Mitochondrial dysfunction in sepsis: mechanisms and therapeutic perspectives.

Sepsis is a severe medical condition characterized by a systemic inflammatory response, often culminating in multiple organ dysfunction and high mortality rates. In recent years, there has been a growing recognition of the pivotal role played by mitochondrial damage in driving the progression of sepsis. Various factors contribute to mitochondrial impairment during sepsis, encompassing mechanisms such as reactive nitrogen/oxygen species generation, mitophagy inhibition, mitochondrial dynamics change, and mitochondrial membrane permeabilization. Damaged mitochondria actively participate in shaping the inflammatory milieu by triggering key signaling pathways, including those mediated by Toll-like receptors, NOD-like receptors, and cyclic GMP-AMP synthase. Consequently, there has been a surge of interest in developing therapeutic strategies targeting mitochondria to mitigate septic pathogenesis. This review aims to delve into the intricate mechanisms underpinning mitochondrial dysfunction during sepsis and its significant impact on immune dysregulation. Moreover, we spotlight promising mitochondria-targeted interventions that have demonstrated therapeutic efficacy in preclinical sepsis models.

Construction of programmed time-released multifunctional hydrogel with antibacterial and anti-inflammatory properties for impaired wound healing.

The successful reprogramming of impaired wound healing presents ongoing challenges due to the impaired tissue microenvironment caused by severe bacterial infection, excessive oxidative stress, as well as the inappropriate dosage timing during different stages of the healing process. Herein, a dual-layer hydrogel with sodium alginate (SA)-loaded zinc oxide (ZnO) nanoparticles and poly(N-isopropylacrylamide) (PNIPAM)-loaded Cu5.4O ultrasmall nanozymes (named programmed time-released multifunctional hydrogel, PTMH) was designed to dynamically regulate the wound inflammatory microenvironment based on different phases of wound repairing. PTMH combated bacteria at the early phase of infection by generating reactive oxygen species through ZnO under visible-light irradiation with gradual degradation of the lower layer. Subsequently, when the upper layer was in direct contact with the wound tissue, Cu5.4O ultrasmall nanozymes were released to scavenge excessive reactive oxygen species. This neutralized a range of inflammatory factors and facilitated the transition from the inflammatory phase to the proliferative phase. Furthermore, the utilization of Cu5.4O ultrasmall nanozymes enhanced angiogenesis, thereby facilitating the delivery of oxygen and nutrients to the impaired tissue. Our experimental findings indicate that PTMHs promote the healing process of diabetic wounds with bacterial infection in mice, exhibiting notable antibacterial and anti-inflammatory properties over a specific period of time.

Clinical epidemiology and a novel predicting nomogram of central line associated bloodstream infection in burn patients.

Burn patients are at high risk of central line-associated bloodstream infection (CLABSI). However, the diagnosis of such infections is complex, resource-intensive, and often delayed. This study aimed to investigate the epidemiology of CLABSI and develop a prediction model for the infection in burn patients. The study analysed the infection profiles, clinical epidemiology, and central venous catheter (CVC) management of patients in a large burn centre in China from January 2018 to December 2021. In total, 222 burn patients with a cumulative 630 CVCs and 5,431 line-days were included. The CLABSI rate was 23.02 CVCs per 1000 line-days. The three most common bacterial species were Acinetobacter baumannii, Staphylococcus aureus, and Pseudomonas aeruginosa; 76.09% of isolates were multidrug resistant. Compared with a non-CLABSI cohort, CLABSI patients were significantly older, with more severe burns, more CVC insertion times, and longer total line-days, as well as higher mortality. Regression analysis found longer line-days, more catheterisation times, and higher burn wounds index to be independent risk factors for CLABSI. A novel nomogram based on three risk factors was constructed with an area under the receiver operating characteristic curve (AUROC) value of 0.84 (95% CI: 0.782-0.898) with a mean absolute error of calibration curve of 0.023. The nomogram showed excellent predictive ability and clinical applicability, and provided a simple, practical, and quantitative strategy to predict CLABSI in burn patients.

