Trauma-associated extracellular histones mediate inflammation via a MYD88-IRAK1-ERK signaling axis and induce lytic cell death in human adipocytes.

Despite advances in the treatment and care of severe physical injuries, trauma remains one of the main reasons for disability-adjusted life years worldwide. Trauma patients often suffer from disturbances in energy utilization and metabolic dysfunction, including hyperglycemia and increased insulin resistance. White adipose tissue plays an essential role in the regulation of energy homeostasis and is frequently implicated in traumatic injury due to its ubiquitous body distribution but remains poorly studied. Initial triggers of the trauma response are mainly damage-associated molecular patterns (DAMPs) such as histones. We hypothesized that DAMP-induced adipose tissue inflammation contributes to metabolic dysfunction in trauma patients. Therefore, we investigated whether histone release during traumatic injury affects adipose tissue. Making use of a murine polytrauma model with hemorrhagic shock, we found increased serum levels of histones accompanied by an inflammatory response in white adipose tissue. In vitro, extracellular histones induced an inflammatory response in human adipocytes. On the molecular level, this inflammatory response was mediated via a MYD88-IRAK1-ERK signaling axis as demonstrated by pharmacological and genetic inhibition. Histones also induced lytic cell death executed independently of caspases and RIPK1 activity. Importantly, we detected increased histone levels in the bloodstream of patients after polytrauma. Such patients might benefit from a therapy consisting of activated protein C and the FDA-approved ERK inhibitor trametinib, as this combination effectively prevented histone-mediated effects on both, inflammatory gene activation and cell death in adipocytes. Preventing adipose tissue inflammation and adipocyte death in patients with polytrauma could help minimize posttraumatic metabolic dysfunction.

Cellular mechanisms of wound closure under cyclic stretching.

Wound closure is a fundamental process in many physiological and pathological processes, but the regulating effects of external force on the closure process are still unclear. Here, we systematically studied the closure process of wounds of different shape under cyclic stretching. We found that the stretching amplitude and direction had significant effect on the healing speed and healing mode. For instance, there was a biphasic dependence of the healing speed on the stretching amplitude. That is, the wound closure was faster under relatively small and large amplitude, while it was slower under intermediate amplitude. At the same time, the stretching could regulate the healing pattern. We showed that the stretching would increase the healing speed along the direction perpendicular to the stretching direction. Specifically, when the stretching was along the major axis of the wound, it accelerated the healing speed along the short axis, which induced a rosette to stitching-line mode transition. In contrast, stretching along the minor axis accelerated the healing speed along the long axis, inducing a stitching-line to rosette mode transition. Our theoretical analyses demonstrated that the wound closure process was coregulated by the mechanical factors including prestress in the cytoskeleton, the protrusion of cells, and the contraction of the actin ring, as well as the geometry of the wound. The cyclic stretch could further modulate the roles of these factors. For example, the stretching changed the stress field in the cell layer, and switched the direction of cell protrusions. This article reveals important cellular mechanisms of the wound healing process under cyclic stretching, and provides an insight into possible approaches of regulating cell collective behaviors via mechanical forces.

Imunoexpressão de ING 4, VEGF e NF-κB em lesões periapicais inflamatórias / Immunoexpression of ING 4, VEGF and NF-κB in inflammatory periapical lesions

