Role In Activation Research Articles

Adjusted Preferential Adsorption of Intermediates via Regulation of the Electronic Structure during the Electrocatalytic CO2 Reduction Process.

The surface electronic structures of catalysts play a crucial role in CO2 adsorption and activation. Here, sulfur vacancies are introduced into CuInS2 nanosheets (Vs-CuInS2) to evaluate the effect of electronic structures at the surface-active sites on the electrochemical CO2 reduction reaction (CO2RR). Vs-CuInS2 exhibits a significant disparity in the highest FEformate/FECO (6.50) compared to that of CuInS2 (1.86). Specifically, the maximum current density (Jmax) of carbon products on Vs-CuInS2 is 78.78 mA cm-2, and a Faraday efficiency of carbon products (FEcarbonproducts) of ≥80% is achieved in 600 mV wide potential windows. In situ Raman measurements and density functional theory calculations elucidate the origin of the apparent alterations in the carbon product selectivity. The introduction of sulfur vacancies realizes the controllable regulation of the local electronic density around the metal active sites, inducing the transformation of *COOH and *OCHO from competitive adsorption on CuInS2 to specific adsorption on Vs-CuInS2. In addition, the regulation of electronic structures on Vs-CuInS2 inhibits *H adsorption. This work reveals the transfer of adsorption of CO2RR intermediates via regulation of the electronic structure, complementing the understanding of the mechanism for the enhanced CO2RR.

Sinomenium acutum Modulates Platelet Aggregation and Thrombus Formation by Regulating the Glycoprotein VI-Mediated Signalosome in Mice.

Sinomenium acutum (SA) has long been used as a traditional medicine in China, Japan, and Korea to treat a wide range of diseases. It has been traditionally used to ameliorate inflammation and improve blood circulation. However, its role in platelet activation has not been thoroughly investigated. Hence, we conducted this study to assess the potential inhibitory effect of SA on platelet aggregation and thrombus formation. The antiplatelet activities of SA were evaluated by assessing platelet aggregation, granular secretion, intracellular Ca2+ mobilization, and the Glycoprotein (GP) VI-mediated signalosome. The thrombosis and bleeding time assays were used to investigate the effect of SA (orally administered at 50 and 100 mg/kg for seven days) in mice. SA treatment at concentrations of 50, 100, and 200 μg/mL significantly reduced GPVI-mediated platelet aggregation, granular secretion, and intracellular Ca2+ mobilization. Further biochemical studies revealed that SA inhibited spleen tyrosine kinase, phospholipase Cγ2, phosphatidylinositol 3-kinase, and AKT phosphorylation. Interestingly, oral administration of SA efficiently ameliorated FeCl3-induced arterial thrombus formation without prolonging the tail bleeding time. These findings suggest that SA has beneficial effects in thrombosis and hemostasis. Therefore, SA holds promise as an effective therapeutic agent for the treatment of thrombotic diseases.

Antibody therapies in cancer and autoimmune disease

Cancer and autoimmune diseases are gradually proven to be "two sides of the same coin". Many cancer patients develop manifestations of autoimmune diseases and rheumatism, especially those receiving immune checkpoint inhibitors. At the same time, patients with autoimmune diseases also have cancer combined, which may be related to chronic inflammation damage to DNA or clinical medication. Antibody therapies, pioneered by monoclonal antibody drugs, are now used extensively in the treatment of cancer and autoimmune diseases. The relationship between cancer and autoimmune diseases is gradually being discovered, and some antibody therapies have therapeutic effects on both types of diseases, perhaps because the two have common targets. In-depth study of the role of various targets in the occurrence and development of the two types of diseases, screen the common targets, and discover the antibody drugs that play an activation or inhibition role against the common targets, so as to achieve the effect of "same treatment for different diseases", which brings hope to patients with "cancer-autoimmune diseases". This paper discusses the relationship between the two types of diseases, summarizes the specific targets and corresponding diseases of some antibody therapies, and analyzes the current status of antibody therapy in the treatment of the two types of diseases, in order to explore the "dual therapy" potential of more antibody therapies in the future, and develop new targets and drugs.

Allosteric inhibition of phosphodiesterase 4D induces biphasic memory-enhancing effects associated with learning-activated signaling pathways.