Tunable Sulfated Alginate-based Hydrogel Platform with enhanced anti-inflammatory and antioxidant capacity for promoting burn wound repair.

Amidst progressive advancements in tissue engineering, there has been a significant enhancement in the efficacy of anti-inflammatory hydrogel dressings, addressing a myriad of clinical challenges on wound healing. A frequent complication during the initial stages of deep second-degree burn wound healing is the onset of an inflammatory storm, typically occurring without effective intervention. This event disrupts normal biological healing sequences, leading to undesirable regression. In response, we have customized a tunable, multidimensional anti-inflammatory hydrogel platform based on sulfated alginates (Algs), loaded with Prussian blue (PB) nanozymes. This platform competently eliminates surplus reactive oxygen species (ROS) present in the wound bed. Algs, functioning as a mimic of sulfated glycosaminoglycans (including heparin, heparan sulfate, and chondroitin sulfate) in the extracellular matrices (ECM), demonstrate a high affinity towards inflammatory chemokines such as interleukin-8 (IL-8) and monocyte chemotactic protein-1 (MCP-1). This affinity effectively impedes the infiltration of inflammatory cells into the wound. Concurrently, Algs markedly modulate the macrophage phenotype transition from M1 to M2. Ultimately, our potent anti-inflammatory hydrogels, which strategically target inflammatory chemokines, M1 macrophages, and ROS, successfully attenuate dysregulated hyperinflammation in wound sites. Precise immunomodulation administered to deep second-degree burn wounds in mice has demonstrated promotion of neovascular maturation, granulation tissue formation, collagen deposition, and wound closure. Our biomimetic hydrogels, therefore, represent a significant expansion in the repertoire of anti-inflammatory strategies available for clinical practice.

A pH/enzyme dual responsive PMB spatiotemporal release hydrogel promoting chronic wound repair.

Suppressing persistent multidrug-resistant (MDR) bacterial infections and excessive inflammation is the key for treating chronic wounds. Therefore, developing a microenvironment-responsive material with good biodegradability, drug-loading, anti-infection, and anti-inflammatory properties is desired to boost the chronic wounds healing process; however, using ordinary assembly remains a defect. Herein, we propose a pH/enzyme dual-responsive polymyxin B (PMB) spatiotemporal-release hydrogel (GelMA/OSSA/PMB), namely, the amount of OSSA and PMB released from GelMA/OSSA/PMB was closely related the wound pH and the enzyme concentration changing. The GelMA/OSSA/PMB showed better biosafety than equivalent free PMB, owing to the controlled release of PMB, which helped kill planktonic bacteria and inhibit biofilm activity in vitro. In addition, the GelMA/OSSA/PMB exhibited excellent antibacterial and anti-inflammatory properties. A MDR Pseudomonas aeruginosa caused infection was effectively resolved by the GelMA/OSSA/PMB hydrogel in vivo, thereby significantly boosting wound closure during the inflammatory phase. Furthermore, GelMA/OSSA/PMB accelerated the sequential phases of wound repair.

Microtubule associated protein 4 phosphorylation-induced epithelial-to-mesenchymal transition of podocyte leads to proteinuria in diabetic nephropathy.

BACKGROUND: Diabetic nephropathy (DN) involves various structural and functional changes because of chronic glycemic assault and kidney failure. Proteinuria is an early clinical manifestation of DN, but the associated pathogenesis remains elusive. This study aimed to investigate the role of microtubule associated protein 4 (MAP4) phosphorylation (p-MAP4) in proteinuria in DN and its possible mechanisms. METHODS: In this study, the urine samples of diabetic patients and kidney tissues of streptozotocin (STZ)-induced diabetic mice were obtained to detect changes of p-MAP4. A murine model of hyperphosphorylated MAP4 was established to examine the effect of MAP4 phosphorylation in DN. Podocyte was applied to explore changes of kidney phenotypes and potential mechanisms with multiple methods. RESULTS: Our results demonstrated elevated content of p-MAP4 in diabetic patients' urine samples, and increased kidney p-MAP4 in streptozocin (STZ)-induced diabetic mice. Moreover, p-MAP4 triggered proteinuria with aging in mice, and induced epithelial-to-mesenchymal transition (EMT) and apoptosis in podocytes. Additionally, p-MAP4 mice were much more susceptible to STZ treatment and showed robust DN pathology as compared to wild-type mice. In vitro study revealed high glucose (HG) triggered elevation of p-MAP4, rearrangement of microtubules and F-actin filaments with enhanced cell permeability, accompanied with dedifferentiation and apoptosis of podocytes. These effects were significantly reinforced by MAP4 hyperphosphorylation, and were rectified by MAP4 dephosphorylation. Notably, pretreatment of p38/MAPK inhibitor SB203580 reinstated all HG-induced pathological alterations. CONCLUSIONS: The findings indicated a novel role for p-MAP4 in causing proteinuria in DN. Our results indicated the therapeutic potential of MAP4 in protecting against proteinuria and related diseases. Video Abstract.