As lesões periapicais inflamatórias (LPIs) são condições patológicas decorrentes de infecções de origem odontogênica, principalmente representadas pelos granulomas periapicais (GPs) e cistos radiculares (CRs). Sua patogênese está associada a mecanismos imunológicos e angiogênicos. O presente estudo, do tipo retrospectivo, teve como objetivo analisar, de forma semiquantitativa, a expressão imuno-histoquímica de ING-4, VEGF e NF-κB em LPIs, e correlacionar o padrão de expressão dessas proteínas. A amostra consistiu de 26 GPs, 17 CRs e 19 cistos radiculares residuais (CRRs). Foram avaliados espessura epitelial e infiltrado inflamatório, e a associação desses achados com o padrão de expressão das proteínas ING-4, VEGF e NF-κB nas LPIs selecionadas. Para a realização da análise estatística, foram utilizados os testes de qui-quadrado, Kruskal-Wallis, Mann-Whitney e correlação de Spearman (p < 0,05). O infiltrado inflamatório exibiu maior intensidade no GP, seguido pelo CR, e por último, o CRR (p < 0,05). Apesar de não haver associação estatisticamente significativa ao associar a expressão de ING-4 nas células inflamatórias do tecido conjuntivo ou cápsula fibrosa entre os grupos de LPIs, o GP e CR evidenciaram, através da média de postos, maior expressão dessa proteína. Não foi evidenciada associação estatisticamente significativa de ING-4 com a intensidade do infiltrado inflamatório. A imunoexpressão de VEGF no núcleo das células inflamatórias do tecido conjuntivo ou cápsula fibrosa exibem associação significativa com as LPIs, que ocorre maior expressão dessa proteína nos cistos (p= 0,002). A maior expressão de NF-κB foi evidenciada nos casos de GPs, tanto a nível nuclear quanto citoplasmático das células inflamatórias (p = 0,005; p = 0,002). Não houve associação estatisticamente significativa quando comparada a expressão de NF-κB entre os cistos, mas a mediana da expressão dessa proteína foi maior para os CRs. Na cápsula fibrosa, a imunoexpressão nuclear e citoplasmática de NF-κB nas células inflamatórias foi superior nas lesões periapicais com intenso infiltrado inflamatório (p < 0,001). Portanto, sugere-se que ING-4, VEGF e NF-κB participam do desenvolvimento das LPIs, e apesar de ocorrer relação diretamente proporcional entre a expressão dessas proteínas, ING-4 não exerceu atividade reguladora na inflamação associada a essas lesões (AU).

Inflammatory periapical lesions (IPLs) are pathological conditions resulting from infections of odontogenic origin, being mainly represented by periapical granulomas (PGs) and radicular cysts (RCs). Its pathogenesis is associated with immunological and angiogenic mechanisms. This retrospective study, semi-quantitative and comparative aimed to analyze the immunohistochemical expression of ING-4, VEGF and NF-κB in IPLs, and to correlate the pattern of expression of these proteins. The sample consisted of 26 were PGs, 17 RCs and 19 residual radicular cysts (RRCs). Epithelial thickness and inflammatory infiltrate were evaluated, and the correlation of these findings with the expression pattern of ING-4, VEGF and NF-κB proteins in selected IPLs. To perform the statistical analysis, the chi-square, Kruskal-Wallis, Mann-Whitney and Spearman correlation tests were used (p < 0.05). The inflammatory infiltrate exhibited greater intensity in the PG, followed by the RC, and finally, the RRC (p < 0.05). Although there was no statistically significant association when associating the expression of ING-4 in inflammatory cells of the connective tissue or fibrous capsule the groups of IPLs, the PG and RC showed higher expression of this protein. There was no statistically significant association between ING-4 and the intensity of the inflammatory infiltrate. Immunoexpression of VEGF in the nucleus of inflammatory cells in the connective tissue or fibrous capsule shows a significant association with IPLs, in which there is greater expression of this protein occurring in cysts (p= 0,002). The highest expression of NF-κB was evidenced in cases of PGs, both at the nuclear and cytoplasmic level of inflammatory cells (p=0,005; p= 0,002). There was no statistically significant association when comparing the expression of NF-κB between the cysts, but the median expression of this protein was expression was higher for the RCs. In the fibrous capsule, nuclear and cytoplasmic NF-κB immunoexpression in inflammatory cells was higher in periapical lesions with intense inflammatory infiltrate (p<0.001). Therefore, it is suggested that ING-4, VEGF and NF-κB participate in the etiopathogenesis of IPLs, and that there is a directly proportional relationship between the expression of these proteins. ING-4 did not exert regulatory activity in the inflammation associated with these lesions (AU).

A New Target of the Four-Herb Chinese Medicine for Wound Repair Promoted by Mitochondrial Metabolism Using Protein Acetylation Analysis.

BACKGROUND Wound healing is a dynamic and complex process that is regulated by a variety of factors and pathways. This study sought to identify the mechanisms of the four-herb Chinese medicine ANBP in enhancing wound repair. MATERIAL AND METHODS By comparing the group treated with ANBP for 6 h (Z6h) with the corresponding control group (C6h), we used the new high-throughput differential acetylation proteomics method to explore the mechanism of ANBP treatment and analyse and identify new targets of ANBP for promoting wound healing. RESULTS ANBP promoted skin wound healing in mice; the wound healing process was accelerated and the wound healing time was shortened (P<0.05). The upregulated proteins were distributed mostly in the mitochondria to nuclear respiratory chain complexes and cytoplasmic vesicles. The dominant pathways for upregulated proteins were fatty acid metabolism, pyruvate metabolism, and tricarboxylic acid cycle. Pdha1 was upregulated with the most acetylation sites, while the downregulated Ncl, and Pfkm were most acetylated. CONCLUSIONS The findings from our study showed that ANBP improved cell aerobic respiration through enhanced glycolysis, pyruvic acid oxidative decarboxylation, and the Krebs cycle to produce more ATP for energy consumption, thus accelerating wound repair of skin.