Phosphodiesterase 4D negative allosteric modulators (PDE4D NAMs) enhance memory and cognitive function in animal models without emetic-like side effects. However, the relationship between increased cyclic adenosine monophosphate (cAMP) signaling and the effects of PDE4D NAM remains elusive. To investigate the roles of hippocampal cAMP metabolism and synaptic activation in the effects of D159687, a PDE4D NAM, under baseline and learning-stimulated conditions. At 3mg/kg, D159687 enhanced memory formation and consolidation in contextual fear conditioning; however, neither lower (0.3mg/kg) nor higher (30mg/kg) doses induced memory-enhancing effects. A biphasic (bell-shaped) dose-response effect was also observed in a scopolamine-induced model of amnesia in the Y-maze, whereas D159687 dose-dependently caused an emetic-like effect in the xylazine/ketamine anesthesia test. At 3mg/kg, D159687 increased cAMP levels in the hippocampal CA1 region after conditioning in the fear conditioning test, but not in the home-cage or conditioning cage (i.e., context only). By contrast, 30mg/kg of D159687 increased hippocampal cAMP levels under all conditions. Although both 3 and 30mg/kg of D159687 upregulated learning-induced Fos expression in the hippocampal CA1 30min after conditioning, 3mg/kg, but not 30mg/kg, of D159687 induced phosphorylation of synaptic plasticity-related proteins such as cAMP-responsive element-binding protein, synaptosomal-associated protein 25kDa, and the N-methyl-D-aspartate receptor subunit NR2A. Our findings suggest that learning-stimulated conditions can alter the effects of a PDE4D NAM on hippocampal cAMP levels and imply that a PDE4D NAM exerts biphasic memory-enhancing effects associated with synaptic plasticity-related signaling activation.

Investigation of the role of von Willebrand factor in shear-induced platelet activation and functional alteration under high non-physiological shear stress.

von Willebrand factor (vWF) plays a crucial role in physiological hemostasis through platelet and subendothelial collagen adhesion. However, its role in shear-induced platelet activation and functional alteration under non-physiological conditions common to blood-contacting medical devices (BCMDs) is not well investigated. Fresh healthy human blood was treated with an anti-vWF antibody to block vWF-GPIbα interaction. Untreated blood was used as a control. They were exposed to three levels of non-physiological shear stress (NPSS) (75, 125, and 175 Pa) through a shearing device with an exposure time of 0.5 s to mimic typical shear conditions in BCMDs. Flow cytometric assays were used to measure the expression levels of PAC-1 and P-Selectin and platelet aggregates for platelet activation and the expression levels of GPIbα, GPIIb/IIIa, and GPVI for receptor shedding. Collagen/ristocetin-induced platelet aggregation capacity was characterized by aggregometry. The levels of platelet activation and aggregates increased with increasing NPSS in the untreated blood. More receptors were lost with increasing NPSS, resulting in a decreased capacity of collagen/ristocetin-induced platelet aggregation. In contrast, the increase in platelet activation and aggregates after exposure to NPSS, even at the highest level of NPSS, was significantly lower in treated blood. Nevertheless, there was no notable difference in receptor shedding, especially for GPIIb/IIIa and GPVI, between the two blood groups at the same level of NPSS. The block of vWF exacerbated the decreased capacity of collagen/ristocetin-induced platelet aggregation. High NPSS activates platelets mainly by enhancing the vWF-GPIbα interaction. Platelet activation and receptor shedding induced by high NPSS likely occur through different pathways.

Proteolytic Activation of the Epithelial Sodium Channel (ENaC): Its Mechanisms and Implications.

Epithelial sodium channel (ENaC) are integral to maintaining salt and water homeostasis in various biological tissues, including the kidney, lung, and colon. They enable the selective reabsorption of sodium ions, which is a process critical for controlling blood pressure, electrolyte balance, and overall fluid volume. ENaC activity is finely controlled through proteolytic activation, a process wherein specific enzymes, or proteases, cleave ENaC subunits, resulting in channel activation and increased sodium reabsorption. This regulatory mechanism plays a pivotal role in adapting sodium transport to different physiological conditions. In this review article, we provide an in-depth exploration of the role of proteolytic activation in regulating ENaC activity. We elucidate the involvement of various proteases, including furin-like convertases, cysteine, and serine proteases, and detail the precise cleavage sites and regulatory mechanisms underlying ENaC activation by these proteases. We also discuss the physiological implications of proteolytic ENaC activation, focusing on its involvement in blood pressure regulation, pulmonary function, and intestinal sodium absorption. Understanding the mechanisms and consequences of ENaC proteolytic activation provides valuable insights into the pathophysiology of various diseases, including hypertension, pulmonary disorders, and various gastrointestinal conditions. Moreover, we discuss the potential therapeutic avenues that emerge from understanding these mechanisms, offering new possibilities for managing diseases associated with ENaC dysfunction. In summary, this review provides a comprehensive discussion of the intricate interplay between proteases and ENaC, emphasizing the significance of proteolytic activation in maintaining sodium and fluid balance in both health and disease.

