Swift Covalent Gelation Coupled with Robust Wet Adhesive Powder: A Novel Approach for Acute Massive Hemorrhage Control in Dynamic and High-Pressure Wound Environments.

The quest for efficient hemostatic agents in emergency medicine is critical, particularly for managing massive hemorrhages in dynamic and high-pressure wound environments. Traditional self-gelling powders, while beneficial due to their ease of application and rapid action, fall short in such challenging conditions. To bridge this gap, the research introduces a novel self-gelling powder that combines ultrafast covalent gelation and robust wet adhesion, presenting a significant advancement in acute hemorrhage control. This ternary system comprises ε-polylysine (ε-PLL) and 4-arm polyethylene glycol succinyl succinate (4-arm-PEG-NHS) forming the hydrogel framework. Na2HPO4 functions as the "H+ sucker" to expedite the amidation reaction, slashing gelation time to under 10 s, crucial for immediate blood loss restriction. Moreover, PEG chains' hydrophilicity facilitates efficient absorption of interfacial blood, increasing the generated hydrogel's cross-linking density and strengthens its tissue bonding, thereby resulting in excellent mechanical and wet adhesion properties. In vitro experiments reveal the optimized formulation's exceptional tissue compliance, procoagulant activity, biocompatibility and antibacterial efficacy. In porcine models of heart injuries and arterial punctures, it outperforms commercial hemostatic agent Celox, confirming its rapid and effective hemostasis. Conclusively, this study presents a transformative approach to hemostasis, offering a reliable and potent solution for the emergency management of massive hemorrhage.

Advancing homogeneous networking principles for the development of fatigue-resistant, low-swelling and sprayable hydrogels for sealing wet, dynamic and concealed wounds in vivo.

Effective sealing of wet, dynamic and concealed wounds remains a formidable challenge in clinical practice. Sprayable hydrogel sealants are promising due to their ability to cover a wide area rapidly, but they face limitations in dynamic and moist environments. To address this issue, we have employed the principle of a homogeneous network to design a sprayable hydrogel sealant with enhanced fatigue resistance and reduced swelling. This network is formed by combining the spherical structure of lysozyme (LZM) with the orthotetrahedral structure of 4-arm-polyethylene glycol (4-arm-PEG). We have achieved exceptional sprayability by controlling the pH of the precursor solution. The homogeneous network, constructed through uniform cross-linking of amino groups in protein and 4-arm-PEG-NHS, provides the hydrogel with outstanding fatigue resistance, low swelling and sustained adhesion. In vitro testing demonstrated that it could endure 2000 cycles of underwater shearing, while in vivo experiments showed adhesion maintenance exceeding 24 h. Furthermore, the hydrogel excelled in sealing leaks and promoting ulcer healing in models including porcine cardiac hemorrhage, lung air leakage and rat oral ulcers, surpassing commonly used clinical materials. Therefore, our research presents an advanced biomaterial strategy with the potential to advance the clinical management of wet, dynamic and concealed wounds.

Temperate grassland vegetation restoration influenced by grazing exclusion and climate change.

Grasslands are one of the most important terrestrial biomes, supporting a wide range of ecological functions and services. Grassland degradation due to overgrazing is a severe issue worldwide, especially in developing regions. However, observations from multiple sources have shown that temperate grasslands in China have significantly increased during the past two decades. It remains controversial what factors have driven the vegetation restoration in this region. In this study, we combined remote-sensing images and field survey datasets to quantify the contributions of different factors to vegetation restoration in six temperate grasslands in northern China. Across the six grasslands, the Normalized Difference Vegetation Index (NDVI) increased by 0.003-0.0319 year-1. The average contributions of grazing exclusion and climate change to the NDVI increase were 49.23 % and 50.77 %, respectively. Precipitation change was the primary climate factor driving vegetation restoration, contributing 50.76 % to the NDVI variance. By contrast, climate warming tended to slow vegetation restoration, and atmospheric CO2 concentration change contributed little to the NDVI increase in the temperate grasslands. These results emphasize the significant contributions of both climate change and human management to grassland vegetation restoration.