Hybrid feature selection-based machine learning Classification system for the prediction of injury severity in single and multiple-vehicle accidents.

To undertake a reliable analysis of injury severity in road traffic accidents, a complete understanding of important attributes is essential. As a result of the shift from traditional statistical parametric procedures to computer-aided methods, machine learning approaches have become an important aspect in predicting the severity of road traffic injuries. The paper presents a hybrid feature selection-based machine learning classification approach for detecting significant attributes and predicting injury severity in single and multiple-vehicle accidents. To begin, we employed a Random Forests (RF) classifier in conjunction with an intrinsic wrapper-based feature selection approach called the Boruta Algorithm (BA) to find the relevant important attributes that determine injury severity. The influential attributes were then fed into a set of four classifiers to accurately predict injury severity (Naive Bayes (NB), K-Nearest Neighbor (K-NN), Binary Logistic Regression (BLR), and Extreme Gradient Boosting (XGBoost)). According to BA's experimental investigation, the vehicle type was the most influential factor, followed by the month of the year, the driver's age, and the alignment of the road segment. The driver's gender, the presence of a median, and the presence of a shoulder were all found to be unimportant. According to classifier performance measures, XGBoost surpasses the other classifiers in terms of prediction performance. Using the specified attributes, the accuracy, Cohen's Kappa, F1-Measure, and AUC-ROC values of the XGBoost were 82.10%, 0.607, 0.776, and 0.880 for single vehicle accidents and 79.52%, 0.569, 0.752, and 0.86 for multiple-vehicle accidents, respectively.

Milk exosomes-mediated miR-31-5p delivery accelerates diabetic wound healing through promoting angiogenesis.

The refractory diabetic wound has remained a worldwide challenge as one of the major health problems. The impaired angiogenesis phase during diabetic wound healing partly contributes to the pathological process. MicroRNA (miRNA) is an essential regulator of gene expression in crucial biological processes and is a promising nucleic acid drug in therapeutic fields of the diabetic wound. However, miRNA therapies have limitations due to lacking an effective delivery system. In the present study, we found a significant reduction of miR-31-5p expression in the full-thickness wounds of diabetic mice compared to normal mice. Further, miR-31-5p has been proven to promote the proliferation, migration, and angiogenesis of endothelial cells. Thus, we conceived the idea of exogenously supplementing miR-31-5p mimics to treat the diabetic wound. We used milk-derived exosomes as a novel system for miR-31-5p delivery and successfully encapsulated miR-31-5p mimics into milk exosomes through electroporation. Then, we proved that the miR-31-5p loaded in exosomes achieved higher cell uptake and was able to resist degradation. Moreover, our miRNA-exosomal formulation demonstrated dramatically improved endothelial cell functions in vitro, together with the promotion of angiogenesis and enhanced diabetic wound healing in vivo. Collectively, our data showed the feasibility of milk exosomes as a scalable, biocompatible, and cost-effective delivery system to enhance the bioavailability and efficacy of miRNAs.

Electrospun multifunctional nanofibrous mats loaded with bioactive anemoside B4 for accelerated wound healing in diabetic mice.

