Macrophage Cell Proliferation Research Articles

Synthesis and analysis of multifunctional graphene oxide/Ag2O-PVA/chitosan hybrid polymeric composite for wound healing applications

The requirement for accurate treatments for skin diseases and wounds, generated a rising interest towards multifunctional polymer composites, that are capable of mimicking the natural compositions in human body. Also, electroactive composite films disseminate endogenous electrical stimulations that encourage cell migration and its proliferation at wound site, proposing greater opportunities in upgrading the conventional wound patches. In this work, the composite film made of graphene oxide, Ag2O, PVA and chitosan were developed for wound healing applications, by the solution casting method. The even dispersibility of nanofiller in polymeric matrix was validated from the physicochemical analyses. The increment in roughness of the composite film surface was noted from AFM images. The thermal stability and porous nature of the polymer composite were also verified. A conductivity value of 0.16 × 10−4 Scm−1 was obtained for the film. From MTT assay, it was noted that the films were non-cytotoxic and supported cell adhesion along with cell proliferation of macrophage (RAW 264.7) cells. Moreover, the composite film also demonstrated non-hemolytic activity of <2 %, as well as excellent antibacterial activity towards E. coli and S. aureus. Thus, the obtained results validated that the prepared composite film could be chosen as an innovative candidate for developing state-of-the-art wound dressings.

Multifunctional Cell Regulation Activities of the Mussel Lectin SeviL: Induction of Macrophage Polarization toward the M1 Functional Phenotype.

SeviL, a galactoside-binding lectin previously isolated from the mussel Mytilisepta virgata, was demonstrated to trigger apoptosis in HeLa ovarian cancer cells. Here, we show that this lectin can promote the polarization of macrophage cell lines toward an M1 functional phenotype at low concentrations. The administration of SeviL to monocyte and basophil cell lines reduced their growth in a dose-dependent manner. However, low lectin concentrations induced proliferation in the RAW264.7 macrophage cell line, which was supported by the significant up-regulation of TOM22, a component of the mitochondrial outer membrane. Furthermore, the morphology of lectin-treated macrophage cells markedly changed, shifting from a spherical to an elongated shape. The ability of SeviL to induce the polarization of RAW264.7 cells to M1 macrophages at low concentrations is supported by the secretion of proinflammatory cytokines and chemokines, as well as by the enhancement in the expression of IL-6- and TNF-α-encoding mRNAs, both of which encode inflammatory molecular markers. Moreover, we also observed a number of accessory molecular alterations, such as the activation of MAP kinases and the JAK/STAT pathway and the phosphorylation of platelet-derived growth factor receptor-α, which altogether support the functional reprogramming of RAW264.7 following SeviL treatment. These results indicate that this mussel β-trefoil lectin has a concentration-dependent multifunctional role in regulating cell proliferation, phenotype, and death in macrophages, suggesting its possible involvement in regulating hemocyte activity in vivo.

Contactless magnetically responsive injectable hydrogel for aligned tissue regeneration

Cellular alignment plays a pivotal role in several human tissues, including skeletal muscle, spinal cord and tendon. Various techniques have been developed to control cellular alignment using 3D biomaterials. However, the majority of 3D-aligned scaffolds require invasive surgery for implantation. In contrast, injectable hydrogels provide a non-invasive delivery method, gaining considerable attention for the treatment of diverse conditions, including osteochondral lesions, volumetric muscle loss, and traumatic brain injury.We engineered a biomimetic hydrogel with magnetic responsiveness by combining gellan gum, hyaluronic acid, collagen, and magnetic nanoparticles (MNPs). Collagen type I was paired with MNPs to form magnetic collagen bundles (MCollB), allowing the orientation control of these bundles within the hydrogel matrix through the application of a remote low-intensity magnetic field. This resulted in the creation of an anisotropic architecture. The hydrogel mechanical properties were comparable to those of human soft tissues, such as skeletal muscle, and proof of the aligned hydrogel concept was demonstrated.In vitro findings confirmed the absence of toxicity and pro-inflammatory effects. Notably, an increased fibroblast cell proliferation and pro-regenerative activation of macrophages were observed. The in-vivo study further validated the hydrogel biocompatibility and demonstrated the feasibility of injection with rapid in situ gelation. Consequently, this magnetically controlled injectable hydrogel exhibits significant promise as a minimally invasive, rapid gelling and effective treatment for regenerating various aligned human tissues.

