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Myocardial infarction (MI), as one of the leading causes of global death, urgently needs effective therapies. Recently, hydrogen sulfide (H2S) has been regarded as a promising therapeutic agent for MI, while its spatiotemporally controlled delivery remains a major issue limiting clinical translation. To address this limitation, we designed and synthesized a novel H2S donor (HSD-R) that can produce H2S and emit fluorescence in response to reactive oxygen species (ROS) highly expressed at diseased sites. HSD-R can specifically target mitochondria and provide red fluorescence to visualize and quantify H2S release in vitro and in vivo. Therapeutically, HSD-R significantly promoted the reconstruction of cardiac structure and function in a rat MI model. Mechanistically, myocardial protection is achieved by reducing cardiomyocyte apoptosis, attenuating local inflammation, and promoting angiogenesis. Furthermore, inhibition of typical pro-apoptotic genes (Bid, Apaf-1, and p53) played an important role in the anti-apoptotic effect of HSD-R to achieve cardioprotection, which were identified as new therapeutic targets of H2S against myocardial ischemia injury. This ROS-responsive, self-immolative, and fluorescent H2S donor can serve as a new theranostic agent for MI and other ischemic diseases., Graphical abstract Image 1, Highlights • A reactive oxygen species-responsive and self-reporting H2S donor (HSD-R) is developed for controlled H2S delivery. • HSD-R shows desirable fluorescence for imaging H2S release upon triggering by reactive oxygen species. • HSD-R displays significant cardioprotective effects in rats. • HSD-R exhibits multiple biological activities including anti-apoptotic, anti-inflammatory, and pro-angiogenic effects. • Anti-apoptotic activity of HSD-R is due to inhibiting the expression of several pro-apoptotic factors.

Growth of capillaries is an essential process after a dermal injury. An immature scar with robust growth of capillaries tends to be hypertrophic. Pulsed dye laser (PDL) causes damage to microvascular structures and is increasingly used for early erythematous scars to limit scar growth. To have a better understanding of the impact of PDL on scar vascularity and to optimize the clinical use of PDL for managing hypertrophic scars, this study aimed to explore changes in scar erythema, blood perfusion, and thickness of immature hypertrophic scars in Asian patients who received PDL treatments at an early stage.This was a 3-month, assessor-blinded, clinical study. There were two groups of patients, the PDL group and the control group, who had hypertrophic scars less than 1-year post-injury. Patients in the PDL group received three PDL sessions at 4-week intervals. A total of three assessments were performed, at baseline, 1 and 3 months, consisting of the Patient and Observer Scar Assessment Scale (POSAS) and objective measurements of scar erythema, blood perfusion, and scar thickness.A total of 45 patients were enrolled, 22 in the PDL group and 23 in the control group. After the 3-month treatment, parameters of scar vascularity (P = 0.003), pigmentation (P = 0.026), color (P 0.001), thickness (P 0.05), and overall scores (P 0.01) on the POSAS significantly decreased in the PDL group. Moreover, objective measurements of scar erythema and blood perfusion showed significant improvements in the PDL group (P = 0.009 and P = 0.022, respectively) but not in the control group (P = 0.296 and P = 0.115, respectively). A stable scar thickness was maintained in the PDL group from baseline to 3 months (0.21 cm vs. 0.22 cm, P 0.05), whereas scar thickness significantly increased in the control group (0.22 cm vs. 0.32 cm, P 0.01).Use of PDL at an early stage controls vascularity of immature hypertrophic scar by improving its poor blood perfusion that further limits scar thickness growth and promotes scar maturation. Lasers Surg. Med. 00:00-00, 2020. © 2020 Wiley Periodicals LLC.

Survival after burn injury has steadily improved in recent decades. The models for assessing the severity of burn injury and predicting burn-associated mortality have been used for over 20 years. The predictive accuracy of these models should be reconsidered now.In this retrospective study on all burn patients (n = 9625) admitted to the Burn Department, Southwest Hospital between 2008 and 2017, we compared the predictive performance of the four burn-severity models (Abbreviated Burn Severity Index, Ryan score, revised Baux score and Belgian Outcome of Burn Injury) by area under the receiver operating curve (AUC) and Hosmer-Lemeshow test. We developed a new model with the data from 2008 to 2012 (5006 patients) by logistic regression, data from 2013 to 2017 (4619 patients) were used for validation.The overall mortality rate of the burn patients was 1.14%. The four previously validated burn models showed good discrimination power of death risk (AUC 0.890) but poor fitness to the observed mortality rate (p 0.001). Risk factors associated with mortality included sex, age, total burn area, full thickness burn area, and inhalation injury. The new logistic model was devised with high sensitivity and specificity (0.913 and 0.806, respectively) and an AUC of 0.940. The new model also had good fitness to the observed mortality of burn patients (p = 0.588).The four widely used burn models have poor accuracy in predicting burn-associated mortality, and an accurate new model was developed based on simple and objective clinical characteristics of burn patients at admission.

