The emerging progress on wound dressings and their application in clinic wound management.

Background: In addition to its barrier function, the skin plays a crucial role in maintaining the stability of the body's internal environment and normal physiological functions. When the skin is damaged, it is important to select proper dressings as temporary barriers to cover the wound, which can exert significant effects on defence against microbial infection, maintaining normal tissue/cell functions, and coordinating the process of wound repair and regeneration. It now forms an important approach in clinic practice to facilitate wound repair. Search strategies: We conducted a comprehensive literature search using online databases including PubMed, Web of Science, MEDLINE, ScienceDirect, Wiley Online Library, CNKI, and Wanfang Data. In addition, information was obtained from local and foreign books on biomaterials science and traumatology. Results: This review focuses on the efficacy and principles of functional dressings for anti-bacteria, anti-infection, anti-inflammation, anti-oxidation, hemostasis, and wound healing facilitation; and analyses the research progress of dressings carrying living cells such as fibroblasts, keratinocytes, skin appendage cells, and stem cells from different origins. We also summarize the recent advances in intelligent wound dressings with respect to real-time monitoring, automatic drug delivery, and precise adjustment according to the actual wound microenvironment. In addition, this review explores and compares the characteristics, advantages and disadvantages, mechanisms of actions, and application scopes of dressings made from different materials. Conclusion: The real-time and dynamic acquisition and analysis of wound conditions are crucial for wound management and prognostic evaluation. Therefore, the development of modern dressings that integrate multiple functions, have high similarity to the skin, and are highly intelligent will be the focus of future research, which could drive efficient wound management and personalized medicine, and ultimately facilitate the translation of health monitoring into clinical practice.

Excessive neutrophil extracellular trap formation induced by Porphyromonas gingivalis lipopolysaccharide exacerbates inflammatory responses in high glucose microenvironment.

Introduction: Neutrophil extracellular trap (NET) is a novel defense strategy of neutrophils and found to be induced by Porphyromonas gingivalis (P. gingivalis) lipopolysaccharide (LPS) or high glucose. The aim of this study was to investigate the roles and mechanisms of NET formation in high glucose inflammatory microenvironment. Methods: NETs induced by 1 µg/ml P. gingivalis LPS and/or 25 mM glucose were visualized using a fluorescence microscopy and the levels of extracellular DNA were determined by a microplate reader. The bactericidal efficiency of NETs was assessed by quantifying the survival P. gingivalis in neutrophils. The levels of NLRP3 and IL-1ß in THP-1 derived-macrophages, and the expressions of p-PKC ßII, p-MEK1/2, p-ERK1/2, ORAI1 and ORAI2 in neutrophils were detected by Western blot. Moreover, levels of intracellular Ca2+ and reactive oxygen species (ROS) in neutrophils were explored by flow cytometry. Results: P. gingivalis LPS enhanced the formation of NETs and increased the levels of extracellular DNA in high glucose microenvironment (p < 0.05). Compared with normal glucose inflammatory microenvironment, quantities of extra- and intracellular viable P. gingivalis in neutrophils exposed to NETs induced in high glucose inflammatory one were increased (p < 0.05) and the expressions of NLRP3 and IL-1ß were dramatically increased in macrophages co-cultured with NETs from high glucose inflammatory microenvironment (p < 0.05). In addition, levels of ROS, intracellular Ca2+, p-PKC ßII, p-MEK1/2, p-ERK1/2, ORAI1 and ORAI2 were increased in neutrophils stimulated with both high glucose and P. gingivalis LPS compared with the single stimulus groups (p < 0.05). Discussion: In high glucose inflammatory microenvironment, formation of NETs was enhanced via oxidative stress, which failed to reverse the decreased bactericidal capacity in high glucose microenvironment, and instead aggravated the subsequent inflammatory responses.

MicroRNAs in the Pathogenesis of Ankylosing Spondylitis and their Clinical Implication.

Ankylosing spondylitis (AS) is a chronic and progressive immunoinflammatory disease, which mainly affects the spine and sacroiliac joints and shows a high rate of late disability. Inflammation, bone destruction, and new bone formation are typical pathological changes of AS. AS is dominated by inflammation at the early stage. While bone destruction and heterotopic ossification, the two contradictory manifestations of AS, occur at a later stage and reflect the imbalance between osteogenesis and osteoclastogenesis in AS patients. Till now, the pathogenesis of AS remains unclear. MicroRNAs (miRNAs) are a class of highly conserved single-stranded noncoding RNAs (ncRNAs) with a length of about 22 bases characterized by temporal sequence and tissue specificity. MiRNAs are key modulators in bone formation, resorption, remodeling and regeneration by regulating the immune responses and the differentiation and functions of osteoblasts, osteoclasts and chondrocytes. The present review summarizes the roles and potential mechanisms of miRNAs' involvement in AS by regulating immuno-inflammatory responses, bone destruction, heterotopic ossification, cell death and autophagy, and the involved signaling including the Wnt/ß-catenin and BMP/Smads pathways. In addition, the feasibility of miRNAs as diagnostic biomarkers and therapeutic targets for AS are also discussed.