TM6SF1 suppresses the progression of lung adenocarcinoma and M2 macrophage polarization by inactivating the PI3K/AKT/mtor pathway

Transmembrane 6 superfamily 1 (TM6SF1) is lowly expressed in lung adenocarcinoma (LUAD), but the function and mechanisms of TM6SF1 remain unclear. Thus, we attempt to explore the function of TM6SF1 and its underlying mechanisms in LUAD. qRT-PCR was used for detecting TM6SF1 mRNA expression. Immunohistochemistry staining was used for detecting the expression of MMP-2, TM6SF1, Ki67, MMP-9, and CD163 proteins. E-cadherin, p-PI3K, Vimentin, AKT, N-cadherin, PI3K, p-AKT, mTOR, p-mTOR, and marker proteins of M2 macrophages were evaluated using Western blot. CD206 protein expression was examined via immunofluorescence. The IL-10 concentration was measured via enzyme-linked immunosorbent assay (ELISA). Using CCK-8, colony formation and transwell assays, cell proliferation, migration, and invasion were assessed. A549 cells were injected into the mice's flank for establishing a mouse tumor model and into the tail vein for establishing the lung metastasis model. HE staining was performed to detect pathological changes in lung tissues. Decreased TM6SF1 expression was found in LUAD tissues and cells. TM6SF1 overexpression inhibited cell viability, proliferation, invasion, migration, EMT, and polarization of M2 macrophages in LUAD cells, along with tumor growth and metastasis in xenograft mice. Bioinformatics analysis demonstrated that TM6SF1 was correlated with the tumor microenvironment. TM6SF1 overexpression reduced expression levels of p-mTOR, p-PI3K, p-AKT, mTOR, and AKT. TM6SF1-caused inhibition of proliferation, migration, invasion and EMT, as M2 macrophage polarization was reversed by the PI3K activator in LUAD cells. TM6SF1 inactivated the PI3K/AKT/mTOR pathway to suppress LUAD malignancy and polarization of M2 macrophages, providing insight for developing new LUAD treatments.

Exploring the anti-atherosclerosis mechanism of ginsenoside Rb1 by integrating network pharmacology and experimental verification.

Ginsenoside Rb1 is the major active constituent of ginseng, which is widely used in traditional Chinese medicine for the atherosclerosis treatment by anti-inflammatory, anti-oxidant and reducing lipid accumulation. We explored cellular target and molecular mechanisms of ginsenoside Rb1 based on network pharmacology and in vitro experimental validation. In this study, we predicted 17 potential therapeutic targets for ginsenoside Rb1 with atherosclerosis from public databases. We then used protein-protein interaction network to screen the hub targets. Gene Ontology enrichment and Kyoto Encyclopedia of Genes and Genomes pathway enrichment showed that the effects of ginsenoside Rb1 were meditated through multiple targets and pathways. Next, molecular docking results revealed that in the 10 core targets, CCND1 has the highest binding energy with ginsenoside Rb1. Vascular cell proliferation plays a critical role in atherosclerosis development. However, the effect and direct target of ginsenoside Rb1 in regulating vascular cell proliferation in atherosclerosis remains unclear. Edu straining results indicated that ginsenoside Rb1 inhibited the cell proliferation of endothelial cells, macrophages, and vascular smooth muscle cells. The protein immunoprecipitation (IP) analysis showed that ginsenoside Rb1 inhibited the vascular cell proliferation by suppressing the interaction of CCDN1 and CDK4. These findings systematically reveal that the anti-atherosclerosis mechanism of ginsenoside Rb1 by integrating network pharmacology and experimental validation, which provide evidence to treat atherosclerosis by using ginsenoside Rb1 and targeting CCND1.

Cold Alkali-Extractable Antioxidative Polysaccharide from Russula pseudocyanoxantha (Agaricomycetes), a Novel Mushroom, Stimulates Immune Responses in RAW264.7 Cells by Regulating the TLR/NF-κB Pathway.

