Topical vanadate improves tensile strength and alters collagen organisation of excisional wounds in a mouse model.

Wound dehiscence, oftentimes a result of the poor tensile strength of early healing wounds, is a significant threat to the post-operative patient, potentially causing life-threatening complications. Vanadate, a protein tyrosine phosphatase inhibitor, has been shown to alter the organisation of deposited collagen in healing wounds and significantly improve the tensile strength of incisional wounds in rats. In this study, we sought to explore the effects of locally administered vanadate on tensile strength and collagen organisation in both the early and remodelling phases of excisional wound healing in a murine model. Wild-type mice underwent stented excisional wounding on their dorsal skin and were divided equally into three treatment conditions: vanadate injection, saline injection control and an untreated control. Tensile strength testing, in vivo suction Cutometer analysis, gross wound measurements and histologic analysis were performed during healing, immediately upon wound closure, and after 4 weeks of remodelling. We found that vanadate treatment significantly increased the tensile strength of wounds and their stiffness relative to control wounds, both immediately upon healing and into the remodelling phase. Histologic analysis revealed that these biomechanical changes were likely the result of increased collagen deposition and an altered collagen organisation composed of thicker and distinctly organised collagen bundles. Given the risk that dehiscence poses to all operative patients, vanadate presents an interesting therapeutic avenue to improve the strength of post-operative wounds and unstable chronic wounds to reduce the risk of dehiscence.

Sciatic nerve block downregulates the BDNF pathway to alleviate the neonatal incision-induced exaggeration of incisional pain via decreasing microglial activation.

Sciatic nerve block is under investigation as a possible therapeutic strategy for neonatal injury-induced exaggeration of pain responses to reinjury. Spinal microglial priming, brain-derived neurotrophic factor (BDNF) and Src homology-2 domain-containing protein tyrosine phosphatase-2 (SHP2) participate in exaggerated incisional pain induced by neonatal incision. However, effects of sciatic nerve block on exacerbated incisional pain and underlying mechanisms remain unclear. Here, we demonstrated that sciatic nerve block alleviates pain hypersensitivity and microglial activation in rats subjected to neonatal incision and adult incision (nIN-IN). Chemogenetic activation or inhibition of spinal microglia attenuates or mimics effects of sciatic nerve block on pain hypersensitivity, respectively. Moreover, α-amino-3-hydroxy- 5-methy- 4-isoxazole propionate (AMPA) receptor subunit GluA1 contributes to the exaggeration of incisional pain. The inhibition of BDNF or SHP2 blocks upregulations of downstream molecules in nIN-IN rats. Knockdown of SHP2 attenuates the increase of GluA1 induced by injection of BDNF in adult rats with only neonatal incision. The inhibition of microglia or ablation of microglial BDNF attenuates upregulations of SHP2 and GluA1. Additionally, sciatic nerve block downregulates the expression of these three molecules. Upregulation of BDNF, SHP2 or AMPA receptor attenuates sciatic nerve block-induced reductions of downstream molecules and pain hypersensitivity. Microglial activation abrogates reductions of these three molecules induced by sciatic nerve block. These results suggest that decreased activation of spinal microglia contributes to beneficial effects of sciatic nerve block on the neonatal incision-induced exaggeration of incisional pain via downregulating BDNF/SHP2/GluA1-containing AMPA receptor signaling. Thus, sciatic nerve block may be a promising therapy.

M2-polarized macrophages mediate wound healing by regulating connective tissue growth factor via AKT, ERK1/2, and STAT3 signaling pathways.