Background and objectives Ablative fractional laser treatment has been used to improve the color and texture of hypertrophic scars with safe and effective results. However, no consensus on the optimal time to initiate fractional laser treatment is available. The effect on early-stage scars remains controversial. This study was designed to assess the efficacy and safety of ablative fractional carbon dioxide (CO2 ) laser treatments for hypertrophic burn scars and to analyze the efficacy and safety in the early period within 3 months after injury. Study design/materials and methods We performed a retrospective study of 221 hypertrophic scar patients. According to the time of the first laser treatment after injury, patients were divided into five subgroups, including less than 1 month, 1-3 months, 3-6 months, 6-12 months, and more than 12 months postinjury. One month after the last laser treatment, the scars were assessed by photography, the Vancouver Scar Scale (VSS), durometry, and spectrocolorimetry. Results The patients included 118 males and 103 females. The average age was 33.6 years. Fire/flame was the primary injury source. Thirty-six percent of the patients underwent at least one fractional CO2 laser treatment. All the included patients, including those treated within 1 month after injury, had significantly decreased VSS scores after laser treatment. We also noted that hardness and redness scores were decreased after treatment for both scars treated within 3 months and those treated more than 12 months after injury. Seepage (17.6%), bleeding (22.2%), and swelling (9.0%) were the main adverse events after laser treatment. Conclusions This study demonstrated the safety and efficacy of ablative fractional CO2 laser treatment applied to early-stage burn scars. The optimal time for laser application for burn patients can be within 1 month after injury. Durometry and spectrocolorimetry were effective for assessing scars as objective modalities. Lasers Surg. Med. © 2020 Wiley Periodicals LLC.

The transition from the proinflammatory phase to the prohealing phase in wound healing is essential for effective skin wound repair, which involves the balance of M1 and M2 polarization of wound-infiltrating macrophages. P311 plays an essential role in promoting wound closure by enhancing the biological function of epidermal stem cells, endothelial cells, and fibroblasts. Nevertheless, whether and how P311 regulates macrophage polarization remains unclear. In this study, we showed that P311 deficiency reduced the M2 polarization of macrophages, thereby attenuating the secretion of M2-like cytokines. The P311 deficiency prolonged the transition from the proinflammatory phase to the prohealing phase, accompanied by weakened angiogenesis and retarded granulation tissue formation, both of which coordinately hinder the healing of skin wounds. Mechanistically, P311 deficiency downregulated the expression of IL-4 receptor on macrophages, followed by less activation of the IL-4 receptor‒signal transducer and activator of transcription 6 signaling pathway, resulting in impaired M2 macrophage polarization. We further revealed that the mTOR signaling pathway was associated with the regulation of P311 on the expression of IL-4 receptor in macrophages. Thus, our study has highlighted the pivotal role of P311 in promoting the M2 polarization of macrophages for effective skin wound healing.

BACKGROUND Hands are one of the most common burn sites in children. Hypertrophic scar contractures in hands after wound healing result in further reductions in their range of motion (ROM), motility, and fine motor activities. Rehabilitation can improve the function of hands. But the optimal time of rehabilitation intervention is still unclear. Therefore, this study was designed to investigate the effects of early rehabilitation management of paediatric burnt hands and to compare the efficacy between early and later rehabilitation intervention. AIM To investigate the effects of early rehabilitation management of paediatric burnt hands. METHODS A total of 52 children with burnt hands were allocated into the early intervention group (≤ 1 mo from onset) and a late intervention group (> 1 mo from onset) between January 2016 and December 2017. The children received the same rehabilitation programme including skin care, scar massage, passive ROM exercises, active ROM exercises, compression therapy, orthotic devices wearing and game or music therapy. Rehabilitation assessments were performed before and after the rehabilitation treatment. RESULTS In the early intervention group, the ROM of the hands was significantly improved after rehabilitation (P = 0.001). But in the late group the effect was not significant statistically (P = 0.142). In the early group, 38.5% of the patients showed significant improvement, while in the late group, 69.2% of the patients showed no significant improvement. The time from onset to posttraumatic rehabilitation (P = 0.0007) and length of hospital stay (P = 0.003) were negatively correlated with the hand function improvement. The length of rehabilitation stay was positively correlated with the hand function improvement (P = 0.005). CONCLUSION These findings suggest that early rehabilitation might show better results in terms of ROM.