In our previous study, we have established Russula pseudocyanoxantha as a unique species, playing a crucial role in indigenous diets through ages. The research also brought attention to bioactive potential of polysaccharide fraction extracted from the unexplored food using hot water. However, residue of the conventional process still contains therapeutic biopolymers that could further be utilized for pharmacological purposes instead of being discarded. Therefore, the current study aims to valorize the solid remnants, contributing to a deeper understanding of the novel taxon. Subsequently, the leftover was treated with cold alkali, leading to the preparation of a high-yield fraction (RP-CAP). Chemical characterization through FT-IR, GC-MS, HPTLC, and spectroscopy demonstrated presence of several monomers in the carbohydrate backbone, predominantly composed of β-glucan. Furthermore, GPC chromatogram indicated presence of a homogeneous polymer with molecular weight of ~ 129.28 kDa. Subsequently, potent antioxidant activity was noted in terms of radical scavenging (O2·-, OH·, DPPH· and ABTS·+), chelating ability, reducing power and total antioxidant activity where EC50 values ranged from 472-3600 μg/mL. Strong immune-boosting effect was also evident, as the biopolymers stimulated murine macrophage cell proliferation, phagocytic activity, pseudopod formation, and NO as well as ROS synthesis particularly at the concentration of 100 μg/mL. In-depth analysis through RT-PCR revealed that the fraction stimulated synthesis of several inflammatory mediators, elucidating the mode of action through TLR/ NF-κB pathway. Therefore, the findings collectively suggest that RP-CAP possesses great potential to serve as a healthimproving component in functional food and pharmaceutical sectors.

Migration, proliferation and cell death of regenerating liver macrophages in an experimental model

Relevance . Macrophages are the leading regulatory cell-lineage taking part in reparative processes in mammals, and the liver is no exception. The ratio of monocyte migration, proliferation and death of macrophages during liver regeneration requires further studies. The aim was to quantify the intensity of monocyte migration, cell proliferation and apoptosis of resident liver macrophages after its 70 % resection in a mouse model. Materials and Methods. We performed 70 % liver resection in sexually mature male BalbC mice. Cells of liver monocyte-macrophage system were obtained by magnetic sorting by marker F4/80. The immunophenotype of the isolated cells was further studied by cytofluorimetry, the level of proliferation and cell death, the content of cyclins and P53 was determined by western blot. Results and Discussion . It was found that after partial hepatectomy there is a marked migration of monocytes/macrophages positive for Ly6C and CD11b markers to the liver, the migration process starts already in the first day after the operation. On the same terms there is a rise in proliferative activity of macrophages, established by Ki67 marker, the peak of proliferation - 3 days after partial hepatectomy. A significant increase in the number of dying macrophages was found early after liver resection. Conclusion . The obtained data indicate that liver regeneration in mammals on the model in mice is accompanied by proliferation migration and cell death of macrophages. Taking into account the immunophenotype of macrophages, we can conclude that Ly6C+ blood monocytes migrate to the liver, and resident macrophages participate in proliferation. The obtained data confirm the universality of the course of reparative processes in mammals.

A carboxymethyl chitosan/oxidized hyaluronic acid composite hydrogel dressing loading with stem cell exosome for chronic inflammation wounds healing

Stem cell exosomes (Exo) play an important role in the transformation of macrophages, but the rapid clearance of Exo in vivo limits their therapeutic effects for chronic inflammation wounds healing. Here, stem cell Exo was isolated and introduced to a composite hydrogel including carboxymethyl chitosan (CMCS) and oxidized hyaluronic acid (OHA) through chemical cross-linking, which formed an Exo-loaded (CMCS/OHA/Exo) hydrogel. The CMCS/OHA/Exo hydrogel exhibited a function of Exo sustained release and an Exo protection within 6 days. This CMCS/OHA/Exo hydrogel was much better than CMCS/OHA hydrogel or Exo solution in macrophage cell phagocytosis, proliferation and migration in vitro, especially, played an obviously positive role in the transformation of macrophages compared with the reference groups. For the treatment of the chronic inflammation wounds in vivo, the CMCS/OHA/Exo hydrogel had the best results at wound heal rate and inhibiting the secretion of inflammatory factors, and it was far superior to reference groups in wound re-epithelization and collagen production. CMCS/OHA/Exo hydrogels can promote Exo release based on hydrogel degradation to regulate macrophages transformation and accelerate chronic wound healing. The study offers a method for preparing Exo-loaded hydrogels that effectively promote the transformation of macrophages and accelerate chronic inflammatory wound healing.

