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Endogenous electric fields (EFs) have been confirmed to facilitate angiogenesis through guiding directional migration of endothelial cells (ECs), but the underlying mechanisms remain obscure. Recent studies suggest that the directed migration of ECs in angiogenesis is correlated with autophagy, and the latter of which could be augmented by EFs. We hypothesize that autophagy may participate in the EFs-guided migration of ECs during angiogenesis. Herein, we showed that EFs induced human umbilical vein endothelial cells (HUVEC) migration toward the cathode with enhanced autophagy. Genetic ablation of autophagy by silencing the autophagy-related gene (Atg) 5 abolished the EFs-directed migration of HUVEC, indicating that autophagy is definitely required for EFs-guided migration of cells. Mechanistically, we identified the intracellular reactive oxygen species (ROS) as a crucial mediator in EFs-triggered autophagy through augmenting the silencing information regulator 2 related enzyme1 (SIRT1)/forkhead box protein O1 (FOXO1) signaling. Either ROS scavenging or SIRT1 knockdown eliminated the EFs-triggered autophagy in HUVEC. Further study showed that SIRT1 promoted FOXO1 deacetylation, facilitating its nuclear accumulation and transcriptional activity, and thereby activating autophagy in EFs-treated HUVECs. In conclusion, our study demonstrated a pivotal role for autophagy in EFs-induced directed migration of HUVECs through the ROS/SIRT1/FOXO1 pathway, and provided a novel theoretical foundation for angiogenesis.

Damage to keratinocytes and other skin cells in a high-glucose environment has been proven to be an important reason for the poor wound healing ability of chronic diabetes mellitus. Histatin-1 has been preliminarily proven to stimulate the wound healing process of the oral and non-oral mucosa and has been found to be related to the activation of extracellular signal-regulated kinase (ERK).The purpose of this study was to investigate the effect of histatin-1 on high-glucose-injured keratinocytes and the role of the Ras-Raf-MEK-ERK signaling pathway on the effect of histatin-1 to improve diabetic wound healing.A human keratinocyte model damaged by high glucose was constructed, cell proliferation was detected by the Cell Counting Kit-8 assay, and cell apoptosis was detected by flow cytometry. The expression level of 8-hydroxy-2'-deoxyguanosine (8-OHdG) was detected by ELISA, and the mitogen-activated protein kinase (MAPK) signaling pathway protein expression level was detected by Western blot. C-fos mRNA expression was detected by real-time PCR.The results indicated that histatin-1 promoted proliferation and reduced the rate of apoptosis and 8-OHdG content in keratinocytes with high-glucose injury. In addition, histatin-1 down-regulated MEK phosphorylation in keratinocytes with high-glucose injury. However, with the extension of the intervention, the effect of histatin-1 on c-fos mRNA expression was different. At the early stage of high-glucose injury (12 h), the expression of c-fos mRNA was not increased in high-glucose-injured keratinocytes treated with histatin-1 but then c-fos mRNA expression was gradually upregulated.Histatin-1 could alleviate keratinocyte injury caused by high glucose levels and promoted wound healing in vitro. In addition, histatin-1 could exert anti-apoptotic and antioxidant damage effects under high-glucose injury states. These effects of histatin-1 may be related to its regulation of the MAPK signaling pathway. Therefore, these findings provide an essential theoretical basis for histatin-1 to become a safe and effective new peptide biological agent to promote wound healing in patients with diabetes.

Engineering smart nano-therapeutics for re-epithelialisation of chronic wounds facilitates the wound healing process. However, due to excessive oxidative stress damage and persistent inflammation in diabetic wound microenvironment, the migration of stimulating epidermal cells in diabetic wounds represents a significant challenge. Here we synthesised P311-loaded micelles by self-assembly of P311 peptides and diblock copolymer poly (ethylene glycol)-block-poly (propylene sulfide) (PEG-b-PPS, denoted as PEPS) that have unique ability to transform an oxidative wound microenvironment into a proregenerative one while also providing cues for epidermal cell migration. The P311@PEPS showed an accelerated migration of epidermal cells via activation of the Akt signalling pathway, simultaneously suppressing the unfavourable oxidative wound microenvironment by scavenging reactive oxygen species (ROS), ultimately leading to the induction of an environment conducive to cell migration. Furthermore, the micelles were able to bypass the inhibitory effect of ROS on the Akt signalling pathway, thereby promoting epidermal cell migration. Additionally, we observed that diabetic wounds treated with P311@PEPS showed accelerated chronic wound healing, granulation tissue formation, collagen deposition and re-epithelialisation, thereby suggesting the efficacy of P311@PEPS as a promising nanoplatform for the treatment of chronic wounds. STATEMENT OF SIGNIFICANCE: Based on the unique conditions of the diabetic wound microenvironment, a smart drug delivery system with ROS-responsive nanomaterials has been widely investigated to enhance diabetic wound healing. In our previous studies, we observed that P311 promotes epidermal cell migration to induce wound re-epithelialisation. However, the application of P311 suffers from its instability. Herein, we developed a therapeutic platform with P311-loaded micelles (P311@PEPS), which were synthesized by the self-assembly of P311 peptides and diblock copolymer poly (ethylene glycol)-block-poly (propylene sulfide) (PEG-b-PPS, denoted as PEPS). These micelles provide continuous migration signals for epidermal cells by ROS-trigged P311 release. Additionally, P311@PEPS scavenges excess ROS and provides a microenvironment that reduces inflammation, which could protect P311 from enzymatic degradation and improve the bioavailability of P311.