Construction of novel 7 integrin-related gene signatures in thyroid cancer construction of model based on integrin genes.

Advanced and metastatic THCA patients usually have a poor prognosis. Thus, this study aimed to establish a risk model to discriminate the high risk population. The expression and clinical data were obtained from TCGA database. The cluster analysis, lasso, univariate and multivariate cox analyses were used to construct risk model. K-M, ROC and DCA were applied to validate the efficiency and stability of the model. GO, KEGG, and ssGSEA analysis were performed to identify the potential mechanism of signatures. The 7-gene prognosis model was constructed, including FAM27E3, FIGN, GSTM4, BEX5, RBPMS2, PHF13, and DCSTAMP. ROC and DCA results showed our model had a better prognosis prediction performance than other risk models. The high risk score was associated with the poor prognosis of THCA patients with different clinical characteristics. The risk score was closely related to cell cycle. Further, we found that the expressions of signatures were significantly dysregulated in THCA and associated with prognosis. These gene expressions were affected by some clinical characteristics, methylation and CNV. Some signatures played a role in drug sensitivity and pathway activation. We constructed a 7-gene signature model based on the integrin-related genes, which showed a great prognostic value in THCA.

Toll-Like Receptor mRNA Levels in Schizophrenia: Association With Complement Factors and Cingulate Gyrus Cortical Thinning.

Previous studies revealed innate immune system activation in people with schizophrenia (SZ), potentially mediated by endogenous pathogen recognition receptors, notably Toll-like receptors (TLR). TLRs are activated by pathogenic molecules like bacterial lipopolysaccharides (TLR1 and TLR4), viral RNA (TLR3), or both (TLR8). Furthermore, the complement system, another key component of innate immunity, has previously been linked to SZ. Peripheral mRNA levels of TLR1, TLR3, TLR4, and TLR8 were compared between SZ and healthy controls (HC). We investigated their relationship with immune activation through complement expression and cortical thickness of the cingulate gyrus, a region susceptible to immunological hits. TLR mRNA levels and peripheral complement receptor mRNA were extracted from 86 SZ and 77 HC white blood cells; structural MRI scans were conducted on a subset. We found significantly higher TLR4 and TLR8 mRNA levels and lower TLR3 mRNA levels in SZ compared to HC. TLRs and complemental factors were significantly associated in SZ and HC, with the strongest deviations of TLR mRNA levels in the SZ subgroup having elevated complement expression. Cortical thickness of the cingulate gyrus was inversely associated with TLR8 mRNA levels in SZ, and with TLR4 and TLR8 levels in HC. The study underscores the role of innate immune activation in schizophrenia, indicating a coordinated immune response of TLRs and the complement system. Our results suggest there could be more bacterial influence (based on TLR 4 levels) as opposed to viral influence (based on TLR3 levels) in schizophrenia. Specific TLRs were associated with brain cortical thickness reductions of limbic brain structures.

New Barrier Role of Iron Plaque: Producing Interfacial Hydroxyl Radicals to Degrade Rhizosphere Pollutants.

Iron plaque, as a natural barrier between rice and soil, can reduce the accumulation of pollutants in rice by adsorption, contributing to the safe production of rice in contaminated soil. In this study, we unveiled a new role of iron plaque, i.e., producing hydroxyl radicals (·OH) by activating root-secreted oxygen to degrade pollutants. The ·OH was produced on the iron plaque surface and then diffused to the interfacial layer between the surface and the rhizosphere environment. The iron plaque activated oxygen via a successive three-electron transfer to produce ·OH, involving superoxide and hydrogen peroxide as the intermediates. The structural Fe(II) in iron plaque played a dominant role in activating oxygen rather than the adsorbed Fe(II), since the structural Fe(II) was thermodynamically more favorable for oxygen activation. The oxygen vacancies accompanied by the structural Fe(II) played an important role in oxygen activation to produce ·OH. The interfacial ·OH selectively degraded rhizosphere pollutants that could be adsorbed onto the iron plaque and was less affected by the rhizosphere environments than the free ·OH. This study uncovered the oxidative role of iron plaque mediated by its produced ·OH, reshaping our understanding of the role of iron plaque as a barrier for rice.