The effect of quercetin, a flavonoid, on lung injury caused by sepsis

Background/Aim: Lung injury is frequently observed in cases with sepsis, which can lead to conditions that progress to acute respiratory distress syndrome (ARDS) causing mortality. There is no specific treatment for sepsis or sepsis-induced lung injury. Antioxidant therapy has been one of the most prominent options for treatment, according to pathophysiological studies. The aim of this study was to investigate the effects of quercetin, a powerful antioxidant, on sepsis and sepsis-related lung injury. Methods: Thirty-two adult male Sprague Dawley rats were divided into five groups. The control group (CNRL) received 1.5 ml saline via the intragastric route. The quercetin group (QUER [n=5]) underwent no sepsis procedure and received 20 mg/kg quercetin via the intragastric route starting 15 days before the procedure. The sham group (SHAM [n=6]) underwent a surgical incision and received 1.5 ml intragastric olive oil (quercetin dissolves in oil). The sepsis group (SEPS [n=7]) underwent the sepsis procedure. The sepsis and quercetin group (SEPS+QUER [n=7]) underwent the sepsis procedure and received 20 mg/kg quercetin via the intragastric route for 15 days before the procedure. Cecal ligation and puncture methods were used to induce sepsis. While ALT, AST, LDH, GGT and CRP values were analyzed from rat blood, MDA and GSH levels were analyzed from lung tissue. Results: The results showed that quercetin reduced neutrophil infiltration (TLIS 3.5 [0.26] in the SEPS group vs TLIS 2.75 [0.29] in the SEPS+QUER group [P=0.01]), intra-alveolar macrophage count (SEPS vs SEPS+QUER [P=0.01]) and cell proliferation (SEPS vs SEPS+QUER [P=0.01]), and that it helped to preserve lung anatomy during sepsis. It was observed that MDA levels in the lung tissue decreased with the treatment of quercetin to septic rats (SEPS vs SEPS+QUER [P=0.046]). Conclusion: These findings suggest that quercetin may be a potential treatment option for sepsis. However, more studies are needed to determine whether quercetin is a viable option as a therapeutic strategy in patients.

Pleiotropic effects of extracellular vesicles from induced pluripotent stem cell–derived cardiomyocytes on ischemic cardiomyopathy: A preclinical study

Stem cell-secreted extracellular vesicles (EVs) play essential roles in intercellular communication and restore cardiac function in animal models of ischemic heart disease. However, few studies have used EVs derived from clinical-grade stem cells and their derivatives with stable quality. Moreover, there is little information on the mechanism and time course of the multifactorial effect of EV therapy from the acute to the chronic phase, the affected cells, and whether the effects are direct or indirect. Induced pluripotent stem cell-derived cardiomyocytes (iPSCM) were produced using a clinical-grade differentiation induction system. EVs were isolated from the conditioned medium by ultracentrifugation and characterized in silico, in vitro, and in vivo. A rat model of myocardial infarction was established by left anterior descending artery ligation and treated with iPSCM-derived EVs. iPSCM-derived EVs contained microRNAs and proteins associated with angiogenesis, antifibrosis, promotion of M2 macrophage polarization, cell proliferation, and antiapoptosis. iPSCM-derived EV treatment improved left ventricular function and reduced mortality in the rat model by improving vascularization and suppressing fibrosis and chronic inflammation in the heart. EVs were uptaken by cardiomyocytes, endothelial cells, fibroblasts, and macrophages in the cardiac tissues. The pleiotropic effects occurred due to the direct effects of microRNAs and proteins encapsulated in EVs and indirect paracrine effects on M2 macrophages. Clinical-grade iPSCM-derived EVs improve cardiac function by regulating various genes and pathways in various cell types and may have clinical potential for treating ischemic heart disease.

Centipeda minima Extract Inhibits Inflammation and Cell Proliferation by Regulating JAK/STAT Signaling in Macrophages and Keratinocytes.