GDF-5 induces epidermal stem cell migration via RhoA-MMP9 signalling.

The migration of epidermal stem cells (EpSCs) is critical for wound re-epithelization and wound healing. Recently, growth/differentiation factor-5 (GDF-5) was discovered to have multiple biological effects on wound healing; however, its role in EpSCs remains unclear. In this work, recombinant mouse GDF-5 (rmGDF-5) was found via live imaging in vitro to facilitate the migration of mouse EpSCs in a wound-scratch model. Western blot and real-time PCR assays demonstrated that the expression levels of RhoA and matrix metalloproteinase-9 (MMP9) were correlated with rmGDF-5 concentration. Furthermore, we found that rmGDF-5 stimulated mouse EpSC migration in vitro by regulating MMP9 expression at the mRNA and protein levels through the RhoA signalling pathway. Moreover, in a deep partial-thickness scald mouse model in vivo, GDF-5 was confirmed to promote EpSC migration and MMP9 expression via RhoA, as evidenced by the tracking of cells labelled with 5-bromo-2-deoxyuridine (BrdU). The current study showed that rmGDF-5 can promote mouse EpSC migration in vitro and in vivo and that GDF-5 can trigger the migration of EpSCs via RhoA-MMP9 signalling.

Wavelength-Tunable, Long Lifetime, and Biocompatible Luminescent Nanoparticles Based on a Vitamin E-Derived Material for Inflammation and Tumor Imaging.

Luminescence imaging is one of the most effective noninvasive strategies for detection and stratification of inflammation and oxidative stress that are closely related to the pathogenesis of numerous acute and chronic diseases. Herein biocompatible nanoparticles based on a peroxalate ester derived from vitamin E (defined as OVE) are developed. In combination with different fluorophores, OVE can generate luminescence systems with emission wavelengths varying from blue to the near-infrared light in its native and nanoparticle forms, in the presence of hydrogen peroxide (H2 O2 ). The OVE-based nanoprobes exhibit high luminescence signals with extremely long lifetime, upon triggering by inflammatory conditions with abnormally elevated H2 O2 . Activated neutrophils and macrophages can be illuminated by this type of luminescent nanoprobes, with luminescence intensities positively correlated with inflammatory cell counts. In mouse models of peritonitis, alcoholic liver injury, drug-induced acute liver injury, and acute lung injury, the developed luminescence nanoprobes enable precision imaging of inflammation and disease progression. Moreover, tumors expressing a high level of H2 O2 can be shined. Importantly, the OVE-based nanoplatform shows excellent in vitro and in vivo biocompatibility.

A moisture balanced antibacterial dressing loaded with lysozyme possesses antibacterial activity and promotes wound healing.