MiR-12135 ameliorates liver fibrosis accompanied with the downregulation of integrin subunit alpha 11

Cirrhosis is becoming one of the most common diseases worldwide. Abnormal upregulation of transforming growth factor β (TGF-β) signaling plays a pivotal role in the excess activation of hepatic stellate cells. However, an efficient countermeasure against abnormal hepatic stellate cell activation is yet to be established because TGF-β signaling is involved in several biological processes. Herein, we demonstrated the antifibrotic effect of miR-12135, a microRNA with unknown function upregulated by isoflavone. Comprehensive transcriptome assay demonstrated that miR-12135 suppressed Integrin Subunit Alpha 11 (ITGA11) and that ITGA11 expression is correlated with alpha smooth muscle actin expression in patients with cirrhosis. miR-12135 suppressed the expression level of ITGA11 and liver fibrosis. Importantly, ITGA11 is overexpressed in activated hepatic stellate cells, whereas ITGA11 knockout mice are viable and fertile. In conclusions, the miR-12135/ITGA11 axis can be an ideal therapeutic target to suppress fibrosis by precisely targeting abnormally upregulated TGF-β signaling in hepatic stellate cells.

Dipeptidyl peptidase 1 inhibition as a potential therapeutic approach in neutrophil-mediated inflammatory disease.

Neutrophils have a critical role in the innate immune response to infection and the control of inflammation. A key component of this process is the release of neutrophil serine proteases (NSPs), primarily neutrophil elastase, proteinase 3, cathepsin G, and NSP4, which have essential functions in immune modulation and tissue repair following injury. Normally, NSP activity is controlled and modulated by endogenous antiproteases. However, disruption of this homeostatic relationship can cause diseases in which neutrophilic inflammation is central to the pathology, such as chronic obstructive pulmonary disease (COPD), alpha-1 antitrypsin deficiency, bronchiectasis, and cystic fibrosis, as well as many non-pulmonary pathologies. Although the pathobiology of these diseases varies, evidence indicates that excessive NSP activity is common and a principal mediator of tissue damage and clinical decline. NSPs are synthesized as inactive zymogens and activated primarily by the ubiquitous enzyme dipeptidyl peptidase 1, also known as cathepsin C. Preclinical data confirm that inactivation of this protease reduces activation of NSPs. Thus, pharmacological inhibition of dipeptidyl peptidase 1 potentially reduces the contribution of aberrant NSP activity to the severity and/or progression of multiple inflammatory diseases. Initial clinical data support this view. Ongoing research continues to explore the role of NSP activation by dipeptidyl peptidase 1 in different disease states and the potential clinical benefits of dipeptidyl peptidase 1 inhibition.

CB2 agonist mitigates cocaine-induced reinstatement of place preference and modulates the inflammatory response in mice.

Chronic exposure to cocaine is known to have profound effects on the brain, leading to the dysregulation of inflammatory signalling pathways, the activation of microglia, and the manifestation of cognitive and motivational behavioural impairments. The endocannabinoid system has emerged as a potential mediator of cocaine's deleterious effects. In this study, we sought to investigate the therapeutic potential of the cannabinoid CB2 receptor agonist, JWH-133, in mitigating cocaine-induced inflammation and associated motivational behavioural alterations in an in vivo model. Our research uncovered compelling evidence that JWH-133, a selective CB2 receptor agonist, exerts a significant dampening effect on the reinstatement of cocaine-induced conditioned place preference. This effect was accompanied by notable changes in the neurobiological landscape. Specifically, JWH-133 administration was found to upregulate Δ-FOSB expression in the nucleus accumbens (Nac), elevate CX3CL1 levels in both the ventral tegmental area and prefrontal cortex (PFC), and concurrently reduce IL-1β expression in the PFC and NAc among cocaine-treated animals. These findings highlight the modulatory role of CB2 cannabinoid receptor activation in altering the reward-seeking behaviour induced by cocaine. Moreover, they shed light on the intricate interplay between the endocannabinoid system and cocaine-induced neurobiological changes, paving the way for potential therapeutic interventions targeting CB2 receptors in the context of cocaine addiction and associated behavioural deficits.