Psoriasis, a chronic inflammation-mediated skin disease, affects 2-3% of the global population. It is characterized by keratinocyte hyperproliferation and immune cell infiltration. The JAK/STAT3 and JAK/STAT1 signaling pathways play an important role in the development of psoriasis when triggered by IL-6 and IFN-γ, which are produced by dendritic cells and T-lymphocytes. Thus, blocking JAK/STAT signaling may be a potential strategy for treating psoriasis. Therefore, we examined the effects of CMX, an extract of Centipeda minima enriched in Brevilin A, Arnicolide D, Arnicolide C, and Microhelenin C, on macrophages and keratinocytes. We established an in vitro model of psoriasis, based on an inflammation-associated keratinocyte proliferation model, and used macrophages and keratinocytes treated with LPS, IL-6, or IFN-γ to evaluate the effect of CMX. We found that CMX reduced pro-inflammatory cytokine production, by inhibiting lipopolysaccharide (LPS)-induced JAK1/2 and STAT1/3 phosphorylation in macrophages. Moreover, CMX-downregulated chemokine expression and cell proliferation compared with components in HaCaT cells, induced by rh-IL-6 and rh-IFN-γ, respectively. Consistently, we demonstrated that the reduction in chemokine expression and hyperproliferation was mediated by the regulation of IFN-γ-activated JAK/STAT1 and IL-6-activated JAK/STAT3 signaling. In conclusion, CMX inhibited JAK/STAT-mediated inflammatory responses and cell proliferation in macrophages and keratinocytes. Consequently, CMX may have potential uses as a therapeutic agent for treating psoriasis.

Synthesis of New Derivatives of Leaf-Eating Ant Toxic Gland Pheromone Compounds and Investigation of their Biological Properties

‌Background: The anti-mycobacterial characteristics of 2-pyrazinoic acid esters have been discovered through recent research. Research has demonstrated that the pyrazine ring and the alkyl part of these compounds interact with the enzyme phytynetase, which in turn inhibits the interaction between NADPH and mycobacterial fatty acids synthase, the enzyme responsible for synthesizing the fatty acids required for the cell wall of mycobacteria. Materials and Methods: Targeted pyrazinoic acid molecules have been synthesized, their structure verified by spectroscopic data, and their anti-mycobacterial activity against Mycobacterium TB H37Rv at a dose of 10 micrograms per milliliter assessed in order to test this theory. Significant anti-mycobacterial capabilities were shown by several compounds, including 3c, 3J, and 3M, which inhibited mycobacterial growth by 45.7%, 45.4%, and 51%, respectively. Findings: The results showed that the compounds exhibited little toxicity and did not inhibit macrophage cell proliferation. Pyrazinamide had significant antibacterial and antifungal activity, despite its lack of fatal action against non-tubercular mycobacteria and both Gram-positive and Gram-negative bacteria. Compound 3B, for example, exhibited excellent antibacterial properties against Gram-positive bacteria, such as S. aureus, with a minimum inhibitory concentration (MIC) of 125 micrograms per milliliter. Conversely, the compounds showed equally potent antibacterial properties against Gram-negative bacteria. Interestingly, compared to Gram-positive bacteria, the ester produced from maltol exhibited greater antibacterial efficacy against Gram-negative bacteria. Compounds synthesized with biodegradable groups also exhibited time-dependent toxicity against K562 leukemia cancer cells in MTT measurements, with compounds 3e and 3J displaying IC50 values of 25 micromolars. Conclusion: After synthesizing pyrazinoic acid monoterpene esters, spectral data was used to confirm their structures. When their biological characteristics were assessed, toxicity studies against K562 leukemia cells produced encouraging results. Through the use of Thio Ester-mediated activation of 2-pyrazinoic acid by 2, 2-dibenzothiazole disulfide and triphenylphosphine, 6-aminopenicillanic acid (6-APA) was coupled with pyrazinoic acid.

Gelatin Microspheres Loaded with Wharton's Jelly Mesenchymal Stem Cells Promote Acute Full-Thickness Skin Wound Healing and Regeneration in Mice.