With the worldwide prevalence of diabetes and considering the complicated microenvironment of diabetic wounds, the design and development of innovative multifunctional wound dressing materials are much wanted for the treatment of hard-to-heal wounds in diabetic patients. In the present study, anti-inflammatory ingredients loaded with nanofibrous wound dressing materials were manufactured by a promising blend-electrospinning strategy, and their capability for treating the diabetic wound was also systematically explored. A polymer blend consisting of Chitosan (CS) and polyvinyl alcohol (PVA) was electrospun into CS-PVA nanofibrous mats as control groups. In the meanwhile, a bioactive ingredient of Chinese medicine Pulsatilla, anemoside B4(ANE), with different contents were loaded into the electrospinning solution to construct CS-PVA-ANE nanofibrous mats. The developed CS-PVA-ANE wound dressing materials exhibited multifunctional properties including prominent water absorption, biomimetic elastic mechanical properties, and sustained ANE releasing behavior, as well as outstanding hemostatic properties. The in vitro studies showed that the CS-PVA-ANE nanofiber mats could significantly suppress lipopolysaccharide (LPS)-stimulated differentiation of pro-inflammatory (M1) macrophage subsets, and notably reduce the reactive oxygen species (ROS) generation, as well as obviously decrease inflammatory cytokine release. The in vivo animal studies showed that the CS-PVA-ANE nanofiber mats promoted the healing of diabetic wounds by significantly enhancing wound closure rates, accelerating excellent angiogenesis, promoting re-epithelization and collagen matrix deposition throughout all stages of wound healing. The present study demonstrated that CS-PVA-ANE nanofiber mats could effectively shorten the wound-healing time by inhibiting inflammatory activity, which makes them promising candidates for the treatment of hard-to-heal wounds caused by diabetes.

Cellular Interaction of Human Skin Cells towards Natural Bioink via 3D-Bioprinting Technologies for Chronic Wound: A Comprehensive Review.

Skin substitutes can provide a temporary or permanent treatment option for chronic wounds. The selection of skin substitutes depends on several factors, including the type of wound and its severity. Full-thickness skin grafts (SGs) require a well-vascularised bed and sometimes will lead to contraction and scarring formation. Besides, donor sites for full-thickness skin grafts are very limited if the wound area is big, and it has been proven to have the lowest survival rate compared to thick- and thin-split thickness. Tissue engineering technology has introduced new advanced strategies since the last decades to fabricate the composite scaffold via the 3D-bioprinting approach as a tissue replacement strategy. Considering the current global donor shortage for autologous split-thickness skin graft (ASSG), skin 3D-bioprinting has emerged as a potential alternative to replace the ASSG treatment. The three-dimensional (3D)-bioprinting technique yields scaffold fabrication with the combination of biomaterials and cells to form bioinks. Thus, the essential key factor for success in 3D-bioprinting is selecting and developing suitable bioinks to maintain the mechanisms of cellular activity. This crucial stage is vital to mimic the native extracellular matrix (ECM) for the sustainability of cell viability before tissue regeneration. This comprehensive review outlined the application of the 3D-bioprinting technique to develop skin tissue regeneration. The cell viability of human skin cells, dermal fibroblasts (DFs), and keratinocytes (KCs) during in vitro testing has been further discussed prior to in vivo application. It is essential to ensure the printed tissue/organ constantly allows cellular activities, including cell proliferation rate and migration capacity. Therefore, 3D-bioprinting plays a vital role in developing a complex skin tissue structure for tissue replacement approach in future precision medicine.

Factors related to severe single-vehicle tree crashes: In-depth crash study.

Vehicle-tree collisions are the most common type of road crash with fixed obstacle in Czech Republic. Based on the literature review and using real world in-depth crash data, this paper aims to define factors, which significantly influence the injury severity of single vehicle-tree crashes. In-depth data provide a comprehensive view to the failure on the system infrastructure-human-vehicle related to crash, the in-depth crash database include very detailed information related to infrastructure, vehicle, human failure and crash participants characteristics and their medical condition and also crash reconstruction. Multinomial logistic regression and generalized linear mixed model were used to determine the individual effect of each predictor. The statistically significant variables were the day period, trunk diameter and impact speed. Using multinomial logistic regression shows also vehicle age as statistically significant. Obtained results can help to efficiently direct countermeasures not only on the road infrastructure-e.g. speed reduction in selected locations with specified tree character. However, the emphasis should be also focused on driver behaviour.

Effect of Taspine hydrochloride on the repair of rat skin wounds by regulating keratinocyte growth factor signal.