KR­12­a6 promotes the osteogenic differentiation of human bone marrow mesenchymal stem cells via BMP/SMAD signaling.

Considering the increased resistance to antibiotics in the clinic and the ideal antibacterial properties of KR­12, the effects of KR­12­a6, an important analogue of KR­12, on the osteogenic differentiation of human bone marrow mesenchymal stem cells (hBMSCs) were investigated. Osteogenic differentiation­associated experiments were conducted in hBMSCs, and KR­12­a6 was used as an additional stimulating factor during osteogenic induction. Quantitative analysis of alkaline phosphatase (ALP) and alizarin red staining, and reverse transcription­quantitative PCR analysis of the expression of osteogenesis­associated genes were performed to determine the effects of KR­12­a6 on the osteogenic differentiation of hBMSCs. LDN­212854 was selected to selectively suppress BMP/SMAD signaling. Western blotting was performed to investigate the underlying mechanisms. The intensity of ALP and alizarin red staining gradually increased with increasing KR­12­a6 concentrations. KR­12­a6 induced the strongest staining at 40 µg/ml, whereas 60 µg/ml and 80 µg/ml concentrations did not further increase the intensity of staining. The mRNA expression levels of RUNX2 and ALP increased in a dose­dependent manner as early as 3 days post­KR­12­a6 treatment. The mRNA expression of COL1A1, BSP and BMP2 exhibited significant upregulation from day 7 post­KR­12­a6 treatment. In contrast, the mRNA levels of OSX, OCN and OPN were enhanced dramatically at day 14 following KR­12­a6 stimulation. Additionally, KR­12­a6 significantly promoted the phosphorylation of Smad1/5. Furthermore, LDN­212854 suppressed the activation of Smad1/5 and inhibited the upregulation of several osteogenic differentiation­associated genes in KR­12­a6­treated hBMSCs. KR­12­a6 promoted the osteogenic differentiation of hBMSCs via BMP/SMAD signaling.

Disruption of the association between drug transporter and actin cytoskeleton abolishes drug resistance in hypertrophic scar.

Hypertrophic scar is characterized by the overgrowth of fibroblasts and often considered as a kind of benign skin tumor, thus chemotherapeutic drugs have been used to treat scars. In view of the similarity, this study aims to investigate whether drug resistance in cancer that contributes to the failure of chemotherapy also exists in hypertrophic scar, and what is the possible mechanism. Fibroblasts derived from hypertrophic scar and normal skin tissues were first compared for their resistance to verapamil and etoposide phosphate. Scar fibroblasts showed stronger resistance to both verapamil and etoposide than normal fibroblasts, also scar fibroblasts expressed more P-glycoprotein and MRP1 than normal fibroblasts. When scar fibroblasts were pre-treated with PSC833 or probenecid, a P-glycoprotein or MRP1 inhibitor respectively, the resistance to verapamil or etoposide was strongly attenuated. Moreover, co-immunoprecipitation revealed more association of P-glycoprotein/MRP1 with actin filaments in scar fibroblasts than normal fibroblasts. The resistance in scar fibroblasts to verapamil and etoposide was almost abolished when pre-treated with latrunculin-A or a specific anti-actin antibody. Taken together, this study suggests that the enhanced expression of drug resistance-related transporters and their increased association with actin cytoskeleton contribute to the resistance to chemotherapeutic drugs in hypertrophic scar. Thus, down-regulating the expession of drug transporters or disrupting drug transporter-actin filament interaction might be novel and effective ways for hypertrophic scar treatment.

Loss of CAR promotes migration and proliferation of HaCaT cells, and accelerates wound healing in rats via Src-p38 MAPK pathway.

The coxsackie and adenovirus receptor (CAR) is a cell adhesion molecule mostly localized to cell-cell contacts in epithelial and endothelial cells. CAR is known to regulate tumor progression, however, its physiological role in keratinocyte migration and proliferation, two essential steps in re-epithelialization during wound healing, has less been investigated. Here we showed that CAR was predominantly expressed in the epidermis of human skin, CAR knockdown by RNAi significantly accelerated HaCaT cell migration and proliferation. In addition, knockdown of CAR in vitro increased p-Src, p-p38, and p-JNK protein levels; however, Src inhibitor PP2 prevented the increase of p-Src and p-p38 induced by CAR RNAi, but not p-JNK, and decelerated cell migration and proliferation. More intriguingly, in vivo CAR RNAi on the skin area surrounding the wounds on rat back visually accelerated wound healing and re-epithelialization process, while treatment with PP2 or p38 inhibitor SB203580 obviously inhibited these effects. By contrast, overexpressing CAR in HaCaT cells significantly decelerated cell migration and proliferation. Above results demonstrate that suppression of CAR could accelerate HaCaT cell migration and proliferation, and promote wound healing in rat skin, probably via Src-p38 MAPK pathway. CAR thus might serve as a novel therapeutic target for facilitating wound healing.