CD248 interacts with ECM to promote hypertrophic scar formation and development.

Hypertrophic scar (HS) presents a significant clinical challenge, frequently arising as a fibrotic sequela of burn injuries and trauma. Characterized by the aberrant activation and proliferation of myofibroblasts, HS lacks a targeted therapeutic approach to effectively reduce this dysregulation. This study offers novel evidence of upregulated expression of CD248 in HS tissues compared to normal skin (NS) tissues. Specifically, the expression of CD248 was predominantly localized to α-SMA+-myofibroblasts in the dermis. To explain the functional role of CD248 in dermal myofibroblast activity, we employed a targeted anti-CD248 antibody, IgG78. Both CD248 intervention and IgG78 treatment effectively suppressed the proliferative, migratory, and ECM-synthesizing activities of myofibroblasts isolated from HS dermis. In addition, IgG78 administration significantly attenuated HS formation in an in vivo rabbit ear model. The LC/MS analysis coupled with co-immunoprecipitation of HS tissues indicated a direct interaction between CD248 and the ECM components Fibronectin (FN) and Collagen I (COL I). These findings collectively suggest that CD248 may function as a pro-fibrotic factor in HS development through its interaction with ECM constituents. The utilization of an anti-CD248 antibody, such as IgG78, represents a promising novel therapeutic strategy for the treatment of HS.

Dietary intake changes the associations between long-term exposure to fine particulate matter and the surrogate indicators of insulin resistance.

The relationship of fine particulate matter (PM2.5) exposure and insulin resistance remains inclusive. Our study aimed to investigate this association in the project of Prediction for Atherosclerotic Cardiovascular Disease Risk in China (China-PAR). Specifically, we examined the associations between long-term PM2.5 exposure and three surrogate indicators of insulin resistance: the triglyceride-glucose index (TyG), TyG with waist circumference (TyG-WC) and metabolic score for insulin resistance (METS-IR). Additionally, we explored potential effect modification of dietary intake and components. Generalized estimating equations were used to evaluate the associations between PM2.5 and the indicators with an unbalanced repeated measurement design. Our analysis incorporated a total of 162,060 observations from 99,329 participants. Each 10 µg/m3 increment of PM2.5 was associated with an increase of 0.22 % [95 % confidence interval (CI): 0.20 %, 0.25 %], 1.60 % (95 % CI: 1.53 %, 1.67 %), and 2.05 % (95 % CI: 1.96 %, 2.14 %) in TyG, TyG-WC, and METS-IR, respectively. These associations were attenuated among participants with a healthy diet, particularly those with sufficient intake of fruit and vegetable, fish or tea (pinteraction < 0.0028). For instance, among participants with a healthy diet, TyG increased by 0.11 % (95 % CI: 0.08 %, 0.15 %) per 10 µg/m3 PM2.5 increment, significantly lower than the association observed in those with an unhealthy diet. The findings of this study emphasize the potential of a healthy diet to mitigate these associations, highlighting the urgency for improving air quality and implementing dietary interventions among susceptible populations in China.

Pretreatment with platelet-rich plasma protects against ischemia-reperfusion induced flap injury by deactivating the JAK/STAT pathway in mice.

BACKGROUND: Ischemia-reperfusion (I/R) injury is a major cause of surgical skin flap compromise and organ dysfunction. Platelet-rich plasma (PRP) is an autologous product rich in growth factors, with tissue regenerative potential. PRP has shown promise in multiple I/R-induced tissue injuries, but its effects on skin flap injury remain unexplored. METHODS: We evaluated the effects of PRP on I/R-injured skin flaps, optimal timing of PRP administration, and the involved mechanisms. RESULTS: PRP protected against I/R-induced skin flap injury by improving flap survival, promoting blood perfusion and angiogenesis, suppressing oxidative stress and inflammatory response, and reducing apoptosis, at least partly via deactivating Janus kinase (JAK)-signal transducers and activators of transcription (STAT) signalling pathway. PRP given before ischemia displayed overall advantages over that given before reperfusion or during reperfusion. In addition, PRP pretreatment had a stronger ability to reverse I/R-induced JAK/STAT activation and apoptosis than AG490, a specific inhibitor of JAK/STAT signalling. CONCLUSIONS: This study firstly demonstrates the protective role of PRP against I/R-injured skin flaps through negative regulation of JAK/STAT activation, with PRP pretreatment showing optimal therapeutic effects.