BACKGROUND: Timely and sufficient M1 recruitment and M2 polarization are necessary for fibrosis during wound healing. The mechanism of how M2 mediates wound healing is worth exploring. Abnormally up-regulated connective tissue growth factor (CTGF) influences multiple organ fibrosis, including cardiac, pulmonary, hepatic, renal, and cutaneous fibrosis. Previous studies reported that M2 contributed to hepatic and renal fibrosis by secreting CTGF. It is worth discussing if M2 regulates fibrosis through secreting CTGF in wound healing. METHODS AND RESULTS: We established the murine wound model and inhibited macrophages during proliferation phase with clodronate liposomes in vivo. Macrophages depletion led to down-regulation of wound healing rates, collagen deposition, as well as expression of collagen 1/3 and Ki67. M2 was induced by interleukin-4 (IL-4) and measured by flow cytometry in vitro. Secreted pro-fibrotic and anti-fibrotic factors were tested by enzyme-linked immunosorbent assay (ELISA). M2 was polarized, which producing more CTGF, transforming growth factor-beta1 (TGF-ß1), and IL-6, as well as less tumor necrosis factor-α (TNF-α) and IL-10. M2 CTGF gene was blocked using siCTGF. Effects of M2 on fibroblasts activities were detected by cell counting kit 8 (CCK8) and cellular wound healing assay. Expressions of related signaling pathway were assessed by western blotting. Blockade of CTGF in M2 deactivated fibroblasts proliferation and migration by regulating AKT, ERK1/2, and STAT3 pathway. Recombinant CTGF restored these effects. CONCLUSIONS: Our research, for the first time, indicated that M2 promoted wound healing by secreting CTGF, which further mediating proliferation and migration of fibroblasts via AKT, ERK1/2, and STAT3 pathway.

In Vivo Calcium Imaging Visualizes Incision-Induced Primary Afferent Sensitization and Its Amelioration by Capsaicin Pretreatment.

Previous studies have shown that infiltration of capsaicin into the surgical site can prevent incision-induced spontaneous pain like behaviors and heat hyperalgesia. In the present study, we aimed to monitor primary sensory neuron Ca2+ activity in the intact dorsal root ganglia (DRG) using Pirt-GCaMP3 male and female mice pretreated with capsaicin or vehicle before the plantar incision. Intraplantar injection of capsaicin (0.05%) significantly attenuated spontaneous pain, mechanical, and heat hypersensitivity after plantar incision. The Ca2+ response in in vivo DRG and in in situ spinal cord was significantly enhanced in the ipsilateral side compared with contralateral side or naive control. Primary sensory nerve fiber length was significantly decreased in the incision skin area in capsaicin-pretreated animals detected by immunohistochemistry and placental alkaline phosphatase (PLAP) staining. Thus, capsaicin pretreatment attenuates incisional pain by suppressing Ca2+ response because of degeneration of primary sensory nerve fibers in the skin.SIGNIFICANCE STATEMENT Postoperative surgery pain is a major health and economic problem worldwide with ∼235 million major surgical procedures annually. Approximately 50% of these patients report uncontrolled or poorly controlled postoperative pain. However, mechanistic studies of postoperative surgery pain in primary sensory neurons have been limited to in vitro models or small numbers of neurons. Using an innovative, distinctive, and interdisciplinary in vivo populational dorsal root ganglia (DRG) imaging (>1800 neurons/DRG) approach, we revealed increased DRG neuronal Ca2+ activity from postoperative pain mouse model. This indicates widespread DRG primary sensory neuron plasticity. Increased neuronal Ca2+ activity occurs among various sizes of neurons but mostly in small-diameter and medium-diameter nociceptors. Capsaicin pretreatment as a therapeutic option significantly attenuates Ca2+ activity and postoperative pain.

Comparison of tear proteomic and neuromediator profiles changes between small incision lenticule extraction (SMILE) and femtosecond laser-assisted in-situ keratomileusis (LASIK).