Wound moisture management is very important in wound healing. Previous wound management has included dry healing and moist healing, and the theory of wound moisture balance is currently generally accepted. However, current studies have not reported which humidity is suitable for wound healing and how to appropriately use antibacterial compounds when the humidity is suitable. Our study explored the moisture balance of polyurethane foam dressings through a moisture balance test and constructed a safe and effective moisture balanced antibacterial dressing by loading lysozyme onto a polyurethane foam dressing. Wound healing experiments showed that the wound healing speed was the fastest when the humidity was 25%. In vivo and in vitro antibacterial experiments showed the superior antibacterial performance of the dressing after lysozyme loading. We loaded lysozyme on moisture balanced polyurethane dressings by means of dopamine adsorption, and the modified dressings were named PU/DA-LYS (polyurethane/dopamine-lysozyme). Experiments on wound healing in infected mice indicated that PU/DA-LYS helps fight infection while promoting wound healing. Cytotoxicity experiments and in vivo biological safety experiments indicated that PU/DA-LYS was safe for use. Our study found that the lysozyme loaded polyurethane dressing can provide appropriate wound moisture and prevent bacterial infection, which is a future developmental direction for wound dressings.

Hypertrophic Scar Improvement by Early Intervention With Ablative Fractional Carbon Dioxide Laser Treatment.

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.

A multifunctional platform with single-NIR-laser-triggered photothermal and NO release for synergistic therapy against multidrug-resistant Gram-negative bacteria and their biofilms.

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.

Correction to: A multifunctional platform with single-NIR-laser-triggered photothermal and NO release for synergistic therapy against multidrug-resistant Gram-negative bacteria and their biofilms.

An amendment to this paper has been published and can be accessed via the original article.

Epidemiology and Outcome Analysis of 470 Patients with Hand Burns: A Five-Year Retrospective Study in a Major Burn Center in Southwest China.

BACKGROUND This retrospective study aimed to investigate the epidemiology of burns to the hand, including the causes, demographic data, management, and outcome in a single center in Southwest China between 2012 and 2017. MATERIAL AND METHODS A retrospective study included 470 patients with hand burns who were treated at a single hospital in Southwest China between 2012 and 2017. Demographic, injury-related, and clinical data were obtained from the clinical electronic data collection system. RESULTS In 470 patients, men were more commonly admitted to hospital with hand burns (73.62%). Children under 10 years (29.57%) were the main patient group. Hospital admissions occurred in the coldest months, from December to March (55.11%). In 60.21% of cases, hand burns occurred outside the workplace. Fire (40.42%), electricity (30.85%), and hot liquids (20.21%) were the main causes of hand burns. Data from 428 patients showed that burns with a larger total body surface area and deeper burns were associated with surgery and amputation. Burn depth was a risk factor for skin grafting, and lack of burn cooling before hospital admission increased the risk of amputation. Data from 117 patients with localized burns showed that full-thickness burns and lack of cooling before admission were associated with an increased hospital stay. CONCLUSIONS The findings suggest that in Southwest China, prevention programs for children aged 0-9 years, injuries occurring in winter and non-workplace sites, and fire burns were imperative.

Vascularity and Thickness Changes in Immature Hypertrophic Scars Treated With a Pulsed Dye Laser.

BACKGROUND AND OBJECTIVES: 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. STUDY DESIGN/MATERIALS AND METHODS: 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. RESULTS: 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). CONCLUSION: 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.

Two-Dimensional Graphene Family Material: Assembly, Biocompatibility and Sensors Applications.

Graphene and its chemically exfoliated derivatives-GO and rGO-are the key members of graphene family materials (GFM). The atomically thick crystal structure and the large continuous π conjugate of graphene imparts it with unique electrical, mechanical, optical, thermal, and chemical properties. Although those properties of GO and rGO are compromised, they have better scalability and chemical tunability. All GFMs can be subject to noncovalent modification due to the large basal plane. Besides, they have satisfying biocompatibility. Thus, GFMs are promising materials for biological, chemical and mechanical sensors. The present review summarizes how to incorporate GFMs into different sensing system including fluorescence aptamer-based sensors, field-effect transistors (FET), and electrochemical sensors, as well as, how to covalently and/or non-covalently modify GFMs to achieve various detection purpose. Sensing mechanisms and fabrication strategies that will influence the sensitivity of different sensing system are also reviewed.

Nitric oxide induces epidermal stem cell de-adhesion by targeting integrin ß1 and Talin via the cGMP signalling pathway.