COVID-19 is spreading almost all over the world at present, which is caused by the 2019 novel coronavirus (2019-nCoV). It was an epidemic firstly in Hubei province of China. The Chinese government has formally set COVID-19 in the statutory notification and control system for infectious diseases according to the Law of the People's Republic of China on the Prevention and Treatment of Infectious Diseases. China currently is still struggling to respond to COVID-19 though intensive actions with progress made. The Burn Department of our hospital is one of sections with the highest infectious risk of COVID-19. Based on our own experience and the guidelines on the diagnosis and treatment of COVID-19 (7th Version) with other regulations and literature, we describe our experience with suggestions for medical practices for burn units during the COVID-19 outbreak. We hope these experiences and suggestions benefit our international colleagues during the pandemic of the COVID-19.

COVID-19 pandemic is sweeping the globe. Any outpatient or new inpatient especial in burn department during the pandemic should be as a potential infectious source of COVID-19. It is very important to manage the patients and wards carefully and correctly to prevent epidemic of the virus in burn centers. This paper provides some strategies regarding management of burn ward during the epidemic of COVID-19 or other respiratory infectious diseases.

Background Infectious diseases caused by multidrug-resistant (MDR) bacteria, especially MDR Gram-negative strains, have become a global public health challenge. Multifunctional nanomaterials for controlling MDR bacterial infections via eradication of planktonic bacteria and their biofilms are of great interest. Results In this study, we developed a multifunctional platform (TG-NO-B) with single NIR laser-triggered PTT and NO release for synergistic therapy against MDR Gram-negative bacteria and their biofilms. When located at the infected sites, TG-NO-B was able to selectively bind to the surfaces of Gram-negative bacterial cells and their biofilm matrix through covalent coupling between the BA groups of TG-NO-B and the bacterial LPS units, which could greatly improve the antibacterial efficiency, and reduce side damages to ambient normal tissues. Upon single NIR laser irradiation, TG-NO-B could generate hyperthermia and simultaneously release NO, which would synergistically disrupt bacterial cell membrane, further cause leakage and damage of intracellular components, and finally induce bacteria death. On one hand, the combination of NO and PTT could largely improve the antibacterial efficiency. On the other hand, the bacterial cell membrane damage could improve the permeability and sensitivity to heat, decrease the photothermal temperature and avoid damages caused by high temperature. Moreover, TG-NO-B could be effectively utilized for synergistic therapy against the in vivo infections of MDR Gram-negative bacteria and their biofilms and accelerate wound healing as well as exhibit excellent biocompatibility both in vitro and in vivo. Conclusions Our study demonstrates that TG-NO-B can be considered as a promising alternative for treating infections caused by MDR Gram-negative bacteria and their biofilms.

Objective This study aims to clarify whether the effect of intralesional triamcinolone acetonide injection during the early stage of scarring differs from the static stage, which still remains unclear. Methods A total of 108 patients with pathological scars were enrolled in this study and were divided into 2 groups according to the time of first treatment after injury: the early stage group(≤6 months after injury) and the static stage group(>6 months after injury). Patients of both groups were then treated with intralesional triamcinolone acetonide injection. The Vancouver scar scale was adopted for the evaluation of scars, and a durometer was utilized for the measurement of the hardness of the scar. The visual analog scale was adopted for the assessment of patients' subjective feelings (pruritus and pain). In the meantime, adverse drug reactions were also recorded. Results After intralesional injection of triamcinolone acetonide, most of the hypertrophic scars and keloids improved in color, thickness, softness, and vascular distribution. The hardness of scars improved significantly. The overall efficacy of the static stage group was superior to the early stage group. Most patients, after the injection of triamcinolone acetonide, had significant alleviation or even total loss of cicatricial pain and pruritus. Conclusions This study demonstrates that the treatment efficacy was better when applied during the static stage of pathological scarring rather than the early stage, which might be due to macrophages and their released cytokines. This study provides new clinical evidence for optimizing drug therapy of pathological scars.