Introduction: The tear proteomics and neuromediators are associated with clinical dry eye parameters following refractive surgery. Purpose: To investigate and compare the tear proteomic and neuromediator profiles following small incision lenticule extraction (SMILE) versus laser-assisted in-situ keratomileusis (LASIK). Methods: In this randomized controlled trial with paired-eye design, 70 patients were randomized to receive SMILE in one eye and LASIK in the other eye. Tear samples were collected preoperatively, and 1 week, 1, 3, 6 and 12 months postoperatively, and were examined for protein concentration changes using sequential window acquisition of all theoretical fragment ion mass spectrometry (SWATH-MS). The data were analyzed with DAVID Bioinformatics Resources for enriched gene ontology terms and over-represented pathways. Tear neuromediators levels were correlated with clinical parameters. Results: Post-SMILE eyes had significantly better Oxford staining scores and tear break-up time (TBUT) than post-LASIK eyes at 1 and 3 months, respectively. Tear substance P and nerve growth factor levels were significantly higher in the LASIK group for 3 months and 1 year, respectively. SMILE and LASIK shared some similar biological responses postoperatively, but there was significant up-regulation in leukocyte migration and wound healing at 1 week, humoral immune response and apoptosis at 1 month, negative regulation of endopeptidase activity at 3 to 6 months, and extracellular structure organization at 1 year in the post-LASIK eyes. Tear mucin-like protein 1 and substance P levels were significantly correlated with TBUT (r = -0.47, r = -0.49, respectively). Conclusion: Significant differences in the tear neuromediators and proteomics were observed between SMILE and LASIK, even though clinical dry eye signs have subsided and became comparable between 2 procedures.

Proinflammatory Extracellular Vesicle-Mediated Signaling Contributes to the Induction of Neuroinflammation in Animal Models of Endotoxemia and Peripheral Surgical Stress.

Peripheral inflammation induced by endotoxemia or surgical stress induces neuroinflammation thereby causing neurological symptoms ranging from sickness behavior to delirium. Thus, proinflammatory signaling must be operative between the periphery and the central nervous system (CNS). In the present study, we tested whether nanometer-sized extracellular vesicles (EVs) that were produced during the peripheral inflammatory process have the capacity to induce neuroinflammation. Conditions of endotoxemia or surgical intervention were simulated in rats by lipopolysaccharide (LPS) injection or partial hepatectomy (HpX). EVs were concentrated from these animals and tested for their proinflammatory action (I) in a microglial cell line and (II) by intracerebroventricular and (III) by intravenous injections into healthy rats. EVs from both conditions induced the secretion of cytokines from the glial cell line. Intracerebroventricular injection of the EVs caused the release of inflammatory cytokines to the cerebrospinal fluid indicating their pro-neuroinflammatory capacity. Finally, proinflammatory EVs were shown to pass the blood-brain barrier and induce neuroinflammation after their intravenous injection. Based on these data, we suggest that EV-associated proinflammatory signaling contributes to the induction of neuroinflammation in endotoxemia and peripheral surgical stress. Preliminary results suggest that peripheral cholinergic signals might be involved in the control of proinflammatory EV-mediated signaling from the periphery to the brain.

Systematic profiling of early regulators during tissue regeneration using zebrafish model.

Great progresses have been made in comprehension of tissue regeneration process. However, one of the central questions in regeneration research remains to be deciphered is what factors initiate regenerative process. In present study, we focused on systematic profiling of early regulators in tissue regeneration via high-throughput screening on zebrafish caudal fin model. Firstly, 53 GO-annotated regeneration-related genes, which were specifically activated upon fin amputation, were identified according to the transcriptomic analysis. Moreover, qRT-PCR analysis of a couple of randomly selected genes from the aforementioned gene list validated our sequencing results. These studies confirmed the reliability of transcriptome sequencing analysis. Fibroblast growth factor 20a (fgf20a) is a key initial factor in the regeneration of zebrafish. Through a gene expression correlation analysis, we discovered a collection of 70 genes correlating with fgf20a, whose expression increased promptly at 2 days post amputation (dpa) and went down to the basal level until the completion of fin regeneration. In addition, two genes, socs3b and nppc, were chosen to investigate their functions during the fin regeneration. Inhibition of either of those genes significantly delayed the regenerative process. Taken together, we provided a simple and effective time-saving strategy that may serve as a tool for identifying early regulators in regeneration and identified 71 genes as early regulators of fin regeneration.