Expert consensus on the diagnosis, treatment, and prevention of respiratory syncytial virus infections in children.

BACKGROUND: Respiratory syncytial virus (RSV) is the leading global cause of respiratory infections and is responsible for about 3 million hospitalizations and more than 100,000 deaths annually in children younger than 5 years, representing a major global healthcare burden. There is a great unmet need for new agents and universal strategies to prevent RSV infections in early life. A multidisciplinary consensus development group comprising experts in epidemiology, infectious diseases, respiratory medicine, and methodology aims to develop the current consensus to address clinical issues of RSV infections in children. DATA SOURCES: The evidence searches and reviews were conducted using electronic databases, including PubMed, Embase, Web of Science, and the Cochrane Library, using variations in terms for "respiratory syncytial virus", "RSV", "lower respiratory tract infection", "bronchiolitis", "acute", "viral pneumonia", "neonatal", "infant" "children", and "pediatric". RESULTS: Evidence-based recommendations regarding diagnosis, treatment, and prevention were proposed with a high degree of consensus. Although supportive care remains the cornerstone for the management of RSV infections, new monoclonal antibodies, vaccines, drug therapies, and viral surveillance techniques are being rolled out. CONCLUSIONS: This consensus, based on international and national scientific evidence, reinforces the current recommendations and integrates the recent advances for optimal care and prevention of RSV infections. Further improvements in the management of RSV infections will require generating the highest quality of evidence through rigorously designed studies that possess little bias and sufficient capacity to identify clinically meaningful end points.

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

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

Fruit and vegetable intake and the risk of arterial hypertension in China: A prospective cohort study.

Background: Population-based epidemiological evidence regarding the association between fruit and vegetable intake and the incidence of hypertension is inconsistent. This prospective cohort study aimed to investigate the association between fruit and vegetable intake and the risk of new-onset hypertension. Methods: Based on the project of Prediction for Atherosclerotic Cardiovascular Disease Risk in China (China-PAR), 58,981 Chinese adults without hypertension at baseline were included. Information on fruit and vegetable intake was collected using a food-frequency questionnaire. Cox proportional hazards models were performed to estimate the hazard ratios (HRs) and 95% confidence intervals (CIs) of incident hypertension. Results: During 640,795 person-years of follow-up, 21,008 new cases of hypertension were recorded. Compared with participants in the lowest quintile (Q1) of total fruit and vegetable (TFV) intake, the HRs (95% CIs) of incident hypertension were 0.90 (0.86-0.95), 0.85 (0.81-0.90), 0.82 (0.78-0.86), and 0.83 (0.78-0.88) for the Q2 to Q5 group (p trend < 0.001), respectively. In further analyses categorizing participants according to the recommended intake level (500 g/day), we found that increasing the intake of TFV, even though it was still insufficient for the recommendation, also had a protective effect against the incident hypertension. When considering the intake of fruit or vegetable separately, we found similar trends as the TFV intake. Conclusion: These results suggest that a higher intake of fruit and vegetable is beneficial for preventing hypertension in Chinese adults.

Effect of Air Pollution on Heart Failure: Systematic Review and Meta-Analysis.

