Diabetic wounds significantly affect the life quality of patients and may cause amputation and mortality if poorly managed. Recently, a wide range of cell-based methods has emerged as novel ...therapeutic methods in treating diabetic wounds. Adipose-derived stem cells (ASCs) are considered to have the potential for widespread clinical application of diabetic wounds treatment in the future. This review summarized the mechanisms of ASCs to promote diabetic wound healing, including the promotion of immunomodulation, neovascularization, and fibro synthesis. We also review the current progress and limitations of clinical studies using ASCs to intervene in diabetic wound healing. New methods of ASC delivery have been raised in recent years to provide a standardized and convenient use of ASCs.
Background. Under septic conditions, LPS induced lung vascular endothelial cell (EC) injury, and the release of inflammatory mediator launches and aggravates acute lung injury (ALI). There are no ...effective therapeutic options for ALI. Genistein-3′-sodium sulfonate (GSS) is a derivative of native soy isoflavone, which exhibits neuroprotective effects via its antiapoptosis property. However, whether GSS protect against sepsis-induced EC injury and release of inflammatory mediators has not been determined. In this study, we found that GSS not only downregulated the levels of TNF-α and IL-6 in the lung and serum of mice in vivo but also inhibited the expression and secretion of TNF-α and IL-6 in ECs. Importantly, we also found that GSS blocked LPS-induced TNF-α and IL-6 expression in ECs via the Myd88/NF-κB signaling pathway. Taken together, our results demonstrated that GSS might be a promising candidate for sepsis-induced ALI via its regulating effects on inflammatory response in lung ECs.
Thrombocytopenia is a common event in severely burned patients and associated with adverse outcome. The underlying relationship between the dynamic changes of platelet counts and mortality has not ...been well defined. We performed a 6-year retrospective chart of adult patients with a burn index of 50 or greater admitted to two burn centers and collected data on patient demographics, laboratory results, and patient outcomes. The mean daily increase in the platelet count (∆PC/∆t) from day 3 to day 10 was calculated, and 30-day mortality was determined. For the study, 141 survivors and 65 nonsurvivors were enrolled. The sequential changes in PCs presented a biphasic pattern after admission, with a slump to the nadir during the first 3 days and a subsequent recovery. With respect to 30-day mortality, compared with the AUC of APACHE-Ⅱ score (0.841), no significant difference was noted between ΔPC/ΔT and APACHE-Ⅱ score (p = 0.0648). The ΔPC/ΔT associated with the best discrimination between survivors and nonsurvivors was 20.57 × 10
9
/L due to the cutoff with optimal Youden index (0.453). By multiple logistic regression, ΔPC/ΔT ＜ 20.57 × 10
9
/L was one of the prognostic predictors of 30-day mortality. Furthermore, Kaplan-Meier estimates of hospital survival according to the size of ΔPC/ΔT revealed that a blunted increase with ΔPC/ΔT ＜ 20.57 × 10
9
/L was associated with increased 30-day mortality. A blunted daily increase in PCs, especially ΔPC/ΔT < 20.57 × 10
9
/L, is associated with increased 30-day mortality, which provides prognostic information for mortality risk assessment in severely burned patients.
Objective
We aimed to construct a novel prognostic model based on N6-methyladenosine (m6A)-related autophagy genes for predicting the prognosis of lung squamous cell carcinoma (LUSC).
Methods
Gene ...expression profiles and clinical information of Patients with LUSC were downloaded from The Cancer Genome Atlas (TCGA) database. In addition, m6A- and autophagy-related gene profiles were obtained from TCGA and Human Autophagy Database, respectively. Pearson correlation analysis was performed to identify the m6A-related autophagy genes, and univariate Cox regression analysis was conducted to screen for genes associated with prognosis. Based on these genes, LASSO Cox regression analysis was used to construct a prognostic model. The corresponding prognostic score (PS) was calculated, and patients with LUSC were assigned to low- and high-risk groups according to the median PS value. An independent dataset (GSE37745) was used to validate the prognostic ability of the model. CIBERSORT was used to calculate the differences in immune cell infiltration between the high- and low-risk groups.
Results
Seven m6A-related autophagy genes were screened to construct a prognostic model: CASP4 , CDKN1A , DLC1 , ITGB1 , PINK1 , TP63 , and EIF4EBP1 . In the training and validation sets, patients in the high-risk group had worse survival times than those in the low-risk group; the areas under the receiver operating characteristic curves were 0.958 and 0.759, respectively. There were differences in m6A levels and immune cell infiltration between the high- and low-risk groups.
Conclusions
Our prognostic model of the seven m6A-related autophagy genes had significant predictive value for LUSC; thus, these genes may serve as autophagy-related therapeutic targets in clinical practice.