Low ambient temperature exposure increases the risk of ischemic stroke by promoting platelet activation

BackgroundAccumulating epidemiological evidence suggests the association between low ambient temperature exposure and the risk of ischemic stroke, but the underlying mechanisms remain unclear. ObjectiveGiven the crucial role of platelet activation and thrombosis in ischemic stroke, this study aims to investigate the effect of ambient temperature on platelet activation through multi-center clinical data in Tianjin as well as animal experiments. MethodsFrom 2018 to 2020, nearly 3000 ischemic stroke patients from three stroke centers in Tianjin were included in the analysis, among them the ADP induced platelet aggregation rate was available. Meteorological data from the same period had also been collected. After controlling for confounding factors, the generalized additive mixed model (GAMM) was used to evaluate the correlation between environmental temperature and platelet aggregation rate. In further animal experiments, platelet function assessments were conducted on mice from the cold exposure group and the normal temperature group, including platelet aggregation, spreading, and clot retraction. Additionally, tail bleeding and mesentery thrombosis were also tested to monitor hemostasis and thrombosis in vivo. ResultA nonlinear “S” shaped relationship between outdoor temperature and platelet aggregation was found. Each 1 °C decrease of mean temperature was associated with an increase of 7.77 % (95 % CI: 2.06 % - 13.48 %) in platelet aggregation. The ambient temperature is not related to other platelet parameters. Subgroup analysis found that males, people aged ≥65 years, and hypertensive individuals are more susceptible to temperature changes. Furthermore, animal experiments demonstrated that the increased CIRBP levels and subsequent activation of p-AKT/p-ERK may be one of the reasons for cold exposure induced platelets activation. ConclusionBoth clinical data and basic research support that low ambient temperature exposure has the potential to increase platelet activation. These results provide a basis for understanding the potential mechanism of temperature variations on the pathogenesis of cerebrovascular diseases.

Lead aggravates Alzheimer's disease pathology via mitochondrial copper accumulation regulated by COX17

Alzheimer's disease (AD) is a common neurodegenerative disease that is associated with multiple environmental risk factors, including heavy metals. Lead (Pb) is a heavy metal contaminant, which is closely related to the incidence of AD. However, the research on the role of microglia in Pb-induced AD-like pathology is limited. To determine the mechanism by which Pb exposure aggravates AD progression and the role of microglial activation, we exposed APP/PS1 mice and Aβ1-42-treated BV-2 cells to Pb. Our results suggested that chronic Pb exposure exacerbated learning and memory impairments in APP/PS1 mice. Pb exposure increased the activation of microglia in the hippocampus of APP/PS1 mice, which was associated with increased deposition of Aβ1-42, and induced hippocampal neuron damage. Pb exposure upregulated copper transporter 1 (CTR1) and downregulated copper P-type ATPase transporter (ATP7A) in the hippocampus of APP/PS1 mice and Aβ1-42-treated BV-2 cells. Moreover, Pb enhanced mitochondrial translocation of the mitochondrial copper transporter COX17, leading to an increase in mitochondrial copper concentration and mitochondrial damage. This could be reversed by copper-chelating agents or by inhibiting the mitochondrial translocation of COX17. The increased mitochondrial copper concentration caused by increased mitochondrial translocation of COX17 after Pb exposure may be related to the enhanced mitochondrial import pathway of AIF/CHCHD4. These results indicate that Pb induces the activation of microglia by increasing the concentration of copper in the mitochondria of microglia, and microglia release inflammatory factors to promote neuroinflammation, thus aggravating the pathology of AD. The present study provides new ideas for the prevention of Pb-induced AD.

The Allosteric Regulation of Β-Ureidopropionase Depends on Fine-Tuned Stability of Active-Site Loops and Subunit Interfaces.