To explore the regulation of keratinocyte growth factor (KGF) in the process of repairing rat skin wounds by taspine hydrochloride (TA/HCl), 45 male Sprague-Dawley (SD) rats were purchased and divided into an experimental group, a dimethyl sulfoxide (DMSO) control group, and a basic fibroblast growth factor (bFGF) control group, each with 15 only. A back trauma model was innovatively adopted to prevent rats from biting and contaminating. The wound healing time and healing rate of the rat, and the Hydroxyproline (Hyp) and KGF expressions were observed. Morphological changes of wound tissue and the number of capillaries were observed after hematoxylin-eosin (HE) staining. The results showed that wound healing rate of experimental group and bFGF group was significantly higher than that of DMSO group (P < 0.05) after 2-15 days, and wound healing time of experimental group was 18 days, which was significantly lower than that of the DMSO group (P < 0.05). Expression levels of Hyp and KGF in the granulation tissue of rats in the experimental group were much higher than those in the DMSO control group after trauma (P < 0.05). In early stage of wound tissue repair, the number of new capillaries formed in experimental group was significantly higher than that in DMSO control group (P < 0.05). In summary, this study innovatively focused on KGF. The mechanism of TA/HCL promoting rat skin wound healing was closely related to KGF.

The emerging therapeutic potential of extracellular vesicles in trauma.

Traumatic injury is a major cause of morbidity and mortality worldwide, despite significant advances in treatments. Most deaths occur either very early, through massive head trauma/CNS injury or exsanguination (despite advances in transfusion medicine), or later after injury often through multiple organ failure and secondary infection. Extracellular vesicles (EVs) are known to increase in the circulation after trauma and have been used to limited extent as diagnostic and prognostic markers. More intriguingly, EVs are now being investigated as both causes of pathologies post trauma, such as trauma-induced coagulopathy, and as potential treatments. In this review, we highlight what is currently known about the role and effects of EVs in various aspects of trauma, as well as exploring current literature from investigators who have begun to use EVs therapeutically to alter the physiology and pathology of traumatic insults. The potential effectiveness of using EVs therapeutically in trauma is supported by a large number of experimental studies, but there is still some way to go before we understand the complex effects of EVs in what is already a complex disease process.

Chronic Histological Outcomes of Indirect Traumatic Optic Neuropathy in Adolescent Mice: Persistent Degeneration and Temporally Regulated Glial Responses.

Injury to the optic nerve, termed, traumatic optic neuropathy (TON) is a known comorbidity of traumatic brain injury (TBI) and is now known to cause chronic and progressive retinal thinning up to 35 years after injury. Although animal models of TBI have described the presence of optic nerve degeneration and research exploring acute mechanisms is underway, few studies in humans or animals have examined chronic TON pathophysiology outside the retina. We used a closed-head weight-drop model of TBI/TON in 6-week-old male C57BL/6 mice. Mice were euthanized 7-, 14-, 30-, 90-, and 150-days post-injury (DPI) to assess histological changes in the visual system of the brain spanning a total of 12 regions. We show chronic elevation of FluoroJade-C, indicative of neurodegeneration, throughout the time course. Intriguingly, FJ-C staining revealed a bimodal distribution of mice indicating the possibility of subpopulations that may be more or less susceptible to injury outcomes. Additionally, we show that microglia and astrocytes react to optic nerve damage in both temporally and regionally different ways. Despite these differences, astrogliosis and microglial changes were alleviated between 14-30 DPI in all regions examined, perhaps indicating a potentially critical period for intervention/recovery that may determine chronic outcomes.

Failure to Rescue in Geriatric Trauma: The Impact of Any Complication Increases with Age and Injury Severity in Elderly Trauma Patients.

INTRODUCTION: The interaction of increasing age, Injury Severity Score (ISS), and complications is not well described in geriatric trauma patients. We hypothesized that failure to rescue rate from any complication worsens with age and injury severity. METHODS: The National Trauma Data Bank (NTDB) was queried for injured patients aged 65 years or older from January 1, 2013 through December 31, 2016. Demographics and injury characteristics were used to compare groups. Mortality rates were calculated across subgroups of age and ISS, and captured with heatmaps. Multivariable logistic regression was performed to identify independent predictors of mortality. RESULTS: 614,496 geriatric trauma patients were included; 151,880 (24.7%) experienced a complication. Those with complications tended to be older, female, non-white, have non-blunt mechanism, higher ISS, and hypotension on arrival. Overall mortality was highest (19%) in the oldest (≥86 years old) and most severely injured (ISS ≥ 25) patients, with constant age increasing across each ISS group was associated with a 157% increase in overall mortality (P < .001, 95% CI: 148-167%). Holding ISS stable, increasing age group was associated with a 48% increase in overall mortality (P < .001, 95% CI: 44-52%). After controlling for standard demographic variables at presentation, the existence of any complication was an independent predictor of overall mortality in geriatric patients (OR: 2.3; 95% CI: 2.2-2.4). CONCLUSIONS: Any complication was an independent risk factor for mortality, and scaled with increasing age and ISS in geriatric patients. Differences in failure to rescue between populations may reflect critical differences in physiologic vulnerability that could represent targets for interventions.