Gram-negative bacterial lipopolysaccharide (LPS) induces a pathologic increase in lung vascular leakage under septic conditions. LPS-induced human pulmonary micro-vascular endothelial cell (HPMEC) ...apoptosis launches and aggravates micro-vascular hyper-permeability and acute lung injury (ALI). Previous studies show that the activation of intrinsic apoptotic pathway is vital for LPS-induced EC apoptosis. Yes-associated protein (YAP) has been reported to positively regulate intrinsic apoptotic pathway in tumor cells apoptosis. However, the potential role of YAP protein in LPS-induced HPMEC apoptosis has not been determined. In this study, we found that LPS-induced activation and nuclear accumulation of YAP accelerated HPMECs apoptosis. LPS-induced YAP translocation from cytoplasm to nucleus by the increased phosphorylation on Y357 resulted in the interaction between YAP and transcription factor P73. Furthermore, inhibition of YAP by small interfering RNA (siRNA) not only suppressed the LPS-induced HPMEC apoptosis but also regulated P73-mediated up-regulation of BAX and down-regulation of BCL-2. Taken together, our results demonstrated that activation of the YAP/P73/(BAX and BCL-2)/caspase-3 signaling pathway played a critical role in LPS-induced HPMEC apoptosis. Inhibition of the YAP might be a potential therapeutic strategy for lung injury under sepsis.
Common commercial porcine acellular dermal matrix (PADM) products take the form of a thin membrane. Given its dense structure, delaying vascularization after implantation remains an issue to be ...solved. In addition, overlaying multiple sheets to address deep wounds and large tissue defects that are difficult to repair by self-tissues could hinder tissue ingrowth, angiogenesis, and integration. Here, we creatively prepared PADM microparticles through a homogenizing treatment and crosslinked them to ADM sponges by thermal crosslinking (VT-ADM) and thermal-glutaraldehyde crosslinking (GA-ADM). The resulting VT-ADM was thicker than GA-ADM, and both maintained the natural dermal matrix microstructure and thermal stability. The porosity of GA-ADM (mean 82%) was lower than that of VT-ADM (mean 90.2%), but the mechanical strength and hydrophilicity were significantly higher. The two types of ADM sponges showed no obvious difference in cell adhesion and proliferation without cytotoxicity. Furthermore, the human adipose stem cells were co-cultured with ADM sponges which promoted proliferation, tube formation, and migration of endothelial cells, and the GA-ADM group exhibited better migration behavior. There were no markable differences among expressions of pro-angiogenesis genes, including vascular endothelial growth factor, insulin-like growth factor-1, and epidermal growth factor. In a nude mouse model, the VT-ADM and GA-ADM pre-cultured with human adipose stem cells for 1 week in advance were implanted subcutaneously. The VT-ADM and the GA-ADM showed great histocompatibility without local redness, swelling, or necrosis. The vascular density of the local skin flap above the material was visualized using indocyanine green and showed no statistical difference between the two groups. The collagen tissue deposition in the pores and vessel formation within the sponges increased with time. Although VT-ADM had a higher degradation rate
in vivo
, the integrity of the two scaffolds was preserved. Collectively, the VT-ADM and the GA-ADM retained a natural matrix structure and presented biocompatibility. Thus, the above-mentioned two crosslinking methods for ADM sponges are safe and practicable. The novel ADM sponges with good physicochemical and biological properties are no longer limited to membrane tissue regeneration but could also realize structure remodeling where they act as scaffolds for a soft tissue filler and three-dimensional reconstruction of the tissue with strength requirements.
The bacterial endotoxin or lipopolysaccharide (LPS) leads to the extensive vascular endothelial cells (EC) injury under septic conditions. Guanine nucleotide exchange factor-H1 (GEF-H1)/ROCK ...signaling not only involved in LPS-induced overexpression of pro-inflammatory mediator in ECs but also implicated in LPS-induced endothelial hyper-permeability. However, the mechanisms behind LPS-induced GEF-H1/ROCK signaling activation in the progress of EC injury remain incompletely understood. GEF-H1 localized on microtubules (MT) and is suppressed in its MT-bound state. MT disassembly promotes GEF-H1 release from MT and stimulates downstream ROCK-specific GEF activity. Since glycogen synthase kinase (GSK-3beta) participates in regulating MT dynamics under pathologic conditions, we examined the pivotal roles for GSK-3beta in modulating LPS-induced activation of GEF-H1/ROCK, increase of vascular endothelial permeability and severity of acute lung injury (ALI). In this study, we found that LPS induced human pulmonary endothelial cell (HPMEC) monolayers disruption accompanied by increase in GSK-3beta activity, activation of GEF-H1/ROCK signaling and decrease in beta-catenin and ZO-1 expression. Inhibition of GSK-3beta reduced HPMEC monolayers hyper-permeability and GEF-H1/ROCK activity in response to LPS. GSK-3beta/GEF-H1/ROCK signaling is implicated in regulating the expression of beta-catenin and ZO-1.