In this study, we have investigated the effect of Astragaloside IV on keratinocytes' proliferation, migration, oxidative stress, apoptosis, inflammation, and relevant signaling pathway, using human keratinocytes exposed to high glucose.Astragaloside IV is one of the main active ingredients of Astragalus membranaceus (Fisch.) Bunge. Previous studies have found that Astragaloside IV exerts positive effects in various disease models and promotes wound healing.Cell proliferation and migration of keratinocytes, oxidative stress indicators, cell apoptosis rate, inflammatory factors, and key proteins in the TGF-β/Smad signaling pathway were evaluated by molecular biology/biochemical techniques, fluorescence microscope, and flow cytometry.High glucose inhibited the cell proliferation and migration of keratinocytes, upregulated the levels of MDA, ROS, IL-6, IL-8, and Smad7, and decreased the levels of SOD, IL-10, TGF-β1, p-Smad2, and p-Smad3. Astragaloside IV attenuated the dysfunction of keratinocytes, oxidative stress, cell apoptosis, and inflammation, but activated TGF-β/Smad signaling pathway. Meanwhile, the addition of SB431542 (the inhibitor of TGF-β/Smad signaling pathway) eliminated the impact of Astragaloside IV on high glucose-induced keratinocytes.These results strongly suggest that Astragaloside IV may be a potential drug candidate for accelerating diabetic wound healing, by protecting keratinocytes against damages induced by high glucose and TGF-β/Smad pathway is involved in this process at the cellular level.

Cutaneous squamous cell carcinoma (CSCC) is the most known form type of metastatic skin cancer. Activation of ephrin B receptor 2 (EphB2) signaling can promote the metastasis, invasion, and angiogenesis of CSCC cells. Therefore, EphB2 may act as a therapeutic target for CSCC. Here, we screened the inhibitors for EphB2 using molecular docking and then evaluated the effects of the identified inhibitors on cancer-related features of CSCC cells.The Schrodinger docking tool was used to predict the three-dimensional structure of EphB2 protein and its ligand binding sites, and EphB2 inhibitors were screened by high-throughput virtual screening combined with molecular docking. The effects of EphB2 inhibitors were analyzed for cell viability, proliferation, apoptosis, migration, invasion, and xenograft tumor growth.EphB2 small-molecule inhibitors had anti-CSCC effects, establishing a solid theoretical basis for clinical research.

Wound healing is a complex and important physiological process that maintains the integrity of skin after various injuries. Abnormal wound healing, especially of chronic wounds, impairs normal physical function. Therefore, the search for effective and safe healing agents is one of the main concerns. Histatins are histidine-rich low molecular weight peptides that are expressed in the saliva of both humans and higher primates. Histatins have two main biological effects, cell stimulation and bacteria killing, with the former playing an important role in wound healing by promoting epithelial cell and fibroblast migration and angiogenesis and enhancing the re-epithelialization of the wounded area. Because of these biological effects, histatins have been shown to be promising agents of improved wound healing. Histatins are categorized into many subtypes, of which histatin 1 and its hydrolysates are the most effective in promoting wound healing. This review addresses the bioactivity of histatins in wound healing, such as their stimulatory effects on epithelial cells and fibroblasts, and elucidates the possible mechanisms by which histatin subtypes induce their biological effects.

The prognostic factors of facial paralysis complicated by middle ear cholesteatoma (MEC) are largely unknown due to limited reports and smaller sample size.This study aimed to analyze prognostic factors of postoperative outcomes of facial paralysis complicated by MEC.Clinical data of 48 patients (48 ears) with facial paralysis complicated by MEC were retrospectively reviewed and analyzed. The outcomes of facial paralysis were compared between different groups.All the eight cases (100%) with intact fallopian canal had complete recovery of facial paralysis after surgery, while only 52.5% cases (21/40 cases) with fallopian canal damage achieved good recovery, with significant difference (p .05). For subgroup analysis of the 40 cases with damaged fallopian canal, the good recovery rate of facial paralysis in shorter duration group (≤2 months) was higher compared to longer duration group (2 months) (81.0% versus 21.1%; p .05). Moreover, the good recovery rate of facial paralysis in moderate facial paralysis group (grade II-IV) was higher compared to severe facial paralysis group (grade V-VI) (82.4% versus 30.4%; p .05).The outcomes of facial paralysis complicated by MEC were associated with fallopian canal integrity, duration and severity of facial paralysis.