Exploring the role of ITGB6: fibrosis, cancer, and other diseases.

Integrin ß6 (ITGB6), a member of the integrin family of proteins, is only present in epithelial tissues and frequently associates with integrin subunit αv to form transmembrane heterodimers named integrin αvß6. Importantly, ITGB6 determines αvß6 expression and availability. In addition to being engaged in organ fibrosis, ITGB6 is also directly linked to the emergence of cancer, periodontitis, and several potential genetic diseases. Therefore, it is of great significance to study the molecular-biological mechanism of ITGB6, which could provide novel insights for future clinical diagnosis and therapy. This review introduces the structure, distribution, and biological function of ITGB6. This review also expounds on ITGB6-related diseases, detailing the known biological effects of ITGB6.

Redox-active polyphenol nanoparticles deprive endogenous glutathione of electrons for ROS generation and tumor chemodynamic therapy.

Chemodynamic therapy (CDT) based on generating reactive oxygen species (ROS) is promising for cancer treatment. However, the intrinsic H2O2 is deficient for CDT, and glutathione (GSH) eliminates ROS to protect tumor cells from ROS cytotoxicity. Herein, we propose a strategy to switch the electron flow direction of GSH for O2 reduction and ROS generation rather than ROS clearance by using P(DA-Fc) nanoparticles, which are polymerized from ferrocenecarboxylic acid (Fc) coupled dopamine. P(DA-Fc) NPs with phenol-quinone conversion ability mimic NOX enzyme to deprive electrons from GSH to reduce O2 for H2O2 generation; the following •OH release can be triggered by Fc. Semiquinone radicals in P(DA-Fc) are significantly enhanced after GSH treatment, further demonstrated with strong single-electron reduction ability by calculation. In vitro and in vivo experiments indicate that P(DA-Fc) can consume intrinsic GSH to produce endogenous ROS; ROS generation strongly depends on GSH/pH level and eventually causes tumor cell death. Our work makes the first attempt to reverse the function of GSH from ROS scavenger to ROS producer, explores new roles of PDA-based nanomaterials in CDT beyond photothermal reagents and drug carriers, and provides a new strategy to improve the efficiency of CDT. STATEMENT OF SIGNIFICANCE: P(DA-Fc) nanoparticles performing tumor microenvironment response capacity and tumor reductive power utilize ability were fabricated for CDT tumor suppression. After endocytosis by tumor cells, P(DA-Fc) deprived GSH of electrons for H2O2 and •OH release, mimicking the intrinsic ROS production conducted by NADPH, further inducing tumor cell necrosis and apoptosis. Our work makes the first attempt to reverse the function of GSH from ROS scavenger to producer, explores new functions of PDA-based nanomaterials in CDT beyond photothermal reagents and drug carriers, and provides a new strategy to improve CDT efficiency.

Harnessing strategies for enhancing diabetic wound healing from the perspective of spatial inflammation patterns.

Diabetic wound is a great threat to patient's health and lives. The refractory diabetic wound shows spatial inflammation patterns, in which the early-wound pattern depicts a deprived acute inflammatory response, and the long-term non-healing wound pattern delineates an excessive and persistent inflammation due to the delayed immune cell infiltration in a positive feedback loop. In this work, we give points to some strategies to normalize the dysregulated immune process based on the spatial inflammation pattern differences in diabetic wound healing. First of all, inhibiting inflammatory response to avoid subsequent persistent and excessive immune infiltration for the early diabetic wound is proposed. However, diabetic wounds are unperceptive trauma that makes patients miss the best treatment time. Therefore, we also introduce two strategies for the long-term non-healing diabetic wound. One strategy is about changing chronic wounds to acute ones, which aims to rejuvenate M1 macrophages in diabetic wounds and make spontaneous M2 polarization possible. To activate the controllable proinflammatory response, western medicine delivers proinflammatory molecules while traditional Chinese medicine develops "wound-pus promoting granulation tissue growth theory". Another strategy to solve long-term non-healing wounds is seeking switches that target M1/M2 transition directly. These investigations draw a map that delineates strategies for enhancing diabetic wound healing from the perspective of spatial inflammation patterns systematically.