Network analysis of trauma in patients with early-stage psychosis.

Childhood trauma (ChT) is a risk factor for psychosis. Negative lifestyle factors such as rumination, negative schemas, and poor diet and exercise are common in psychosis. The present study aimed to perform a network analysis of interactions between ChT and negative lifestyle in patients and controls. We used data of patients with early-stage psychosis (n = 500) and healthy controls (n = 202). Networks were constructed using 12 nodes from five scales: the Brief Core Schema Scale (BCSS), Brooding Scale (BS), Dietary Habits Questionnaire, Physical Activity Rating, and Early Trauma Inventory Self Report-Short Form (ETI). Graph metrics were calculated. The nodes with the highest predictability and expected influence in both patients and controls were cognitive and emotional components of the BS and emotional abuse of the ETI. The emotional abuse was a mediator in the shortest pathway connecting the ETI and negative lifestyle for both groups. The negative others and negative self of the BCSS mediated emotional abuse to other BCSS or BS for patients and controls, respectively. Our findings suggest that rumination and emotional abuse were central symptoms in both groups and that negative others and negative self played important mediating roles for patients and controls, respectively.Trial Registration: ClinicalTrials.gov identifier: CUH201411002.

Macroscopic, Histologic, and Immunomodulatory Response of Limb Wounds Following Intravenous Allogeneic Cord Blood-Derived Multipotent Mesenchymal Stromal Cell Therapy in Horses.

Limb wounds are common in horses and often develop complications. Intravenous multipotent mesenchymal stromal cell (MSC) therapy is promising but has risks associated with intravenous administration and unknown potential to improve cutaneous wound healing. The objectives were to determine the clinical safety of administering large numbers of allogeneic cord blood-derived MSCs intravenously, and if therapy causes clinically adverse reactions, accelerates wound closure, improves histologic healing, and alters mRNA expression of common wound cytokines. Wounds were created on the metacarpus of 12 horses. Treatment horses were administered 1.51-2.46 × 108 cells suspended in 50% HypoThermosol FRS, and control horses were administered 50% HypoThermosol FRS alone. Epithelialization, contraction, and wound closure rates were determined using planimetric analysis. Wounds were biopsied and evaluated for histologic healing characteristics and cytokine mRNA expression. Days until wound closure was also determined. The results indicate that 3/6 of treatment horses and 1/6 of control horses experienced minor transient reactions. Treatment did not accelerate wound closure or improve histologic healing. Treatment decreased wound size and decreased all measured cytokines except transforming growth factor-ß3. MSC intravenous therapy has the potential to decrease limb wound size; however, further work is needed to understand the clinical relevance of adverse reactions.

Skin models for cutaneous melioidosis reveal Burkholderia infection dynamics at wound's edge with inflammasome activation, keratinocyte extrusion and epidermal detachment.

ABSTRACTMelioidosis is a serious infectious disease endemic in Southeast Asia, Northern Australia and has been increasingly reported in other tropical and subtropical regions in the world. Percutaneous inoculation through cuts and wounds on the skin is one of the major modes of natural transmission. Despite cuts in skin being a major route of entry, very little is known about how the causative bacterium Burkholderia pseudomallei initiates an infection at the skin and the disease manifestation at the skin known as cutaneous melioidosis. One key issue is the lack of suitable and relevant infection models. Employing an in vitro 2D keratinocyte cell culture, a 3D skin equivalent fibroblast-keratinocyte co-culture and ex vivo organ culture from human skin, we developed infection models utilizing surrogate model organism Burkholderia thailandensis to investigate Burkholderia-skin interactions. Collectively, these models show that the bacterial infection was largely limited at the wound's edge. Infection impedes wound closure, triggers inflammasome activation and cellular extrusion in the keratinocytes as a potential way to control bacterial infectious load at the skin. However, extensive infection over time could result in the epidermal layer being sloughed off, potentially contributing to formation of skin lesions.

miR-125a-5p-abundant exosomes derived from mesenchymal stem cells suppress chondrocyte degeneration via targeting E2F2 in traumatic osteoarthritis.