Adipocyte lipolysis drives acute stress-induced insulin resistance.

Stress hyperglycemia and insulin resistance are evolutionarily conserved metabolic adaptations to severe injury including major trauma, burns, or hemorrhagic shock (HS). In response to injury, the neuroendocrine system increases secretion of counterregulatory hormones that promote rapid mobilization of nutrient stores, impair insulin action, and ultimately cause hyperglycemia, a condition known to impair recovery from injury in the clinical setting. We investigated the contributions of adipocyte lipolysis to the metabolic response to acute stress. Both surgical injury with HS and counterregulatory hormone (epinephrine) infusion profoundly stimulated adipocyte lipolysis and simultaneously triggered insulin resistance and hyperglycemia. When lipolysis was inhibited, the stress-induced insulin resistance and hyperglycemia were largely abolished demonstrating an essential requirement for adipocyte lipolysis in promoting stress-induced insulin resistance. Interestingly, circulating non-esterified fatty acid levels did not increase with lipolysis or correlate with insulin resistance during acute stress. Instead, we show that impaired insulin sensitivity correlated with circulating levels of the adipokine resistin in a lipolysis-dependent manner. Our findings demonstrate the central importance of adipocyte lipolysis in the metabolic response to injury. This insight suggests new approaches to prevent insulin resistance and stress hyperglycemia in trauma and surgery patients and thereby improve outcomes.

Uterine Scarring Leads to Adverse Pregnant Consequences by Impairing the Endometrium Response to Steroids.

Uterine surgical scarring is an increasing risk factor for adverse pregnant consequences that threaten fetal-maternal health. The detailed molecular features of scar implantation remain largely unknown. We aim to study the pathologic features of uterine surgical scarring and the mechanisms of compromised pregnancy outcomes of scar implantation. We generated a mouse model of uterine surgical scarring with a uterine incision penetrating the myometrium to endometrium to examine the pathologic changes and transcriptome profiles of uterine scarring at various postsurgery (PS) time points, as well as features of the feto-maternal interface during scar implantation. We found that uterine surgical scar recovery was consistently poor at PS3 until PS90, as shown by a reduced number of endometrial glands, inhibition of myometrial smooth muscle cell growth but excessive collagen fiber deposition, and massive leukocyte infiltration. Transcriptome annotation indicated significant chronic inflammation at the scarring site. At the peri-implantation and postimplantation stages, abnormal expression of various steroid-responsive genes at the scarring site was in parallel with lumen epithelial cell hyperplasia, inappropriate luminal closure, and disorientation of the implanted embryo, restricted stromal cell proliferation, and defective decidualization. High embryonic lethality (around 70%) before E10.5 was observed, and the small amount of survival embryos at E10.5 exhibited restricted growth and aberrant placenta defects including overinvasion of trophoblast cells into the decidua and insufficient fetal blood vessel branching in the labyrinth. The findings indicate that chronic inflammation and compromised responses to steroids in uterine scar tissues are the pivotal molecular basis for adverse pregnancy consequences of scar implantation.

Tranexamic acid has positive effect in early period of tendon healing by stimulating the tumor necrosis factor-alpha and matrix metalloproteinase-3 expression levels.