Additional file 1. Additional figures.

Table S1. Range of motion severity ratings by joint muscle action. (PDF 125 kb)

In order to facilitate the rate and quality of burn wound healing, many advanced techniques emerged in recent years, which contribute to the improved level of diagnosis and treatment of burn injury. Precise diagnosis; early, modified cooling therapy; and surgical intervention for burn wound healing are discussed firstly in this review. Then some new methods or materials such as modern wound dressing, negative pressure wound therapy, phototherapy, ultrasound therapy, platelet-rich plasma (PRP), and others applied for burn wound healing are addressed in this paper.

Objective The aims of this study were to evaluate the epidemiological and clinical characteristics of candidemia in a typical burn ICU, and to determine the risk factors associated with candidemia among major burn patients. Method This retrospective observational study of candidemia from 2012 to 2017 in a burn ICU was conducted in the Department of Burn, Southwest hospital, Chongqing, China. Results The study included 410 major burn patients (≥40% total body surface area), 39 (9.51%) of which were diagnosed with candidemia. The annual incidences of candidemia varied from 6.06% to 17.54%, and increased gradually in the 6 years. Candida parapsilosis was the dominant pathogen (28.21% strains). The overall resistance rate of Candida spp. to fluconazole was 35.89%. Candidemia cases most frequently occurred in the 2nd (30.77%) and 3rd (23.08%) weeks after burn, and intravascular catheters were the most common sources of bloodstream Candida infections (31.58%). The crude mortality of candidemia was 23.08%, and the mortality attributable to candidemia was 14.99%. Risk factors of candidemia included inhalation injury, renal dysfunction with replacement therapy, severe gastrointestinal complications, T-cell lymphopenia and prior Candida colonization. Conclusion Candidemia has a high incidence and mortality in major burn patients. The changes in etiology and drug sensitivity may make new challenges for the management of candidemia in burn ICUs.

Spatial information has been shown to be critical for cell differentiation and function. Therefore, a better understanding of skin microstructures is very important for biomimetic and bioengineered scaffolds of engineering skin. The purpose of the study was to generate collagen/elastin-based three-dimensional (3D) images of human dermis to further understand the microstructures of the skin, which is believed to be helpful in the fabrication of bionic engineered skin. Skin samples were fixed, embedded, serially sectioned, stained with aldehyde-fuchsin, and photographed as serial panoramas. Dermal subregions were divided according to dermal depth and distance to hair follicle. The porosity, pore diameters, and wall thickness of human acellular dermal matrix (ADM) were measured by microcomputed tomography (micro-CT). Three-dimensional reconstructed images of collagen and elastic fibers were generated. Our results showed that there were fewer elastic fibers in the subregions close to hair follicles than in the subregions far away from hair follicles (p0.001), but the collagen fibers were evenly distributed. Both collagen and elastic fibers were found in fewer numbers in the layers either close to the epidermis or close to the hypodermis. The mean proportions of collagen fibers and elastic fibers in the whole dermis were 28.96%±14.63% and 8.06%±3.75%, respectively. The porosity of ADM calculated by micro-CT was 68.3%±5.8%. The mean pore diameter of ADM was 131.2±96.8 μm, and the wall thickness of pores was 207.2±251.7 μm. This study represents for the first time that 3D histological cutaneous structures have been presented, which may be helpful for the next generation of skin engineering.

Burns are a major cause of injury worldwide. We investigated the epidemiology and outcomes of burn patients in a major burn center in southwest China between 2011 and 2015 to provide guidance for burn prevention. Of the 6,325 included burn patients, 66.8% were male and 34.7% were 0 ~ 6 years old. The incidence of burns peaked in autumn. Scald was the most common cause of burns, which was predominant in patients aged 0 ~ 6 years. The mean total body surface area (TBSA) of burns was 13.4%, and patients with burns ≤10% TBSA comprised 64.1% of all cases. Patients with full-thickness burns accounted for 40.1% of all patients and 81.0% of operated patients; these burns were primarily caused by flame (34.8%), scald (21.0%), and electricity (20.4%). Fifty-six deaths occurred (mortality 0.9%), and risk factors included full-thickness burns, larger TBSA and older age. The median length of stay was 17 days, and major risk factors included more operations, better outcomes and larger TBSA. Our data showed that closer attention should be paid to children under 6 years old, males, incidents in autumn and scald burns to prevent burn injuries. Furthermore, individualized burn prevention and treatment measures based on related risk factors should be adopted.