OBJECTIVE: Nitric oxide (NO) has emerged as a critical molecule in wound healing, but the mechanism underlying its activity is not well defined. Here, we explored the effect of NO on the de-adhesion of epidermal stem cells (ESCs) and the mechanism involved in this process. METHODS: The effects of NO on isolated human and mouse ESCs cultured in the presence of different concentrations of the NO donor S-nitroso-N-acetyl penicillamine (SNAP) were evaluated in cell de-adhesion assays mediated by integrin ß and collagen IV. Subsequently, changes in the expression of integrin ß1 and the phosphorylation of Talin in response to different doses of SNAP were detected by Western blot analysis and real-time PCR in vitro. Furthermore, the roles of various soluble guanylyl cyclase (sGC)- and protein kinase G (PKG)-specific inhibitors and agonists in the effects of NO on ESC de-adhesion, integrin ß1 expression and Talin phosphorylation were analysed. Moreover, the effects of NO on integrin ß1 expression and sGC/cGMP/PKG signalling-mediated wound healing were detected in vivo using 5-bromo-2-deoxyuridine (BrdU) label-retaining cells (LRCs) in a scald model and an excision wound healing model, respectively. RESULTS: SNAP promoted primary human and mouse ESC de-adhesion in a concentration-dependent manner in the integrin ß1-and collagen IV-mediated adhesion assay, and this effect was suppressed by the sGC and PKG inhibitors. Additionally, integrin ß1 expression and Talin phosphorylation at serine 425 (S425) were negatively correlated with SNAP levels, and this effect was blocked by the sGC and PKG inhibitors. Moreover, the roles of NO in integrin ß1 expression and cGMP signalling pathway-mediated wound healing were confirmed in vivo. CONCLUSION: Our data indicate that the stimulatory effects of NO on ESC de-adhesion related to integrin ß1 expression and Talin phosphorylation were mediated by the cGMP signalling pathway, which is likely involved in wound healing.

Nitric oxide promotes epidermal stem cell proliferation via FOXG1-c-Myc signalling.

OBJECTIVE: Epidermal stem cells (ESCs) play a critical role in wound repair, but the mechanism underlying ESC proliferation is unclear. Here, we explored the effects of nitric oxide (NO) on ESC proliferation and the possible underlying mechanism. METHODS: The effect of NO (two NO donors, SNAP and spermine NONOate, were used) on cell proliferation was detected using cell proliferation and DNA synthesis assays. Thereafter, expression of FOXG1 and c-Myc induced by NO was determined by immunoblot analysis. pAdEasy-FOXG1 adenovirus and c-Myc siRNA plasmids were infected or transfected, respectively, into human ESCs to detect the effect of FOXG1 and c-Myc on NO-induced cell proliferation. Additionally, NO-induced ESC proliferation in vivo was detected by BrdU incorporation and a superficial second-degree mouse burn model. Moreover, the relationships among NO, FOXG1 and c-Myc were detected by western blotting, real-time PCR and dual luciferase assay. RESULTS: NO exerted a biphasic effect on ESC proliferation, and 100 µM SNAP and 10 µM spermine NONOate were the optimal concentrations to promote cell proliferation. Additionally, NO-promoted human ESC proliferation was mediated by FOXG1 and c-Myc in vitro and vivo. Furthermore, NO regulated FOXG1 expression through cGMP signalling, and NO-induced transcription of c-Myc was regulated by FOXG1-mediated c-Myc promoter activity. CONCLUSION: This study showed that the biphasic effect of NO on ESC proliferation as well as NO induced ESC proliferation were regulated by the cGMP/FOXG1/c-Myc signalling pathway, suggesting that NO may serve as a new disparate target for wound healing.

An efficient antimicrobial depot for infectious site-targeted chemo-photothermal therapy.