OBJECTIVES: This study aims to evaluate the effect of tranexamic acid (TXA) application in tendon healing by using its immunohistochemical effects on tumor necrosis factor-alpha (TNF-α), matrix metalloproteinase-3 (MMP-3), and transforming growth factor-beta (TGF-ß) expression; and to identify if TNF-α, MMP-3, and TGF-ß can be used to monitor and evaluate tendon healing or not in tenotomized rat Achilles tendons. MATERIALS AND METHODS: Twelve male Wistar-Albino rats (age 6-7-month-old; weighing 300-350 g) were used in this retrospective study conducted between November 2016 and May 2017. The rats were divided into two groups with similar weights. The right legs of the rats were determined as the study group (TXA), and the left legs as the control serum physiologic (SP) group. Under anesthesia, bilateral Achilles tenotomy was performed and surgically repaired. 1 mL of TXA was applied locally for the right side and 1 mL of SP was locally applied for the left side. Half of the rats were sacrificed at the third week (right leg-TXA3, left leg-SP3) and the other half at sixth week (right leg-TXA6, left leg-SP6) and tendon samples were taken from the extremities. Immunohistochemical findings of TNF-α, MMP-3, and TGF-ß were evaluated on the basis of the frequency and intensity of staining. RESULTS: In TNF-α and MMP-3 and TXA groups, there was a significant difference in staining compared to SP groups (p<0.05). Regarding TNF-α expression, the total index score in the TXA6 subgroup was higher than the TXA3, SP6, and SP3 subgroups (8, 7, 3, and 4, respectively). Overall scores of TNF-α showed that TXA groups had significantly higher scores when compared to SP groups (p<0.05). In addition, total MMP-3 expression scores were significantly higher in TXA groups than in SP groups, respectively; TXA3: 14, TXA6: 11, SP3: 10, and SP6: 9 (p<0.05). However, the degree of staining with TNF-α was found to be significantly lower than MMP-3 (p<0.05). Immunohistochemical reactivity was not observed with TGF-ß. CONCLUSION: Tranexamic acid has positive effect in early period of tendon healing by stimulating the TNF-α and MMP-3 expression levels. TNF-α and MMP-3 can be used to monitor and evaluate tendon healing.

Chitosan hydrogels functionalized with either unfractionated heparin or bemiparin improve diabetic wound healing.

Diabetes mellitus causes severe impairment in the cutaneous wound healing process, which has led to extensive research striving to establish new treatments. In this work, we describe the effects of chitosan hydrogels functionalized with either unfractionated heparin or bemiparin (a low molecular weight heparin, LMWH) as topical treatments in an experimental diabetic wound healing model. Although wound morphometry showed similar values at the end of the study, microscopic analyses revealed impaired healing in diabetic animals in terms of inflammation and tissue formation. However, both types of loaded hydrogels accelerated inflammation resolution and improved the epithelialization process, while showing a neodermal thickness similar to that of nondiabetic animals. Immunohistochemistry analyses revealed an intermediate response in macrophage evolution between diabetic and nondiabetic controls in the treated groups, as well as enhanced collagenization and myofibroblast progression patterns. However, these changes were not accompanied by differences among groups in collagen I, III and TGF-ß1 gene expression. Functionalized hydrogels improved diabetes-associated impaired wound healing, thus promoting the progression of the process and inducing the formation of high-quality cicatricial tissue. Although the beneficial healing effect observed after topical treatment with chitosan hydrogels loaded with bemiparin or unfractionated heparin was similar, the chitosan hydrogel loaded with bemiparin is the preferred choice as it exhibited high-quality tissue in the neoformed dermal tissue.

A new role for anandamide: defective link between the systemic and skin endocannabinoid systems in hypertrophic human wound healing.

The use of cannabinoids to treat fibrotic skin diseases is an emergent issue. Therefore, we aimed to evaluate systemic and skin endocannabinoid responses in the wound-healing process in humans. A prospective study was performed in 50 patients who underwent body-contouring surgery. Anandamide (N-arachidonoylethanolamine, AEA), 2-arachidonoylglycerol (2-AG), palmitoylethanolamide (PEA) and oleoylethanolamide (OEA) were quantified using LC-MS/MS. Ten (20%) patients developed hypertrophic (HT) scars. No significant changes were observed between the normal (N) scar and HT scar groups in terms of plasma and skin endocannabinoids. Nevertheless, a positive correlation between plasma and skin AEA concentrations was found in the N group (r = 0.38, p = 0.015), which was absent in the HT group. Moreover, the AEA concentration was significantly lower in HT scar tissue than in normal scar tissue (0.77 ± 0.12 ng/g vs 1.15 ± 0.15 ng/g, p < 0.001). Interestingly, in all patients, the surgical intervention produced a time-dependent effect with a U shape for AEA, PEA and OEA plasma concentrations. In contrast, 2-AG plasma concentrations increased 5 days after surgery and were reduced and stabilized 3 months later. These results suggest crosstalk between systemic and local skin endocannabinoid systems during human wound healing. AEA appears to be the most likely candidate for this link, which is deficient in patients with HT scars.