BACKGROUND: Heart failure (HF) poses a significant global disease burden. The current evidence on the impact of air pollution on HF remains inconsistent. OBJECTIVES: We aimed to conduct a systematic review of the literature and meta-analysis to provide a more comprehensive and multiperspective assessment of the associations between short- and long-term air pollution exposure and HF from epidemiological evidences. METHODS: Three databases were searched up to 31 August 2022 for studies investigating the association between air pollutants (PM2.5, PM10, NO2, SO2, CO, O3) and HF hospitalization, incidence, or mortality. A random effects model was used to derive the risk estimations. Subgroup analysis was conducted by geographical location, age of participants, outcome, study design, covered area, the methods of exposure assessment, and the length of exposure window. Sensitivity analysis and adjustment for publication bias were performed to test the robustness of the results. RESULTS: Of 100 studies covering 20 countries worldwide, 81 were for short-term and 19 were for long-term exposure. Almost all air pollutants were adversely associated with the risk of HF in both short- and long-term exposure studies. For short-term exposures, we found the risk of HF increased by 1.8% [relative risk (RR)=1.018, 95% confidence interval (CI): 1.011, 1.025] and 1.6% (RR=1.016, 95% CI: 1.011, 1.020) per 10-µg/m3 increment of PM2.5 and PM10, respectively. HF was also significantly associated with NO2, SO2, and CO, but not O3. Positive associations were stronger when exposure was considered over the previous 2 d (lag 0-1) rather than on the day of exposure only (lag 0). For long-term exposures, there were significant associations between several air pollutants and HF with RR (95% CI) of 1.748 (1.112, 2.747) per 10-µg/m3 increment in PM2.5, 1.212 (1.010, 1.454) per 10-µg/m3 increment in PM10, and 1.204 (1.069, 1.356) per 10-ppb increment in NO2, respectively. The adverse associations of most pollutants with HF were greater in low- and middle-income countries than in high-income countries. Sensitivity analysis demonstrated the robustness of our results. DISCUSSION: Available evidence highlighted adverse associations between air pollution and HF regardless of short- and long-term exposure. Air pollution is still a prevalent public health issue globally and sustained policies and actions are called for to reduce the burden of HF. https://doi.org/10.1289/EHP11506.

Activation of Sestrin2 accelerates deep second-degree burn wound healing through PI3K/AKT pathway.

Deep second-degree burns heal slowly, and promoting the healing process is a focus of clinical research. Sestrin2 is a stress-inducible protein with antioxidant and metabolic regulatory effects. However, its role during acute dermal and epidermal re-epithelialization in deep second-degree burns is unknown. In this study, we aimed to explore the role and molecular mechanism of sestrin2 in deep second-degree burns as a potential treatment target for burn wounds. To explore the effects of sestrin2 on burn wound healing, we established a deep second-degree burn mouse model. Then we detected the expression of sestrin2 by western blot and immunohistochemistry after obtaining the wound margin of full-thickness burned skin. The effects of sestrin2 on burn wound healing were explored in vivo and in vitro through interfering sestrin2 expression using siRNAs or the small molecule agonist of sestrin2, eupatilin. We also investigated the molecular mechanism of sestrin2 in promoting burn wound healing by western blot and CCK-8 assay. Our in vivo and in vitro deep second-degree burn wound healing model demonstrated that sestrin2 was promptly induced at murine skin wound edges. The small molecule agonist of sestrin2 accelerated the proliferation and migration of keratinocytes, as well as burn wound healing. Conversely, the healing of burn wounds was delayed in sestrin2-deficient mice and was accompanied by the secretion of inflammatory cytokines as well as the suppression of keratinocyte proliferation and migration. Mechanistically, sestrin2 promoted the phosphorylation of the PI3K/AKT pathway, and inhibition of PI3K/AKT pathway abrogated the promoting role of sestrin2 in keratinocyte proliferation and migration. Therefore, sestrin2 plays a critical role in activation of the PI3K/AKT pathway to promote keratinocyte proliferation and migration, as well as re-epithelialization in the process of deep second-degree burn wound repair.

The deacetylation of Akt by SIRT1 inhibits inflammation in macrophages and protects against sepsis.

Sepsis is characterized by uncontrolled inflammatory response and altered polarization of macrophages at the early phase. Akt is known to drive macrophage inflammatory response. However, how macrophage inflammatory response is fine-tuned by Akt is poorly understood. Here, we found that Lys14 and Lys20 of Akt is deacetylated by the histone deacetylase SIRT1 during macrophage activation to suppress macrophages inflammatory response. Mechanistically, SIRT1 promotes Akt deacetylation to inhibit the activation of NF-κB and pro-inflammatory cytokines. Loss of SIRT1 facilitates Akt acetylation and thus promotes inflammatory cytokines in mouse macrophages, potentially worsen the progression of sepsis in mice. By contrast, the upregulation of SIRT1 in macrophages further contributes to the inhibition of pro-inflammatory cytokines via Akt activation in sepsis. Taken together, our findings establish Akt deacetylation as an essential negative regulatory mechanism that curtails M1 polarization.