The activity of β-ureidopropionase, which catalyses the last step in the degradation of uracil, thymine, and analogous antimetabolites, is cooperatively regulated by the substrate and product of the reaction. This involves shifts in the equilibrium of the oligomeric states of the enzyme, but how these are achieved and result in changes in enzyme catalytic competence has yet to be determined. Here, the regulation of human β-ureidopropionase was further explored via site-directed mutagenesis, inhibition studies, and cryo-electron microscopy. The active-site residue E207, as well as H173 and H307 located at the dimer-dimer interface, are shown to play crucial roles in enzyme activation. Dimer association to larger assemblies requires closure of active-site loops, which positions the catalytically crucial E207 stably in the active site. H173 and H307 likely respond to ligand-induced changes in their environment with changes in their protonation states, which fine-tunes the active-site loop stability and the strength of dimer-dimer interfaces and explains the previously observed pH influence on the oligomer equilibrium. The correlation between substrate analogue structure and effect on enzyme assembly suggests that the ability to favourably interact with F205 may distinguish activators from inhibitors. The cryo-EM structure of human β-ureidopropionase assembly obtained at low pH provides first insights into the architecture of its activated state. and validates our current model of the allosteric regulation mechanism. Closed entrance loop conformations and dimer-dimer interfaces are highly conserved between human and fruit fly enzymes.

In vitro bioactivity and biocompatibility assessment of PCL/PLA–scaffolded mesoporous silicate bioactive glass: Role of boron activation

Bioactive glasses with rapid biodegradation and efficient biomineralization for damaged bone tissue repair remain deficient. Based on this fact, some new types of boron-activated mesoporous Bioactive silicate glasses (BMSGs) were made to determine the feasibility of achieving their improved mechanical strength, structure, porosity, biodegradability and bone healing performance. Four samples of the form xB2O3 – (80–x) SiO2 – 15CaO – 5P2O5 with x is 0, 5, 10, and 15 mol% were prepared using a unified sol-gel/evaporation induced self-assembly (SG-EISA) process. Furthermore, the solvent casting/partial leaching method was used to Scaffold the proposed BMSGs by polycaprolactone/polylacticacid (named as BMSG-PPS). The role of boron concentration fine-tuning in modifying the glasses morphology, structure, Bioactivity and Biocompatibility was assessed in vitro by immersing them in simulated body fluid (SBF) at various durations. Intense XRD peak at 31.7° confirmed the existence of crystalline hydroxyl carbonate apatite (HCA) in the glasses. Glass made with 10 mol% of boron (BMSG-PPS10) showed the strongest crystalline peak of HCA amongst all the studied samples. FESEM image of the Scaffold surface also revealed the presence of HCA agglomeration after 168 h of immersion in the SBF. The boron-free sample (BMSG-PPS0) showed strong agglomeration of HCA and Ca to P ratio (1.78±0.01) close to bone. After 168 h of immersion in the SBF solution, the symmetric stretching of PO43–and CO32–bands in the glass became more prominent. After 168 h of immersion in the SBF, the samples’ weight loss and solution pH correspondingly varied in the range of 5.66–7.37 % and 6.80–7.02. In addition, ICP–OES analyses of the glasses verified an increase of Si release in the SBF from the silicate network, indicating their rapid biodegradation. Briefly, the proposed BMSG–PPS with improved Bioactivity and Biocompatibility may be beneficial for various bio-medical implant coating applications.

RAS and SHOC2 Roles in RAF Activation and Therapeutic Considerations.

Mutations in RAS proteins play a pivotal role in the development of human cancers, driving persistent RAF activation and deregulating the Mitogen-Activated Protein Kinase (MAPK) signaling pathway. While progress has been made in targeting specific oncogenic RAS proteins, effective drug-based therapies for the majority of RAS mutations remain limited. Recent investigations on RAS-RAF complexes and the SHOC2-MRAS-PP1C holoenzyme complex have provided crucial insights into the structural and functional aspects of RAF activation within the MAPK signaling pathway. Moreover, these studies have also unveiled new blueprints for developing inhibitors allowing us to think beyond the current RAS and MEK inhibitors. In this review, we explore the roles of RAS and SHOC2 in activating RAF and discuss potential therapeutic strategies to target these proteins. A comprehensive understanding of the molecular interactions involved in RAF activation and their therapeutic implications holds the potential to drive innovative approaches in combating RAS/RAF-driven cancers.