BACKGROUND: Silver and photothermal therapy (PTT) have been widely used for eradicating the drug-resistant bacteria. However, the risks of excess of silver for humans and the low efficiency of PTT still limit their in vivo therapeutic application. Integration of two distinctive bactericides into one entity is a promising platform to improve the efficiency of antimicrobial agents. RESULTS: In this study, a chemo-photothermal therapeutic platform based on polydopamine (PDA)-coated gold nanorods (GNRs) was developed. The PDA coating acquired high Ag+ ions loading efficiency and Cy5-SE fluorescent agent labeled glycol chitosan (GCS) conjugation (Ag+-GCS-PDA@GNRs). This platform became positively charged in the low pH environment of the abscess, allowing their accumulation in local infection site as revealed by thermal/florescence imaging. The loaded Ag+ ions was released in a pH-sensitive manner, resulting in selective Ag+ ions delivery to the abscess environment (pH ~ 6.3). More importantly, the ultralow dose of Ag+ ions could effectively damage the bacterial membrane, causing the permeability increase and the heat resistance reduction of the cell membrane, leading to the large improvement on bactericidal efficiency of PTT. On the other hand, the hyperthermia could trigger more Ag+ ions release, resulting in further improvement on bactericidal efficiency of chemotherapy. Combinational chemo-hyperthermia therapy of Ag+-GCS-PDA@GNRs could thoroughly ablate abscess and accelerate wound healing via a synergistic antibacterial effect. CONCLUSIONS: Our studies demonstrate that Ag+-GCS-PDA@GNRs is a robust and practical platform for use in chemo-thermal focal infection therapy with outstanding synergistic bacteria ablating.

Nano-silver-incorporated biomimetic polydopamine coating on a thermoplastic polyurethane porous nanocomposite as an efficient antibacterial wound dressing.

BACKGROUND: Developing an ideal wound dressing that meets the multiple demands of good biocompatibility, an appropriate porous structure, superior mechanical property and excellent antibacterial activity against drug-resistant bacteria is highly desirable for clinical wound care. Biocompatible thermoplastic polyurethane (TPU) membranes are promising candidates as a scaffold; however, their lack of a suitable porous structure and antibacterial activity has limited their application. Antibiotics are generally used for preventing bacterial infections, but the global emergence of drug-resistant bacteria continues to cause social concerns. RESULTS: Consequently, we prepared a flexible dressing based on a TPU membrane with a specific porous structure and then modified it with a biomimetic polydopamine coating to prepare in situ a nano-silver (NS)-based composite via a facile and eco-friendly approach. SEM images showed that the TPU/NS membranes were characterized by an ideal porous structure (pore size: ~ 85 µm, porosity: ~ 65%) that was decorated with nano-silver particles. ATR-FITR and XRD spectroscopy further confirmed the stepwise deposition of polydopamine and nano-silver. Water contact angle measurement indicated improved surface hydrophilicity after coating with polydopamine. Tensile testing demonstrated that the TPU/NS membranes had an acceptable mechanical strength and excellent flexibility. Subsequently, bacterial suspension assay, plate counting methods and Live/Dead staining assays demonstrated that the optimized TPU/NS2.5 membranes possessed excellent antibacterial activity against P. aeruginosa, E. coli, S. aureus and MRSA bacteria, while CCK8 testing, SEM observations and cell apoptosis assays demonstrated that they had no measurable cytotoxicity toward mammalian cells. Moreover, a steady and safe silver-releasing profile recorded by ICP-MS confirmed these results. Finally, by using a bacteria-infected (MRSA or P. aeruginosa) murine wound model, we found that TPU/NS2.5 membranes could prevent in vivo bacterial infections and promote wound healing via accelerating the re-epithelialization process, and these membranes had no obvious toxicity toward normal tissues. CONCLUSION: Based on these results, the TPU/NS2.5 nanocomposite has great potential for the management of wounds, particularly for wounds caused by drug-resistant bacteria.

Eukaryotic initiation factor 6 modulates myofibroblast differentiation at transforming growth factor-ß1 transcription level via H2A.Z occupancy and Sp1 recruitment.

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-ß1 (TGF-ß1) 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-ß1 promoter by H2A.Z (Swiss-Prot P0C0S6) and Sp1. Accordingly, modulation of eIF6 expression in myofibroblasts significantly affects their differentiation via the TGF-ß/Smad signaling pathway, which was verified in vivo by the observation that heterozygote eIF6(+/-) mice exhibited enhanced TGF-ß1 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-ß1 promoter via H2A.Z depletion and thus results in increased TGF-ß1 transcription, which contributes to myofibroblast differentiation.