Infiltration and Water Use Efficiency of Maize Fields with Drip Irrigation and Biodegradable Mulches in the West Liaohe Plain, China.

Biodegradable mulches have the same temperature- and moisture-preservation effects as ordinary plastic mulches before degradation. After degradation, rainwater enters the soil through the damaged parts, improving precipitation utilization. Under drip irrigation with mulching, this study explores precipitation utilization of biodegradable mulches under different precipitation intensities and the effects of different biodegradable mulches on the yield and water use efficiency (WUE) of spring maize in the West Liaohe Plain, China. In this paper, in situ field observation experiments were conducted for three consecutive years from 2016 to 2018. Three types of white degradable mulch films were set up, with induction periods of 60 d (WM60), 80 d (WM80), and 100 d (WM100). Three types of black degradable mulch films were also used, with induction periods of 60 d (BM60), 80 d (BM80), and 100 d (BM100). Precipitation utilization, yield, and WUE under biodegradable mulches were studied, with ordinary plastic mulches (PM) and bare land (CK) set as controls. The results showed that as precipitation increased, the effective infiltration of precipitation decreased first and then increased. When precipitation reached 89.21 mm, plastic film mulching no longer affected precipitation utilization. Under the same precipitation intensity, the precipitation effective infiltration ratio increased as the damage to the biodegradable film increased. Still, the intensity of this increase gradually decreased as the damage increased. The highest yield and WUE were observed for the degradable mulch film with an induction period of 60 days in years with normal rainfall and for the degradable mulch film with an induction period of 100 days in dry years. In the West Liaohe Plain, maize planted under film receives drip irrigation. We recommend that growers select a degradable mulch film with a degradation rate of 36.64% and an induction period of approximately 60 days in years with normal rainfall, and a degradable mulch film with an induction period of 100 days in dry years.

Exosome/metformin-loaded self-healing conductive hydrogel rescues microvascular dysfunction and promotes chronic diabetic wound healing by inhibiting mitochondrial fission.

Chronic diabetic wounds remain a globally recognized clinical challenge. They occur due to high concentrations of reactive oxygen species and vascular function disorders. A promising strategy for diabetic wound healing is the delivery of exosomes, comprising bioactive dressings. Metformin activates the vascular endothelial growth factor pathway, thereby improving angiogenesis in hyperglycemic states. However, multifunctional hydrogels loaded with drugs and bioactive substances synergistically promote wound repair has been rarely reported, and the mechanism of their combinatorial effect of exosome and metformin in wound healing remains unclear. Here, we engineered dual-loaded hydrogels possessing tissue adhesive, antioxidant, self-healing and electrical conductivity properties, wherein 4-armed SH-PEG cross-links with Ag+, which minimizes damage to the loaded goods and investigated their mechanism of promotion effect for wound repair. Multiwalled carbon nanotubes exhibiting good conductivity were also incorporated into the hydrogels to generate hydrogen bonds with the thiol group, creating a stable three-dimensional structure for exosome and metformin loading. The diabetic wound model of the present study suggests that the PEG/Ag/CNT-M + E hydrogel promotes wound healing by triggering cell proliferation and angiogenesis and relieving peritraumatic inflammation and vascular injury. The mechanism of the dual-loaded hydrogel involves reducing the level of reactive oxygen species by interfering with mitochondrial fission, thereby protecting F-actin homeostasis and alleviating microvascular dysfunction. Hence, we propose a drug-bioactive substance combination therapy and provide a potential mechanism for developing vascular function-associated strategies for treating chronic diabetic wounds.

miR-125b-5p in adipose derived stem cells exosome alleviates pulmonary microvascular endothelial cells ferroptosis via Keap1/Nrf2/GPX4 in sepsis lung injury.