miRNAs are broad participants in vertebrate biological processes, and they are also the major players in pathological processes. miR-125a-5p was recently found a modulator in the progression of osteoarthritis (OA). Our study was aimed to explore the role and underlying mechanisms of miR-125a-5p-abundant exosomes derived from mesenchymal stem cells (MSC) on OA progression. We separated bone marrow mesenchymal stem cells (BMSCs) as well as the exosomes from traumatic OA patients. The immunofluorescence and cartilage staining were implemented for the observation and the assessment on endocytosis of chondrocytes and exosomal miR-125a-5p efficacy to cartilage degradation. Dual luciferase reporter assay was performed to verified the relationship between miR-125a-5p and E2F2. Then, the function of exosomal miR-125a-5p were examined on chondrocyte degeneration in vitro and in vivo. Our findings indicated that E2F2 expression was elevated while the miR-125a-5p was down in traumatic OA cartilage tissue, showing a negative correlation of the former and the latter. miR-125a-5p targets E2F2 in traumatic OA cartilage tissue and leads to the down-expression of E2F2. The E2F2 expression in chondrocytes was decreased after internalization of exosomes. We additionally found that BMSCs-derived exosomes were rich in miR-125a-5p content and chondrocytes can have it internalized. miR-125a-5p is endowed with a trait of accelerating chondrocytes migration, which is going along with the up-expressions of Collagen II, aggrecan and SOX9 and the down-expression of MMP-13 in vitro. Besides that, the mice model with post-traumatic OA turned out that exosomal miR-125a-5p might beget an alleviation in chondrocyte extracellular matrix degradation. All these outcomes revealed that BMSCs-derived exosomal miR-125a-5p is a positive regulator for chondrocyte migration and inhibit cartilage degeneration We thus were reasonable to believe that transferring of exosomal miR-125a-5p is a prospective strategy for OA treatment.

p38-mediated cell growth and survival drive rapid embryonic wound repair.

Embryos repair wounds rapidly, with no inflammation or scarring, in a process that involves polarization of the actomyosin cytoskeleton. Actomyosin polarization results in the assembly of a contractile cable around the wound that drives wound closure. Here, we demonstrate that a contractile actomyosin cable is not sufficient for rapid wound repair in Drosophila embryos. We show that wounding causes activation of the serine/threonine kinase p38 mitogen-activated protein kinase (MAPK) in the cells adjacent to the wound. p38 activation reduces the levels of wound-induced reactive oxygen species in the cells around the wound, limiting wound size. In addition, p38 promotes an increase in volume in the cells around the wound, thus facilitating the collective cell movements that drive rapid wound healing. Our data indicate that p38 regulates cell volumes through the sodium-potassium-chloride cotransporter NKCC1. Our work reveals cell growth and cell survival as cell behaviors critical for embryonic wound repair.

Intentional endometrial injury enhances angiogenesis through increased production and activation of MMP-9 by TNF-α and MMP-3 in a mouse model.

There have been reports of improved pregnancy rates after performing intentional endometrial injuries, also known as endometrial scratching, in patients with recurrent implantation failure. In our previous study on intentional endometrial injury, we found an increased expression of matrix metalloproteinase (MMP)-3 following induced injuries to the mice endometrium. In the current study, we further examine whether the rise in MMP-3 could contribute to increased angiogenesis. Female C57B1/6 mice were obtained at 12 weeks of age, and intentional endometrial injuries were induced mechanically in the left uterine horns. Using the appropriate media, uterine-washes were performed on the injured and uninjured (control) horns of the harvested uteri. The uterine tissues were further processed for tissue lysates, histopathology and immunohistochemistry. The results show that intentional endometrial injuries caused an increase in secreted LPA in the injured horns, which were detected in the uterine-washes. In addition, LPA induced increased production of TNF-α in human endometrial epithelial cells (hEEpCs). Furthermore, TNF-α appeared to induce differential and cell-specific upregulation of the MMPs: MMP-3 was upregulated in the epithelial (hEEpCs), while MMP-9 was upregulated in the endothelial cells (human endometrial endothelial cells; hEEnCs). The upregulation of MMP-3 appeared to be necessary for the activation of MMP-9, whose active form stimulated the formation of vessel-like structure by the hEEnCs. The results of this study suggest that there may be enhanced angiogenesis following intentional endometrial injuries, which is mediated in part by TNF-α-induced and MMP-3-activated MMP-9 production.