, GSK-3beta inhibition attenuated LPS-induced activation of GEF-H1/ROCK pathway, lung edema and subsequent ALI. These findings present a new mechanism of GSK-3beta-dependent exacerbation of lung micro-vascular hyper-permeability and escalation of ALI via activation of GEF-H1/ROCK signaling and disruption of intracellular junctional proteins under septic condition.
Quick and effective sterilization of drug-resistant bacteria inevitably became an ever-growing global challenge. In this study, a multifunctional composite (PDA/Cu-CS) hydrogel mainly composed of ...polydopamine (PDA) and copper-doped calcium silicate ceramic (Cu-CS) was prepared. It was confirmed that PDA/copper (PDA/Cu) complexing in the composite hydrogel played a key role in enhancing the photothermal performance and antibacterial activity. Through a unique “hot ions effect”, created by the heating of Cu ions through the photothermal effect of the composite hydrogel, the hydrogel showed high-efficiency, quick, and long-term inhibition of methicillin-resistant Staphylococcus aureus and Escherichia coli. In addition, the hydrogel possessed remarkable bioactivity to stimulate angiogenesis. The in vivo results confirmed that the “hot ions effect” of the composite hydrogel removed existing infection in the wound area efficiently and significantly promoted angiogenesis and collagen deposition during infectious skin wound healing. Our results suggested that the design of multifunctional hydrogels with “hot ions effect” may be an effective therapeutic approach for the treatment of infectious wounds.
Due to the complexity of the skin tissue structure, the regeneration of the entire skin, including skin appendages such as hair follicles, is a big challenge. In addition, skin trauma is often ...accompanied by bacterial infections that delay the wound healing. Therefore, developing wound dressings, which promote hair follicle regeneration and inhibit bacterial infection in the wound healing process, is of great clinical significance. In this study, Zn doped hollow mesoporous silica nanospheres (HMZS) were synthesized by a sol-gel method and a novel wound healing dressing was prepared by incorporation of drug ciprofloxacin hydrochloride (CiH)-loaded Zn containing mesoporous silica nanospheres (CiH-HMZS) into polycaprolactone (PCL) electrospun fibers. The CiH-HMZS/P nano-composite electrospun fibers exhibit the ability to promote angiogenesis and skin regeneration by releasing Si ions, and the activity to enhance hair follicle regeneration and inhibit bacterial growth by releasing zinc ions and achieve the synergistic antibacterial effect with both Zn ions and CiH in low concentrations. Thus, the CiH-HMZS/P nano-composite membrane is a promising multi-functional wound healing material for inhibiting bacterial growth in infected wounds and enhancing skin wound healing including hair follicle regeneration.
Acute lung injury (ALI) is characterized by protein-rich pulmonary edema, critical hypoxemia, and influx of pro-inflammatory cytokines and cells. There are currently no effective pharmacon therapies ...in clinical practice. Syndecan-1 in endothelial cells has potential to protect barrier function of endothelium and suppress inflammation response. Thus, the present study was to identify whether exosomes with encapsulation of syndecan-1 could achieve ideal therapeutic effects in ALI. Exosomes were isolated from the conditional medium of lentivirus-transfected mouse pulmonary microvascular endothelial cells (MPMVECs) and characterized by nanoparticle tracking analysis (NTA), transmission electron microscopy (TEM), and western blotting. ALI mouse models were induced via intratracheal administration of lipopolysaccharide (LPS) and treated with exosomes. Lung edema, inflammation, and glycocalyx thickness were examined. The possible mechanism was verified by immunoblotting in MPMVECs. The purified exosomes included SDC1-high-Exos and SDC1-low-Exos which loaded with up-regulated syndecan-1 and down-regulated syndecan-1 respectively. Compared with SDC1-low-Exos, administration of SDC1-high-Exos could ameliorate lung edema and inflammation, attenuate number of cells and protein levels in bronchoalveolar lavage fluid (BALF), and preserve glycocalyx. Furthermore, SDC1-high-Exos also mitigated the expression of pro-inflammatory cytokines such as IL-1β, TNF-α, and IL-6 following LPS challenge. In MPMVECs, SDC1-high-Exos decreased stress fiber formation and ameliorated monolayer hyper-permeability after LPS stimulation. Western blotting analysis demonstrated that FAK/p190RhoGAP/RhoA/ROCK/NF-κB signaling pathway may be involved in LPS-induced ALI. In conclusion, SDC1-high-Exos play a pivotal role in ameliorating LPS-stimulated ALI models and may be served as a potential therapeutic agent for clinical application in the future.
•Syndecan-1, a novel therapeutic agent for acute lung injury, is proposed.•Exosomes (SDC1-high-Exos) serve as a new carrier for delivering syndecan-1.•SDC1-high-Exos ameliorate lung inflammation, edema and preserve glycocalyx.•The mechanism relies on FAK/p190RhoGAP/RhoA/ROCK/NF-κB pathway.
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