Expression of Metalloproteinases and Type I and III Collagens during Healing of Excisional Skin Wound on the Abdomen and Back in Rats.

The study was carried out using a novel rat model developed in our laboratory, namely16 mm diameter circular excisional wounds were generated on the abdomen which resulted in minimal scarring. Restoration of the skin integrity was completed by day 60 after the wounding surgery. By this time, regenerates on the abdomen were stronger than on the back (at, respectively, 58 and 17.4 % of the tensile strength of the intact skin at corresponding location) and the ratio of type I and type III collagens in regenerates on the abdomen reached the level of intact skin at the same location. On days 3 to 14, the ratio of Mmp9/Timp1 expression levels on the abdomen was higher than on the back. On days 20 and 30, the Mmp9/Timp1 ratio on the abdomen was identical to the level of intact skin, whereas the increased MMPs expression levels on the back were maintained until day 30. It has been shown for the first time that according to functional and molecular characteristics, wound healing on the abdomen of an adult rat is more similar to complete regeneration than scarring repair of the back skin.

Knockout of E2F1 enhances the polarization of M2 phenotype macrophages to accelerate the wound healing process.

Wound healing is a complex process, which is classically divided into inflammation, proliferation, and remodeling phases. Macrophages play a key role in wound healing, however, whether E2F1 mediates the M1/M2 polarization during the wound healing process is not known. Skin wounds were surgically induced in E2F1-/- mice and their WT littermates. At day 2 and day 7 post-surgery, the wounded skin tissues including 2 to 3 mm normal skin were obtained. The wounded skin tissues were used for the analyses of immunofluorescence staining (CD68, iNOS, CD206), western blotting (CD68, iNOS, CD206, PPAR-γ) and Co-immunoprecipitation (E2F1-PPAR-γ interactions). E2F1-/- mice exhibited faster wound healing process. At day 2, the M2 macrophages were remarkably increased in the E2F1-/- mice. Surprisingly, in the border zone of the wound, E2F1-/- mice had also more M2 macrophages and fewer M1 macrophages at day 7 post-surgery, suggesting a certain degree of polarization amongst the M1 and M2 phenotypes. Co-IP revealed that E2F1 indeed interacted with PPAR-γ, meanwhile western blotting and RT-PCR showed higher expression of PPAR-γ in the E2F1-/- mice as compared to that in the WT mice. Therefore, the findings suggest that wound healing process could be accelerated with enhanced M2 polarization through increased PPAR-γ expression in E2F1 knockout mice.

Molecular and histological studies of bladder wound healing in a rodent model.

The field of regenerative medicine encounters different challenges. The success of tissue-engineered implants is dependent on proper wound healing. Today, the process of normal urinary bladder wound healing is poorly characterized. We aspired to explore and elucidate the natural response to injury in an in vivo model in order to further optimize tissue regeneration in future studies. In this study, we aimed to characterize histological and molecular changes during normal healing in a rat model by performing a standardized incisional wound followed by surgical closure. We used a rodent model (n = 40) to follow the healing process in the urinary bladder for 28 days. Surgical exposure of the bladder without incision (n = 40) was performed in controls. Histological characterization and western blot analyses of proteins was carried out using specific staining and markers for inflammation, proliferation, angiogenesis, and tissue maturation. For the molecular characterization of gene expression total RNA was collected for RT2 -PCR in wound healing pathway arrays. Analysis of histology revealed distinct, but overlapping, phases of healing with a local inflammatory response (days 1-8) simultaneous with a rapid formation of granulation tissue and proliferation (days 2-8). We also identified significant changes in gene expression related to inflammation, proliferation, and extracellular matrix formation. Healing of an incisional wound in a rodent urinary bladder demonstrated that all the classical phases of wound healing: hemostasis, inflammation, proliferation followed by tissue maturation were present. Our data suggest that the bladder and the skin share similar molecular signaling during wound healing, although we noted differences in the duration of each phase compared to previous studies in rat skin. Further studies will address whether our findings can be extrapolated to the human bladder.