BACKGROUND: Sepsis is a fatal disease with a high rate of morbidity and mortality, during which acute lung injury is the earliest and most serious complication. Injury of pulmonary microvascular endothelial cells (PMVECs) induced by excessive inflammation plays an important role in sepsis acute lung injury. This study is meant to explore the protective effect and mechanism of ADSCs exosomes on excessive inflammation PMVECs injury. RESULTS: We successfully isolated ADSCs exosomes, the characteristic of which were confirmed. ADSCs exosomes reduced excessive inflammatory response induced ROS accumulation and cell injury in PMVECs. Besides, ADSCs exosomes inhibited excessive inflammatory response induced ferroptosis while upregulated expression of GPX4 in PMVECs. And further GPX4 inhibition experiments revealed that ADSCs exosomes alleviated inflammatory response induced ferroptosis via upregulating GPX4. Meanwhile, ADSCs exosomes could increase the expression and nucleus translocation of Nrf2, while decrease the expression of Keap1. miRNA analysis and further inhibition experiments verified that specific delivery of miR-125b-5p by ADSCs exosomes inhibited Keap1 and alleviated ferroptosis. In CLP induced sepsis model, ADSCs exosomes could relieve the lung tissue injury and reduced the death rate. Besides, ADSCs exosomes alleviated oxidative stress injury and ferroptosis of lung tissue, while remarkably increase expression of Nrf2 and GPX4. CONCLUSION: Collectively, we illustrated a novel potentially therapeutic mechanism that miR-125b-5p in ADSCs exosomes could alleviate the inflammation induced PMVECs ferroptosis in sepsis induced acute lung injury via regulating Keap1/Nrf2/GPX4 expression, hence improve the acute lung injury in sepsis.

Spatial distribution and quantitative source identification of nutrients and beneficial elements in the soil of a typical suburban area, Beijing.

Source identification and quality monitoring of soil nutrients and beneficial elements (NBEs) are crucial for agricultural production and environmental protection. In this study, grid sampling (223 topsoil samples and 223 subsoil samples) was carried out in the Tongzhou District of Beijing. The concentration level of representative NBEs (N, P, K, Ca, Mg, Se, V, Ge, Mn, Zn) and some typical soil properties representing indicators (total organic carbon, TFe2O3, Al2O3/SiO2, and pH) in soils and their spatial distribution were analyzed. The major sources contributing to these NBEs were assessed by principal component analysis (PCA), redundancy analysis (RDA), and positive matrix factorization (PMF) analysis. The results suggested that the soil parent material contributed 40.09-69.84% to Zn, V, Ge, Mn, F, and K in soils; the local external source contributed 54.89-75.04% to N, Se, and TOC; and the hydrous system contributed 40.67-77.31% to Ca and Mg. The enrichment degree of each NBE was calculated using the standardized concentration ratio method. These indices exhibited the influence and mixing process of different sources on the target NBEs in topsoils. The individual concentrations of the target NBEs and the combined concentrations of N, P, and K were used to evaluate the soil quality. Our study estimated the relative contributions from dominant sources to NBEs in soils from a typical suburban area, providing a basis for agricultural activities and environmental protection.

Deacetylation of IRF8 inhibits iNOS expression and inflammation via SIRT1 in macrophages.

AIMS: Dysregulated interferon regulatory factor 8 (IRF8) mediated inducible nitric oxide synthase (iNOS) transcription is crucial to the pathogenesis of several inflammatory disorders. However, the molecular mechanism that control the transcription activity of IRF8 in the regulation of iNOS is not fully elucidated. This study is undertaken to determine whether SIRT1 impacts IRF8 acetylation level in the macrophages. MAIN METHODS: The silver stain, mass spectrum, bone marrow-derived monocytes differentiation, lentiviral transduction, immunoprecipitation and chromatin immunoprecipitation assay were used to investigate the relationship between IRF8 and SIRT1. KEY FINDINGS: We demonstrate that deacetylation of IRF8 is induced by lipopolysaccharide (LPS) and suppresses iNOS expression. Macrophages expressing acetylation-defective iNOS are highly septic upon transfer to macrophages cleaned up mice. Mechanistically, deacetylation IRF8 facilitates the binding of silent information regulator 1 (SIRT1) to the iNOS promoter and restricts iNOS transcription. The expression of iNOS was enhanced in the macrophages from SIRT1 conditional knockout mice and the progression of sepsis is more serious. SIGNIFICANCE: The discovery of the IRF8-SIRT1 interaction that governs iNOS expression may exploit new therapeutic strategies for inflammatory disorders.