Nitrogen and Sulfur Co-doped Carbon Dots as a Turn-Off Fluorescence Probe for the Detection of Cerium and Iron.

Carbon dots has becoming one of the most promising fluorescence sensors to determine the trace level of heavy metals in environments because of their advantages in optical properties, response time, and convenient operation procedures. Herein, a novel nitrogen and sulfur co-doped carbon dots (NS-CDs) were prepared though microwave assisted approach using DL-malic acid and allyl thiourea for the first time. Due to the existence of nitrogen and sulfur, the as-prepared NS-CDs exhibited bright blue fluorescence at 430 nm upon 330 nm excitation, with a fluorescence quantum yield of 19.8%. The sensitivity study of NS-CDs against metal ions and organic molecules has approved that the fluorescence could be further quenched by Ce4+ and Fe3+ ions, with the same linear detection ranges varying from 10 to 90 µM. The limits of detection (LOD) were determined as low as 0.75 µM and 0.67 µM for Ce4+ and Fe3+ ions, respectively. The possible quenching mechanism is explained by inner filter effect and static quenching mechanism for Ce4+ ions, while the quenching effect caused by Fe3+ ions is attributed to the inner filter effect, static and dynamic quenching mechanisms. Additionally, the developed sensor was used for the detection of Ce4+ and Fe3+ ions in tap water with satisfactory recoveries. Finally, the designed NS-CDs sensor possesses good biocompatibility against MA104 cells, suggesting the sensor can be potentially applied to detect Ce4+ and Fe3+ ions in environment and biological systems.

Towards improved modeling of SOC decomposition: soil water potential beyond the wilting point.

Soils are important carbon (C) reservoirs and play a critical role in regulating the global C cycle. Soil water potential (SWP) measures the energy with which water is retained in the soil and is one of the most vital factors that constrain the decomposition of soil organic C (SOC). The measurements for soil water retention curve (SWRC), on which the estimation of SWP depends, are usually carried out above -1.5 MPa (i.e., the wilting point for many plants). However, the average moisture threshold at which soil microbial activity ceases is usually below -10 MPa in mineral soils. Beyond the measurement range, the SWP estimation has to be derived from extrapolating the SWRC, which violates the statistical principle, resulting in possibly inaccurate SWP estimations. To date, it is unclear to what extent the extrapolated SWP estimation deviates from the "true value" and how it impacts the modeling of SOC decomposition. This study combined SWRC measurements down to -43.7 MPa, a 72-day soil incubation experiment with four moisture levels, and an SOC decomposition model. In addition to the complete SWRC (SWRCall ), we fitted two more SWRCs by using measurements above -0.5 MPa (SWRC0.5 ) and -1.7 MPa (SWRC1.7 ), respectively, to quantify the deviations of extrapolated SWPs from the complete SWRC. Results showed that extrapolating the SWRC beyond its measurement range significantly underestimated the SWP. Incorporating the extrapolated SWP in the model significantly underestimated the SOC decomposition under relatively dry conditions. With the extrapolated SWP, the model predicted no SOC decomposition in the driest treatment, while the experiment observed a significant CO2 emission. The results emphasize that accurate SWP estimations beyond the wilting point are critically needed to improve the modeling of SOC decomposition.

INTEDE: interactome of drug-metabolizing enzymes.