Invasive fungal infection is one of the major complication of severe burns which can induce local or systemic inflammatory response and cause serious substantial damage to the patient. The incidence of fungal infection for burn victims is increasing dramatically during recent years. This guideline, organized by Chinese Society of Burn Surgeons, aims to standardize the diagnosis, prevention and treatment of burn invasive fungal infection. It can be used as one of the tools for treatment of major burn patients.

Background Burns are a major form of injury in children worldwide. This study aimed to investigate the epidemiology, outcome, cost and risk factors of pediatric burns in southwest China. Methods This retrospective study was performed at the Institute of Burn Research of the Third Military Medical University from 2011 to 2015. Data, including demographic, injury-related, and clinical data and patient outcome, were collected from medical records. Results A total of 2478 children with burns (58.03% boys), accounting for 39.2% of total burn patients, were included. The average age of the burn patients was 2.86 ± 2.86 years, and most patients (85.55%) were under five years old. The incidence of burns peaked in January, February and May. Scald burns were the most frequent (79.06%), followed by flame burns (14.0%) and electrical burns (3.35%). Limbs were the most common burn sites (69.73%), and the average total body surface area (TBSA) was 11.57 ± 11.61%. The percentage of children who underwent operations and the number of operations were significantly increased in cases of electrical burns, the older-age group, a larger TBSA and full-thickness burns. Six deaths were recorded, yielding a mortality of 0.24%. The median length of stay and cost were 14 days and 9541 CNY, respectively, and the major risk factors for length of stay and cost were the TBSA, number of operations, full-thickness burns and outcome. Conclusions In southwest China, among children under five years old, scald and flame burns should become the key prevention target, and future prevention strategies should be based on related risk factors.

Background Epithelial to mesenchymal transition, especially to myofibroblasts, plays an important role in wound healing, fibrosis, and carcinogenesis. Epidermal stem cells (EpSCs) are responsible for epidermal renewal and wound re-epithelialization. However, it remains unclear whether and how EpSCs transdifferentiate into myofibroblasts or myofibroblast-like cells (MFLCs). Here, we provide the first evidence showing that P311 induces EpSC to MFLC transdifferentiation (EpMyT) via TGFβ1/Smad signaling. Methods Wound healing and mesenchymal features were observed in the P311 KO and P311 WT mouse model of superficial second-degree burns. After the primary human or mouse EpSCs were forced to highly express P311 using an adenoviral vector, EpMyT was observed by immunofluorescence, real-time PCR, and western blot. The activity of TGFβ1 and Smad2/3 in EpSCs with different P311 levels was observed by western blot. The TβRI/II inhibitor LY2109761 and Smad3 siRNA were applied to block the EpMyT in P311-overexpressing EpSCs and exogenous TGFβ1 was to restore the EpMyT in P311 KO EpSCs. Furthermore, the mechanism of P311 regulating TGFβ1 was investigated by bisulfite sequencing PCR, luciferase activity assay, and real-time PCR. Results P311 KO mouse wounds showed delayed re-epithelialization and reduced mesenchymal features. The human or mouse EpSCs with overexpressed P311 exhibited fusiform morphological changes, upregulated expression of myofibroblast markers (α-SMA and vimentin), and downregulated expression of EpSC markers (β1-integrin and E-cadherin). P311-expressing EpSCs showed decreased TGFβ1 mRNA and increased TGFβ1 protein, TβRI/II mRNA, and activated Smad2/3. Moreover, LY2109761 and Smad3 siRNA reversed P311-induced EpMyT. Under the stimulation of exogenous TGFβ1, the phosphorylation of Smad2 and Smad3 in P311 KO EpSCs was significantly lower than that in P311 WT EpSCs and the EpMyT in P311 KO EpSCs was restored. Furthermore, P311 enhanced the methylation of TGFβ1 promoter and increased activities of TGFβ1 5′/3′ untranslated regions (UTRs) to stimulate TGFβ1 expression. P311+α-SMA+ cells and P311+vimentin+ cells were observed in the epidermis of human burn wounds. Also, P311 was upregulated by IL-1β, IL-6, TNFα, and hypoxia. Conclusions P311 is a novel TGFβ1/Smad signaling-mediated regulator of transdifferentiation in EpSCs during cutaneous wound healing. Furthermore, P311 might stimulate TGFβ1 expression by promoting TGFβ1 promoter methylation and by activating the TGFβ1 5′/3′ UTR.