In the present study, a novel polysaccharide, APS2-1, was isolated and purified from Astragalus membranaceus using DEAE-cellulose and Sephadex G-100 chromatography. The effect of APS2-1 on the promotion of wound healing was evaluated and its preliminary mechanism was investigated. In vitro experiments showed that APS2-1 was able to promote human skin fibroblast (HSF) propagation and accelerate cell cycle progression. For further examination, a scalded mice model was used to verify the effect of APS2-1 and investigate its mechanism of action. The analysis of biochemical parameters, including cyclin D1, inhibitor of nuclear factor κBα (IκBα), transforming growth factor (TGF)-β1, basic fibroblast growth factor (bFGF) and epidermal growth factor (EGF) showed that APS2-1 inhibited the increase in cyclin D1 and IκBα, and promoted the expression of TGF-β1, bFGF and EGF, which was further confirmed by histopathological observation. These results suggested that APS2-1 possessed high potential in wound healing and its mechanism was associated with inhibiting inflammation, accelerating cell cycle and promoting the secretion of repair factors.

Objective To investigate clinical features and outcomes of delayed facial palsy after head trauma. Methods The cases who had delayed facial palsy after head trauma treated from March 2008 to March 2013 at our hospital were enrolled in the study, and their clinical features and outcomes were analyzed. Results Thirty-five of 1620 cases developed delayed facial palsy after head trauma. Facial palsy occurred within day 3–7 in 23 cases, during day 8–14 in 8 cases, and 2 weeks later in 4 cases. Thirty-three cases were treated by prednisolone alone, and two cases who showed ≥90% degeneration of nerve fibers underwent surgical exploration and decompression. Among the 33 cases who received conservative treatment, 27 cases (81.8%) recovered completely, 3 cases (9.1%) recovered to Grade II, and only 3 cases (9.1%) recovered to Grade III or IV. The two surgically treated patients recovered to Grade II and III, respectively. Conclusion The incidence of delayed facial palsy was 2.2% after head trauma. Delayed facial palsy mainly occurred within 2 weeks after head trauma. And over 90% patients achieved good recovery (HB Grade I or II) of facial nerve after conservative treatment.

Dexamethasone (DXM) can regulate the balance of neutrophil and cytokine and enhance the ischemia-reperfusion tolerance of the skin flap; amlodipine besylate (AB) can selectively expand the peripheral blood vessels and relieve the vascular smooth muscle spasm. To investigate the percutaneous penetration ability of DXM/AB compound gel and evaluate its effect on survival of ischemic skin flap.Sodium carboxymethylcellulose was used to make blank gel, which was mixed in DXM, AB, azone (AZ), and propylene glycol (PG) respectively to make the compound gel containing 0.3%DXM/0.5%AB only (group D), the compound gel containing 3%AZ/2%PG, 3%AZ, and 2%PG (groups A, B, and C), the 0.3%DXM gel containing 3%AZ/2%PG (group E), the 0.5%AB gel containing 3%AZ/2%PG (group F). The accumulative penetration of DXM and AB in compound gel, 0.3%DXM gel, 0.5%AB gel through excised rat skin and its penetration within flap tissue were investigated by ultraviolet spectrophotometry. Fifty SD rats were selected to make 100 mm x 10 mm random flap at the back, and were randomly divided into 5 groups according to different gels which were used to treat flaps (n = 10): compound gel group (group A1), 0.3%DXM gel group (group B1), 0.5%AB gel group (group C1), blank gel group (group D1), and peritoneal injection of DXM (5 mg/kg) and AB (2 mg/kg) (group E1). The survival area of ischemic random skin flap was measured on the 7th day by planimetry. Twenty-four SD rats were selected to make 100 mm x 10 mm random flap at the back, and were randomly divided into 2 groups (n = 12). The accumulative penetration of DXM and AB within skin flap were also detected at 2 and 6 hours after application of 2 g of compound gel containing 3%AZ/2%PG (group A2) and peritoneal injection AB (2 mg/kg) / DXM (5 mg/kg) (group B2).The accumulative penetration of DXM and AB in compound gel were increased in time-dependent manner (P0.05), and it was the highest in group A, and was significantly higher than that in group B and group C (P0.01), but there was no significant difference when compared with group E or group F (P0.05). The accumulative penetration of DXM and AB in groups A, B, and C were significant higher than that in group D (P0.05). After 7 days, the survival area of flaps in groups A1, B1, C1, D1, and E1 were (695.0 +/- 4.6), (439.3 +/- 7.1), (477.5 +/- 14.5), (215.2 +/- 3.8), and (569.4 +/- 9.7) mm2, respectively; group A1 was significantly higher than other groups (P0.05). After 2 and 6 hours, the quantities of DXM and AB in skin flap of group A2 were significantly higher than that of group B2 (P0.05).In 0.3%DXM/0.5%AB compound gel, DXM and AB might penetrate into skin tissue, which could significantly increase the survival area of ischemic skin flap.