Drug-metabolizing enzymes (DMEs) are critical determinant of drug safety and efficacy, and the interactome of DMEs has attracted extensive attention. There are 3 major interaction types in an interactome: microbiome-DME interaction (MICBIO), xenobiotics-DME interaction (XEOTIC) and host protein-DME interaction (HOSPPI). The interaction data of each type are essential for drug metabolism, and the collective consideration of multiple types has implication for the future practice of precision medicine. However, no database was designed to systematically provide the data of all types of DME interactions. Here, a database of the Interactome of Drug-Metabolizing Enzymes (INTEDE) was therefore constructed to offer these interaction data. First, 1047 unique DMEs (448 host and 599 microbial) were confirmed, for the first time, using their metabolizing drugs. Second, for these newly confirmed DMEs, all types of their interactions (3359 MICBIOs between 225 microbial species and 185 DMEs; 47 778 XEOTICs between 4150 xenobiotics and 501 DMEs; 7849 HOSPPIs between 565 human proteins and 566 DMEs) were comprehensively collected and then provided, which enabled the crosstalk analysis among multiple types. Because of the huge amount of accumulated data, the INTEDE made it possible to generalize key features for revealing disease etiology and optimizing clinical treatment. INTEDE is freely accessible at: https://idrblab.org/intede/.

Exercise protects the heart against myocardial infarction through upregulation of miR-1192.

Myocardial infarction (MI) is known as a serious global problem, which has a high mortality rate and cause severe heart damage. Mounting evidence has suggested that exercise provides direct endogenous cardiac protection against various cardiovascular diseases including MI. However, the underlying mechanism of exercise's cardioprotective effect against MI has not been fully understood. Here, we found that a 4-wk swim training exerted protective effects against MI in C57 mice, as evidenced by increased cardiac function and decreased cardiac apoptosis. A plasma miRNA profiling assay was then performed, and 10 differentially expressed miRNAs were detected. Among them, miR-1192 was increased after exercise, and it exerted significant protective effect against hypoxia in cultured neonatal cardiomyocytes. In addition, intramyocardially injection of agomiR-1192 exerted similar cardioprotective effect as exercise, and inhibition of miR-1192 using antgomiR-1192 abolished the cardioprotective effect of exercise in MI mice, suggesting that exercise exerted cardioprotection against MI through upregulation of miR-1192. Furthermore, we found that miR-1192 exerted cardioprotective effect via targeting caspase 3 in cardiomyocytes. These findings suggested that exercise protects the heart against MI through upregulation of miR-1192, and miR-1192 is a novel exerkine in exercise-induced cardioprotection against MI.

Alpha2,3-Sialylation regulates the stability of stem cell marker CD133.

CD133 is widely used as a marker for the isolation and characterization of normal and cancer stem cells. The dynamic alternation of CD133 glycosylation contributes to the isolation of normal and cancer stem cells, and is supposed to be associated with cell differentiation. Although CD133 has been identified as a N-glycosylated protein, the specific glycosylation status of CD133 remain unclear. Here, we found that CD133 could be sialylated in neural stem cells and glioma-initiating cells, and the sialyl residues attach to CD133 N-glycan terminal via alpha2,3-linkage. Furthermore, desialylation of CD133 by neuraminidase specifically accelerates its degradation in lysosomes-dependent pathway. Taken together, our results characterized CD133 as an alpha2,3-sialylated glycoprotein and revealed that the sialylation modification contributes to the stability of CD133 protein, providing clues to understanding the function of CD133 molecular and to understanding the utility of glycosylated CD133 epitopes in defining neural stem cells and tumour-initiating cells.

The effect of receptor protein tyrosine phosphatase kappa on the change of cell adhesion and proliferation induced by N-acetylglucosaminyltransferase V.

N-acetylglucosaminyltransferase V (GnT-V) has been reported to be positively associated with tumor progression, but its mechanism still remains unknown. In the present study, we found that GnT-V overexpression not only changed the glycosylation of receptor protein tyrosine phosphatase kappa (RPTPkappa) but also decreased its protein level. Moreover, GnT-V overexpression decreased cell calcium-independent adhesion and increased the tyrosine phosphorylation level of beta-catenin, in which RPTPkappa played an important role. Since RPTPkappa has an RXKR motif, which is a favored cleavage site for furin, we used furin inhibitor to further explore the effect of RPTPkappa on the change of cell adhesion and beta-catenin signaling induced by GnT-V. Our results showed that preventing RPTPkappa cleavage rescued the above effects of GnT-V, suggesting that furin cleavage could be one of the factors for RPTPkappa to regulate cell adhesion and beta-catenin signaling in GnT-V overexpression cell lines. In addition, the increased tyrosine phosphorylation level of beta-catenin was associated with the increased nuclear level of beta-catenin and downstream signaling molecules such as c-myc and cyclin D1 that were associated with cell proliferation. Our results suggest that GnT-V could decrease human hepatoma SMMC-7721 cell adhesion and promote cell proliferation partially through RPTPkappa.