Aims P311 is an 8 kDa protein that has been shown to be of importance in the process of myofibroblast transformation, glioblastoma invasion and nerve regeneration. However, the interaction protein of P311 has yet to be found. The purpose of this study was to find the interactive protein of P311. Main methods The yeast two-hybrid system was used for screening the potential interaction proteins of P311. Joint expression of the potential interactive protein and P311 was immunohistochemically stained. The interaction between P311 and the selected protein was further confirmed by fluorescence resonance energy transfer (FRET) in pulmonary adenocarcinoma tissue sections, and by coimmunoprecipitation in HEK293. Key findings Integrin β4 binding protein (ITGB4BP) was confirmed as the interaction protein of P311. Co-expression and interaction of ITGB4BP and P311 were demonstrated in pulmonary adenocarcinoma by both immunohistochemistry and FRET. Moreover the interaction between P311 and ITGB4BP was demonstrated by coimmunoprecipitation in HEK293. Significance The interactions between P311 and ITGB4BP may be very important in the process of tumor cell differentiation and metastasis. ITGB4BP may provide a potential new target for the therapy of tumors.

Vasoactive intestinal peptide (VIP) was reported to promote angiogenesis. Electrospun nanofibers lead to idea wound dressing substrates. Here we report a convenient and novel method to produce VIP loaded microspheres in polycaprolactone (PCL) nanofibrous membrane without complicated processes. We first coated mussel-inspired dopamine (DA) to nanofibers, then used strong adhesive DA to absorb the functional peptide. PCL membrane was then immersed into acetone to generate microspheres with VIP loading. We employed high pressure liquid chromatography to record encapsulation efficiency of (31.8 ± 2.2)% and loading capacity of (1.71 ± 0.16)%. The release profile of VIP from nanosheets showed a prolonged release. The results of laser scanning confocal microscope, scanning electron microscope and cell counting kit-8 proliferation assays showed that cell adhesion and proliferation were promoted. In order to verify the efficacy on wound healing, in vivo implantation was applied in the full-thickness defect wounds of BALB/c mice. Results showed that the wound healing was significantly promoted via favoring the growth of granulation tissue and angiogenesis. However, we found wound re-epithelialization was not significantly improved. The resulting VIP-DA-coated PCL (PCL-DA-VIP) nanosheets with spatiotemporal delivery of VIP could be a potential application in wound treatment and vascular tissue engineering.

Supplementary information containing Table S1. presenting primer sequences used for real-time PCR, and Table S2. presenting the characterization of epithelial to myofibroblast/ myofibroblast-like cell transdifferentiation in 36 articles. (PDF 487 kb)

Supplementary information containing Supplementary Materials and Methods presenting methods of Gel contraction assay and in-vitro scratch wound assay, Figure S1. showing the α-SMA expression in the epidermis of mouse burn wounds, Figure S2. showing characterization of primary mouse and human EpSCs, Figure S3. showing successful transfection of the P311 adenovirus into mouse EpSCs, Figure S4. showing that P311 induced a myofibroblast-like phenotype in primary human EpSCs, Figure S5. showing the effect of P311 on the mesenchymal function of EpSCs, Figure S6. showing the quantification of the total Smad2 and Smad3 protein, and Figure S7. showing the effect of P311 on TGFβ1 promoter activity. (DOC 14540 kb)

P311, a gene that was identified in 1993, has been found to have diverse biological functions in processes such as cell proliferation, migration and differentiation. However, its role in fibrosis is unknown. We previously observed that P311 is highly expressed in skin hypertrophic scars. In this study, P311 over-expression was detected in a subset of tubular epithelial cells in clinical biopsy specimens of renal fibrosis; this over-expression, was found concurrent with α-smooth muscle actin (α-SMA) and transforming growth factor beta1 (TGFβ1) expression. Subsequently, these results were verified in a mouse experimental renal fibrosis model induced by unilateral ureteral obstruction. The interstitial deposition of collagen, α-SMA and TGF-β1 expression and macrophage infiltration were dramatically decreased when P311 was knocked out. Moreover, TGFβ/Smad signaling had a critical effect on the promotion of renal fibrosis by P311. In conclusion, this study demonstrate that P311 plays a key role in renal fibrosis via TGFβ1/Smad signaling, which could be a novel target for the management of renal fibrosis.