Increased extracellular ubiquitin in surgical wound fluid provides a chemotactic signal for myeloid dendritic cells.

PURPOSE: Myeloid dendritic cells (MDC) decline significantly after multiple traumas which might be due to an increased migration into injured regions. Ubiquitin is released from dying cells and is increased in serum after trauma. Ubiquitin can bind to the chemokine receptor CXCR4. Thus, we hypothesized that elevated ubiquitin provides a chemotactic signal for MDC to injured regions. METHODS: Surgical wound fluid (SWF) and serum from patients with mono-trauma (n = 20) were used to simulate the humoral situation in injured tissue. MDC were identified by flow cytometry. Chemotaxis was measured using transwell migration assays. Ubiquitin and CXCL12 (natural CXCR4 ligand) were determined by ELISA. RESULTS: MDC express CXCR4 and fluorescence-labeled ubiquitin binds to MDC. Ubiquitin exerts a dose-dependent chemotactic effect (fourfold at 100 ng/mL, p < 0.05). Ubiquitin concentration was sixfold higher in SWF (p < 0.05), whereas CXCL12 was increased in serum. MDC migration towards SWF was significantly reduced (- 40%, p < 0.05), if ubiquitin was neutralized by specific antibodies. CONCLUSIONS: Ubiquitin is increased in SWF and exerts a significant chemotactic effect on MDC. This mechanism might play a role in attraction of immune cells to injured regions and might contribute to the decline of circulating MDC in multiple traumas.

Rapid, economical healing of two large Mohs surgery wounds with transforming powder dressing.

As dermatology has evolved into a medical/surgical specialty, care for the patient with difficult postsurgical wounds has emerged as an aspect of practice for an increasing number of dermatologists. Here, we present a transforming powder dressing which yielded fast, cost-effective healing of two such wounds, while also relieving the patient and his family of any wound care responsibility.

Activation of liver x receptors prevents the spinal LTP induced by skin/muscle retraction in the thigh via SIRT1/NF-Κb pathway.

It has been reported that skin/muscle incision and retraction (SMIR) in the thigh, produces mechanical allodynia in the hind paw, far from the site of incision/retraction. The mechanical allodynia lasts about 22 days, indicating chronic post-operative pain develops. The precise mechanisms, however, are largely unclear. In the current study, we further found that SMIR surgery induced LTP of c-fiber evoked field potentials that lasted at least 4 h. The mRNA and protein level of tumor necrosis factor-alpha (TNFα) and acetylated nuclear factor-kappaB p65 (ac-NF-κB p65) in the lumbar spinal dorsal horn was gradually increased during LTP development, while pretreatment with either TNFα neutralization antibody or NF-κB inhibitor PDTC completely prevented the induction of LTP. Moreover, the expression of Silent information regulator 1 (SIRT1) in the lumbar spinal dorsal horn was decreased and activation of SIRT1 by SRT1720 also prevented the induction of LTP. Importantly, the spinal expression of Liver X receptors (LXRs) was increased, both at mRNA and protein level following SMIR. Application of LXRs agonist T0901317 to the spinal dorsal horn prevented LTP induction following SMIR. Mechanistically, T0901317 enhanced the expression of SIRT1 and decreased the expression of ac-NF-κB p65 and TNFα. Spinal application of SIRT1 antagonist EX-527, 30 min before T0901317 administration, completely blocked the inhibiting effect of T0901317 on LTP, and on expression of ac-NF-κB p65 and TNFα. These results indicated that activation of LXRs prevented SMIR-induced LTP by inhibiting NF-κB/TNFα pathway via increasing SIRT1 expression.