Characterization and immunostimulatory activity of a polysaccharide from the spores of Ganoderma lucidum.

Spores of Ganoderma lucidum contain a large amount of bioactive substances and have a higher bioactivity than the fruit bodies of G. lucidum. However, ingredients from spores are less studied due to the difficulties in collecting the spores and breaking the rigid shell. In this study, a water-soluble polysaccharide named GSG was extracted from the spores of G. lucidum. GSG is characterized to be a branched glucan that contains several different kinds of linkages. It was an effective inducer of MAPKs- and Syk-dependent TNF-alpha and IL-6 secretion in murine resident peritoneal macrophages. Dectin-1 could recognize GSG and partially mediate its biological activities. Additionally, in vivo administration of GSG potentiated the Con A-induced proliferative response of splenocytes and induced anti-tumor activity against Lewis lung cancer in mice. Therefore, these results suggest that GSG is an effective immunomodulator and may be a promising adjuvant remedy for anti-tumor therapies.

HSP70 protects BCL2L12 and BCL2L12A from N-terminal ubiquitination-mediated proteasomal degradation.

BCL2L12 has been found to be associated with favorable prognosis in breast cancer patients while correlated with tumorigenesis of glioblastoma and colon cancer. Here, we report that BCL2L12 and its transcript variant BCL2L12A are degraded through ubiquitin-proteasome system (UPS). Interestingly, the ubiquitinations and degradations of BCL2L12 and BCL2L12A are independent of the internal lysine residues but the first N-terminal residues. In addition, HSP70 was identified to interact with BCL2L12 and BCL2L12A and protected them from ubiquitinations and degradations in mammalian cells. In summary, HSP70 protects BCL2L12 and BCL2L12A from N-terminal ubiquitination-mediated proteasomal degradation.

Trihydrophobin 1 Interacts with PAK1 and Regulates ERK/MAPK Activation and Cell Migration.

The Rac1/Cdc42 effector, p21-activated kinase (PAK), is activated by various signaling cascades, including receptor-tyrosine kinases and integrins, and regulates a number of processes such as cell proliferation and motility. PAK activity has been shown to be required for maximal activation of the canonical RAF-MEK-MAPK signaling cascade, possibly because of PAK co-activation of RAF and MEK. Here we have shown that trihydrophobin 1 (TH1), originally identified as a negative regulator of A-RAF kinase, also interacted with PAK1 in cultured cells. Confocal microscopy assay indicated that TH1 colocalized with PAK1 in both the cytoplasm and nucleus, which is consistent with our previous results. GST pulldown and coimmunoprecipitation experiments demonstrated that TH1 interacted directly with PAK1 and bound selectively to the carboxyl-terminal kinase domain of PAK1, and the ability of the binding was enhanced along with activation of PAK1. The binding pattern of PAK1 implies that this interaction was mediated in part by PAK1 kinase activity. As indicated by in vitro kinase activity assays and Western blot detections, TH1 inhibited PAK1 kinase activity and negatively regulated MAPK signal transduction. Interestingly, TH1 bound with MEK1/ERK in cells and in vitro without directly suppressing their kinase activity. Furthermore, we observed that TH1 localized to focal adhesions and filopodia in the leading edge of cells, where TH1 reduced cell migration through affecting actin and adhesion dynamics. Based on these observations, we propose a model in which TH1 interacts with PAK1 and specifically restricts the activation of MAPK modules through the upstream region of the MAPK pathway, thereby influencing cell migration.