Exosomes Derived from Adipose Mesenchymal Stem Cells Promote Diabetic Chronic Wound Healing through SIRT3/SOD2.

Chronic wounds resulting from diabetes are a major health concern in both industrialized and developing countries, representing one of the leading causes of disability and death. This study aimed to investigate the effect of adipose mesenchymal stem cell-derived exosomes (ADSC-exos) on diabetic wounds and the mechanism underlying this effect. The results showed that ADSC-exos could improve oxidative stress and secretion of inflammatory cytokines in diabetic wounds, thereby increasing periwound vascularization and accelerating wound healing. At the cellular level, ADSC-exos reduced reactive oxygen species (ROS) generation in human umbilical vein endothelial cells (HUVECs) and improved mitochondrial function in a high-glucose environment. Moreover, the Western blot analysis showed that the high-glucose environment decreased Sirtuin 3 (SIRT3) expression, while exosome treatment increased SIRT3 expression. The activity of superoxide dismutase 2 (SOD2) was enhanced, and the level of inflammatory cytokines was decreased. Further, SIRT3 interference experiments indicated that the effects of ADSC-exos on oxidative stress and angiogenesis were partly dependent on SIRT3. After SIRT3 was inhibited, ROS production increased, while mitochondrial membrane potential and SOD2 activity decreased. These findings confirmed that ADSC-exos could improve the level of high-glucose-induced oxidative stress, promote angiogenesis, and reduce mitochondrial functional impairment and the inflammatory response by regulating SIRT3/SOD2, thus promoting diabetic wound healing.

Functionalizing multi-component bioink with platelet-rich plasma for customized in-situ bilayer bioprinting for wound healing.

In-situ three-dimensional (3D) bioprinting has been emerging as a promising technology designed to rapidly seal cutaneous defects according to their contour. Improvements in the formulations of multi-component bioink are needed to support cytocompatible encapsulation and biological functions. Platelet-rich plasma (PRP), as a source of patient-specific autologous growth factors, exhibits capabilities in tissue repair and rejuvenation. This study aimed to prepare PRP-integrated alginate-gelatin (AG) composite hydrogel bioinks and evaluate the biological effects in vitro and in vivo. 3D bioprinted constructs embedded with dermal fibroblasts and epidermal stem cells were fabricated using extrusion strategy. The integration of PRP not only improved the cellular behavior of seeded cells, but regulate the tube formation of vascular endothelial cells and macrophage polarization in a paracrine manner, which obtained an optimal effect at an incorporation concentration of 5%. For in-situ bioprinting, PRP integration accelerated the high-quality wound closure, modulated the inflammation and initiated the angiogenesis compared with the AG bioink. In conclusion, we revealed the regenerative potential of PRP, readily available at the bedside, as an initial signaling provider in multi-component bioink development. Combined with in-situ printing technology, it is expected to accelerate the clinical translation of rapid individualized wound repair.

The Notch pathway attenuates burn-induced acute lung injury in rats by repressing reactive oxygen species.