Preparation and Activity of Hemostatic and Antibacterial Dressings with Greige Cotton/Zeolite Formularies Having Silver and Ascorbic Acid Finishes

The need for prehospital hemostatic dressings that exert an antibacterial effect is of interest for prolonged field care. Here, we consider a series of antibacterial and zeolite formulary treatment approaches applied to a cotton-based dressing. The design of the fabric formulations was based on the hemostatic dressing TACGauze with zeolite Y incorporated as a procoagulant with calcium and pectin to facilitate fiber adherence utilizing silver nanoparticles, and cellulose-crosslinked ascorbic acid to confer antibacterial activity. Infra-red spectra were employed to characterize the chemical modifications on the dressings. Contact angle measurements were employed to document the surface hydrophobicity of the cotton fabric which plays a role in the contact activation of the coagulation cascade. Ammonium Y zeolite-treated dressings initiated fibrin equal to the accepted standard hemorrhage control dressing and showed similar improvement with antibacterial finishes. The antibacterial activity of cotton-based technology utilizing both citrate-linked ascorbate-cellulose conjugate analogs and silver nanoparticle-embedded cotton fibers was observed against Staphylococcus aureus and Klebsiella pneumoniae at a level of 99.99 percent in the AATCC 100 assay. The hydrogen peroxide levels of the ascorbic acid-based fabrics, measured over a time period from zero up to forty-eight hours, were in line with the antibacterial activities.

AML alters bone marrow stromal cell osteogenic commitment via Notch signaling.

Acute myeloid leukemia (AML) is a highly heterogeneous malignancy caused by various genetic alterations and characterized by the accumulation of immature myeloid blasts in the bone marrow (BM). This abnormal growth of AML cells disrupts normal hematopoiesis and alters the BM microenvironment components, establishing a niche supportive of leukemogenesis. Bone marrow stromal cells (BMSCs) play a pivotal role in giving rise to essential elements of the BM niche, including adipocytes and osteogenic cells. Animal models have shown that the BM microenvironment is significantly remodeled by AML cells, which skew BMSCs toward an ineffective osteogenic differentiation with an accumulation of osteoprogenitors. However, little is known about the mechanisms by which AML cells affect osteogenesis. We studied the effect of AML cells on the osteogenic commitment of normal BMSCs, using a 2D co-culture system. We found that AML cell lines and primary blasts, but not normal hematopoietic CD34+ cells, induced in BMSCs an ineffective osteogenic commitment, with an increase of the early-osteogenic marker tissue non-specific alkaline phosphatase (TNAP) in the absence of the late-osteogenic gene up-regulation. Moreover, the direct interaction of AML cells and BMSCs was indispensable in influencing osteogenic differentiation. Mechanistic studies identified a role for AML-mediated Notch activation in BMSCs contributing to their ineffective osteogenic commitment. Inhibition of Notch using a γ-secretase inhibitor strongly influenced Notch signaling in BMSCs and abrogated the AML-induced TNAP up-regulation. Together, our data support the hypothesis that AML infiltration produces a leukemia-supportive pre-osteoblast-rich niche in the BM, which can be partially ascribed to AML-induced activation of Notch signaling in BMSCs.

Magnetic Resonance Imaging Nanoprobe Quantifies Nitric Oxide for Evaluating M1/M2 Macrophage Polarization and Prognosis of Cancer Treatments.

Macrophages play a crucial role in immune activation and provide great value in the prognosis of cancer treatments. Current strategies for prognostic evaluation of macrophages mainly target the specific biomarkers to reveal the number and distribution of macrophages in the tumors, whereas the phenotypic change of M1 and M2 macrophages in situ is less understood. Here, we designed an ultrasmall superparamagnetic iron oxide nanoparticle-based molecular imaging nanoprobe to quantify the repolarization of M2 to M1 macrophages by magnetic resonance imaging (MRI) using the redox-active nitric oxide (NO) as a vivid chemical target. The nanoprobe equipped with O-phenylenediamine groups could react with the intracellular NO molecules during the repolarization of M2 macrophages to the M1 phenotype, leading to electrical attraction and colloidal aggregation of the nanoprobes. Consequently, the prominent changes of the T1 and T2 relaxation in MRI allow for the quantification of the macrophage polarization. In a 4T1 breast cancer model, the MRI nanoprobe was able to reveal macrophage polarization and predict treatment efficiency in both immunotherapy and radiotherapy paradigms. This study presents a noninvasive approach to monitor the phenotypic changes of M2 to M1 macrophages in the tumors, providing insight into the prognostic evaluation of cancer treatments regarding macrophage-mediated immune responses.