To explore the role of dentritic epidermal T lymphocytes ( DETCs) in immune rejection of skin allograft in mice and its related mechanism. Methods (1) Full-thickness skin was harvested from back of one male wild type (WT) C57BL/6 mouse. Epithelial cells were isolated for detection of the expression of DETCs and their phenotype with flow cytometer. Another male WT C57BL/6 mouse was used to harvest full-thickness skin from the back. Epidermis was isolated for observation of the morphological characteristics of DETCs with immunofluorescence technology. (2) Four male green fluorescence protein (GFP)-marked C57BL/6 mice, 7 female WT C57BL/6 mice (group WT), and 7 female ybT lymphocytes 8 gene knock-out (GK) C57BL/6 mice (group GK) were used. Full-thickness skin in the size of 1.4 cm x 1.4 cm on the back of mice in groups WT and GK were excised, and the wounds were transplanted with full-thickness skin in the size of 1.2 cm x 1.2 cm obtained from male GFP-marked C57BL/6 mice. The survival time of skin grafts was affirmed with small animal in vivo imager and naked eyes and recorded. (3) Two male WT C57BL/6 mice were used to isolate epithelial cells. Cells were inoculated into 48-well plate and divided into activation group (A) and control group (C) according to the random number table, with 4 wells in each group. Cells in group A were treated with 10 pL concanavalin A in the concentration of 2 microg/mL for 24 hours, while those in group C with PBS in the same volume as that in group A. The expression of interferon y in DETCs was detected with flow cytometer. (4) Four male GFP-marked C57BL/6 mice were used as donors. Fourteen female WT C57BL/6 mice were used as receptors and divided into interferon gamma neutralizing group (IN) and control group (C) according to the random number table, with 7 mice in each group. The skin transplantation model of C57BL/6 male to C57BL/6 female was established as in part (2). Before surgery and 72 hours after, mice in group IN were intraperitoneally injected with 200 pL interferon y neutralizing antibody in the concentration of 1 mg/mL, and those in group C with normal saline in the same volume as that in group IN. The survival time of skin grafts was observed and recorded using the methods in part (2), and the result of group IN was compared with that of group GK in part (2). The survival curve of skin grafts was processed with Log-rank ( Mantel-Cox) test. Results (1) The positive expression rate of DETCs in epithelial cells of skin in mouse was 7.27%, and they were all CD3 cells. DETCs were found to be scattered in the epidermis of skin in mouse with dendritic morphology. (2) The survival time of skin grafts of mice in group GK was 22-35 d, obviously longer than that in group WT (12-16 d, y2 = 14. 10 , P0.001). (3) Expression of interferon gamma was detected in 22. 70% DETCs in group A, which was obviously higher than that in group C (0.51%). (4) The survival time of skin grafts of mice in group IN was 19-24 d, which was obviously longer than that in group C (12-16 d, chi 2 = 13.60, P0.001) but close to that in group GK as in part (2) (chi2 = 0.06, P = 0.810). Conclusions DETCs are involved in promotion of immune rejection of skin allograft probably by secretinf interferon gamma.

The migration and reepithelization of epidermal stem cells (ESCs) are the most critical processes in wound healing. The gaseous messenger nitric oxide (NO) has multiple biological effects, but its actions on ESCs are poorly understood. In this study, an NO donor, S-nitroso-N-acetylpenicillamine (SNAP), was found to facilitate the in vitro migration of human ESCs (huESCs) in both live-imaging and scratch models. In addition, pull-down assays demonstrated that SNAP could activate the small GTPases RhoA and Rac1 of the Rho family, but not Cdc42. Moreover, the effects of SNAP on the migration and F-actin polymerization of ESCs could be blocked by inhibitors of cGMP, PKG, RhoA or Rac1, and by a specific siRNA of RhoA or Rac1, but not by a Cdc42 inhibitor or siRNA. Furthermore, the roles of NO in ESC migration via cGMP-Rho GTPase signalling in vivo were confirmed by tracing 5-bromo-2-deoxyuridine (BrdU)-labelled cells in a superficial, partial-thickness scald mouse model. Thus, the present study demonstrated that the NO donor SNAP could promote huESC migration in vitro. Furthermore, NO was found to induce ESC migration via cGMP-Rho GTPase RhoA and Rac1 signalling, but not Cdc42 signalling, both in vivo and in vitro.