Background: Acute lung injury (ALI) is a common complication following severe burns. The underlying mechanisms of ALI are incompletely understood; thus, available treatments are not sufficient to repair the lung tissue after ALI. Methods: To investigate the relationship between the Notch pathway and burn-induced lung injury, we established a rat burn injury model by scalding and verified lung injury via lung injury evaluations, including hematoxylin and eosin (H&E) staining, lung injury scoring, bronchoalveolar lavage fluid and wet/dry ratio analyses, myeloperoxidase immunohistochemical staining and reactive oxygen species (ROS) accumulation analysis. To explore whether burn injury affects Notch1 expression, we detected the expression of Notch1 and Hes1 after burn injury. Then, we extracted pulmonary microvascular endothelial cells (PMVECs) and conducted Notch pathway inhibition and activation experiments, via a γ-secretase inhibitor (GSI) and OP9-DLL1 coculture, respectively, to verify the regulatory effect of the Notch pathway on ROS accumulation and apoptosis in burn-serum-stimulated PMVECs. To investigate the regulatory effect of the Notch pathway on ROS accumulation, we detected the expression of oxidative-stress-related molecules such as superoxide dismutase, nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (NOX) 2, NOX4 and cleaved caspase-3. NOX4-specific small interfering RNA (siRNA) and the inhibitor GKT137831 were used to verify the regulatory effect of the Notch pathway on ROS via NOX4. Results: We successfully established a burn model and revealed that lung injury, excessive ROS accumulation and an inflammatory response occurred. Notch1 detection showed that the expression of Notch1 was significantly increased after burn injury. In PMVECs challenged with burn serum, ROS and cell death were elevated. Moreover, when the Notch pathway was suppressed by GSI, ROS and cell apoptosis levels were significantly increased. Conversely, these parameters were reduced when the Notch pathway was activated by OP9-DLL1. Mechanistically, the inhibition of NOX4 by siRNA and GKT137831 showed that the Notch pathway reduced ROS production and cell apoptosis by downregulating the expression of NOX4 in PMVECs. Conclusions: The Notch pathway reduced ROS production and apoptosis by downregulating the expression of NOX4 in burn-stimulated PMVECs. The Notch-NOX4 pathway may be a novel therapeutic target to treat burn-induced ALI.

Regulation of SIRT1 and Its Roles in Inflammation.

The silent information regulator sirtuin 1 (SIRT1) protein, a highly conserved NAD+-dependent deacetylase belonging to the sirtuin family, is a post-translational regulator that plays a role in modulating inflammation. SIRT1 affects multiple biological processes by deacetylating a variety of proteins including histones and non-histone proteins. Recent studies have revealed intimate links between SIRT1 and inflammation, while alterations to SIRT1 expression and activity have been linked to inflammatory diseases. In this review, we summarize the mechanisms that regulate SIRT1 expression, including upstream activators and suppressors that operate on the transcriptional and post-transcriptional levels. We also summarize factors that influence SIRT1 activity including the NAD+/NADH ratio, SIRT1 binding partners, and post-translational modifications. Furthermore, we underscore the role of SIRT1 in the development of inflammation by commenting on the proteins that are targeted for deacetylation by SIRT1. Finally, we highlight the potential for SIRT1-based therapeutics for inflammatory diseases.

A Novel 3D Culture Model of Human ASCs Reduces Cell Death in Spheroid Cores and Maintains Inner Cell Proliferation Compared With a Nonadherent 3D Culture.

3D cell culture technologies have recently shown very valuable promise for applications in regenerative medicine, but the most common 3D culture methods for mesenchymal stem cells still have limitations for clinical application, mainly due to the slowdown of inner cell proliferation and increase in cell death rate. We previously developed a new 3D culture of adipose-derived mesenchymal stem cells (ASCs) based on its self-feeder layer, which solves the two issues of ASC 3D cell culture on ultra-low attachment (ULA) surface. In this study, we compared the 3D spheroids formed on the self-feeder layer (SLF-3D ASCs) with the spheroids formed by using ULA plates (ULA-3D ASCs). We discovered that the cells of SLF-3D spheroids still have a greater proliferation ability than ULA-3D ASCs, and the volume of these spheroids increases rather than shrinks, with more viable cells in 3D spheroids compared with the ULA-3D ASCs. Furthermore, it was discovered that the SLF-3D ASCs are likely to exhibit the abovementioned unique properties due to change in the expression level of ECM-related genes, like COL3A1, MMP3, HAS1, and FN1. These results indicate that the SLF-3D spheroid is a promising way forward for clinical application.