepsis-induced acute lung injury by targeting SIRT1.

MicroRNA-199a (miR-199a) is a novel gene regulator with an important role in inflammation and lung injury. However, its role in the pathogenesis of sepsis-induced acute respiratory distress syndrome (ARDS) is currently unknown. Our study explored the role of miR-199a in sepsis-induced ARDS and its mechanism of action. First, we found that LPS could upregulate miR-199a in alveolar macrophages. Downregulation of miR-199a inhibited the upregulation of inflammatory cytokines in alveolar macrophages and induced the remission of histopathologic changes, the reduction of proinflammatory cytokines, and the upregulation of apoptosis protein expression in an ARDS lung, showing a protective role for miR-199a. We further identified sirtuin 1 (SIRT1) as a direct target of miR-199a in alveolar macrophages, and the expression of SIRT1 was negatively correlated with the level of miR-199a. The protective role of miR-199a downregulation in LPS-stimulated alveolar macrophages and sepsis-induced ARDS could be attenuated by SIRT1 inhibitor. Taken together, these results indicate that downregulation of miR-199a might protect lung tissue against sepsis-induced ARDS by upregulation of SIRT1 through the suppression of excessive inflammatory responses and the inhibition of cellular apoptosis in lung tissue, suggesting its potential therapeutic effects on sepsis-induced ARDS.

BMP4 rs17563 polymorphism and nonsyndromic cleft lip with or without cleft palate: A meta-analysis.

BACKGROUND: Previous studies have investigated the relationship between human bone morphogenetic protein 4 gene (BMP4) rs17563 polymorphism and nonsyndromic cleft lip with or without cleft palate (NSCL/P). However, the results remained inconsistent. Therefore, we conducted a meta-analysis to assess the effect of BMP4 rs17563 polymorphism on NSCL/P. METHODS: Electronic searches in 5 databases were conducted to select all eligible studies up to March 2017. Odds ratios (ORs) with the corresponding 95% confidence intervals (CIs) were calculated to estimate the association. Sensitivity analysis was performed to evaluate the results stability by excluding each study in turn. Publication bias was assessed by Begg funnel plots and Egger test. RESULTS: A total of 11 case-control studies were included in the meta-analysis. The pooled frequency of the minor allele C for BMP4 rs17563 was lower in Asians (pooled frequency = 0.33, 95% CI: 0.29-0.37) than in Brazilian population (pooled frequency = 0.47, 95% CI: 0.40-0.54). The overall results showed no significant association of BMP4 rs17563 polymorphism with NSCL/P risk. However, the results turned out to be different when stratified by ethnicity. BMP4 rs17563 polymorphism was associated with a higher risk of NSCL/P among Asian ethnicity (C vs T: OR = 1.33, 95% CI: 1.02-1.73; CC vs TT: OR = 2.10, 95% CI: 1.28-3.43; CC vs TT + TC: OR = 2.16, 95% CI: 1.34-3.47) and among Caucasian population (TC vs TT: OR = 3.36, 95% CI: 2.03-5.54; TC + CC vs TT: OR = 3.71, 95% CI: 2.43-5.69). Among Brazilian population, BMP4 rs17563 polymorphism exerted a significantly protective effect on NSCL/P (C vs T: OR = 0.70, 95% CI: 0.58-0.84; CC vs TT: OR = 0.54, 95% CI: 0.33-0.88; TC vs TT: OR = 0.55, 95% CI: 0.44-0.69; TC + CC vs TT: OR = 0.56, 95% CI: 0.45-0.69). CONCLUSION: The results suggest that the C allele of BMP4 rs17563 may be a risk factor for NSCL/P among Asians and Caucasians, and may be a protective factor for NSCL/P in Brazilian population. Future large-sample studies with appropriate designs among specific populations are warranted to evaluate the association.