Background A hypertrophic scar is a unique fibrotic disease that only exists in humans. Despite advances in burn care and rehabilitation, as well as progress in the management during these decades, the hypertrophic scar remains hard to cure following surgical methods and drugs for treatment. In this study, we are looking forward to finding the multitude of possible traumatic mechanisms and the underlying molecular signal ways in the formation of the hypertrophic scar. Methods We used isobaric tags for relative and absolute quantitation (iTRAQ) labeling technology, followed by high-throughput 2D LC-MS/MS, to determine relative quantitative differential proteins between the hypertrophic scar and normal skin tissue. Results A total of 3166 proteins were identified with a high confidence (≥95 % confidence). And, a total of 89 proteins were identified as the differential proteins between the hypertrophic scar and normal skin, among which 41 proteins were up-regulated and 48 proteins were down-regulated in the hypertrophic scar. GO-Analysis indicated the up-regulated proteins were involved in extracellular matrix, whereas the down-regulated proteins were involved in dynamic junction and structural molecule activity. Conclusions In our study, we demonstrate 89 proteins present differently in the hypertrophic scar compared to normal skin by iTRAQ technology, which might indicate the pathologic process of hypertrophic scar formation and guide us to propose new strategies against the hypertrophic scar.

Eukaryotic initiation factor 6 (eIF6) is a pivotal regulator of ribosomal function, participating in translational control. Previously our data suggested that eIF6 acts as a key binding protein of P311 (a hypertrophic scar-related protein; also known as NREP). However, a comprehensive investigation of its functional role and the underlying mechanisms in modulation of myofibroblast (a key effector of hypertrophic scar formation) differentiation remains unclear. Here, we identified that eIF6 is a novel regulator of transforming growth factor-β1 (TGF-β1) expression at transcription level, which plays a key role in myofibroblast differentiation. Mechanistically, this effect is associated with eIF6 altering the occupancy of the TGF-β1 promoter by H2A.Z (Swiss-Prot P0C0S6) and Sp1. Accordingly, modulation of eIF6 expression in myofibroblasts significantly affects their differentiation via the TGF-β/Smad signaling pathway, which was verified in vivo by the observation that heterozygote eIF6(+/-) mice exhibited enhanced TGF-β1 production coupled with increased α-smooth muscle actin (α-SMA)(+) myofibroblasts after skin injury. Overall, our data reveal a novel transcriptional regulatory mechanism of eIF6 that acts on facilitating Sp1 recruitment to TGF-β1 promoter via H2A.Z depletion and thus results in increased TGF-β1 transcription, which contributes to myofibroblast differentiation.

Eukaryotic initiation factor 6 (eIF6) is a pivotal regulator of ribosomal function, participating in translational control. Previously our data suggested that eIF6 acts as a key binding protein of P311 (a hypertrophic scar-related protein; also known as NREP). However, a comprehensive investigation of its functional role and the underlying mechanisms in modulation of myofibroblast (a key effector of hypertrophic scar formation) differentiation remains unclear. Here, we identified that eIF6 is a novel regulator of transforming growth factor-β1 (TGF-β1) expression at transcription level, which plays a key role in myofibroblast differentiation. Mechanistically, this effect is associated with eIF6 altering the occupancy of the TGF-β1 promoter by H2A.Z (Swiss-Prot P0C0S6) and Sp1. Accordingly, modulation of eIF6 expression in myofibroblasts significantly affects their differentiation via the TGF-β/Smad signaling pathway, which was verified in vivo by the observation that heterozygote eIF6(+/-) mice exhibited enhanced TGF-β1 production coupled with increased α-smooth muscle actin (α-SMA)(+) myofibroblasts after skin injury. Overall, our data reveal a novel transcriptional regulatory mechanism of eIF6 that acts on facilitating Sp1 recruitment to TGF-β1 promoter via H2A.Z depletion and thus results in increased TGF-β1 transcription, which contributes to myofibroblast differentiation.