Objective: At present, there is an urgent need to develop a novel and practical therapeutic approach to accelerate the healing of acute wounds. Mesenchymal stem cell (MSC)-based therapy is emerging as a promising therapeutic approach for acute skin wounds. However, there are still challenges in clinical application of this strategy, such as low survivability, low retention time, and less engraftment in skin wounds. Approach: Wharton's jelly mesenchymal stem cells (WJMSCs) were seeded into three-dimensional (3D) gelatin microspheres (GMs) to identify the biocompatibility of GMs. WJMSCs were embedded in GMs and then encapsulated with Pluronic F-127 (PF-127) and sodium ascorbyl phosphate (SAP) combination to transplant onto acute full-thickness skin wound in mice. Histology, immunohistochemistry, and immunofluorescence assay were used to investigate the skin wound healing, dermis regeneration, collagen deposition, cell proliferation, and neovascularization. Results: Three-dimensional GM had strong biocompatibility, compared with two-dimensional adherent culturing, GM loading increased the cell viability and proliferation ability of WJMSCs. WJMSCs+GM+PF-127+SAP transplantation increased skin wound healing rate, dermis regeneration, and type III collagen deposition through improving macrophage polarization, cell proliferation, neovascularization, cell retention, and engraftment at skin wound site. Innovation: The effective 3D encapsulation technology for WJMSCs solved the main problems of cell activity and residence time during MSC transplantation. WJMSCs+GM+PF-127+SAP transplantation will be a new and effective MSC biomaterials-based therapeutic strategy for acute skin traumatic wounds. Conclusion: WJMSCs+GM+PF-127+SAP transplantation facilitated acute full-thickness skin wound healing and regeneration and might be a new and effective therapy for acute skin traumatic wounds.

Silence of a dependence receptor CSF1R in colorectal cancer cells activates tumor-associated macrophages

BackgroundColony-stimulating factor 1 receptor (CSF1R), a classic tyrosine kinase receptor, has been identified as a proto-oncogene in multiple cancers. The CSF1/CSF1R axis is essential for the survival and differentiation of...

TMIC-60. THE ROLE OF ICAM1 IN GLIOBLASTOMA TUMORIGENESIS UNDER HYPOXIC CONDITIONS

Abstract Glioblastoma (GBM) is a fatal brain cancer in adults with ineffective existing treatment methods. Cell adhesion molecules (CAMs) are proteins that are expressed on the surface of cells and enable them to interact with one another and the surrounding microenvironment. Intracellular adhesion molecule 1 (ICAM-1) is a cell adhesion molecule expressed by macrophages, tumor cells and endothelial cells in GBM. Preliminary data showed that ICAM-1 is associated with poorer overall and progression free survival in GBM patients and ICAM-1 expression levels increase in recurrent GBM tumors. TAMs enhance tumor growth and proliferation, within GBM. The goal of this study was to determine whether and how ICAM-1 expression on TAMs contributes to GBM tumorigenesis, specifically within the hypoxic tumor microenvironment. We hypothesized that ICAM1 facilitates TAM migration, proliferation and phagocytosis, thus enhancing tumor growth. We found that upon incubation of human and mouse primary macrophages in hypoxia, ICAM-1 expression levels increased and were further exasperated upon culturing with tumor cell-conditioned medium. Incubation of ICAM-1 deficient macrophages in hypoxia resulted in lower migration and proliferation in ICAM-1 deficient cells compared to wild type cells. When cultured with tumor cell condition media, migration and proliferation of ICAM-1 deficient macrophages was lower than wild type macrophages. Further, intracranial injection of tumor cells into ICAM-1 deficient and wild type mice revealed that ICAM1 deficient mice survived longer and had lower overall tumor volume than wild type mice. In conclusion, the expression of ICAM1 in TAMs likely promotes GBM tumorigenesis by enhancing their proliferation and migration into the tumor microenvironment. ICAM-1 plays a role in macrophage migration, proliferation, and its expression on TAMs, resulting in more aggressive and invasive tumors. In addition, certain environmental factors like hypoxia further enhance the expression of ICAM-1 in macrophages which is associated with more aggressive features of GBM.

Involvement of plasma lncRNA GSEC in sepsis discrimination and prognosis, and its correlation with macrophage cell inflammation and proliferation

BackgroundDespite the dysregulation and function of G-quadruplex-forming sequence containing lncRNA (GSEC) have been widely reported in human cancers, there are few available data revealing its role in sepsis. ObjectiveTo assess the expression and function of GSEC in the development of sepsis and its potential molecular mechanism. Materials and methodsA total of 78 sepsis patients, 55 non-sepsis intensive care unit patients, and 42 healthy individuals were enrolled in this study. The expression of GSEC was evaluated in plasma and macrophage cells with polymerase chain reaction. The inflammation response of sepsis patients and macrophage cells was analyzed with an enzyme-linked immunosorbent assay. The diagnostic and prognostic value of GSEC in sepsis patients were estimated by receiver operator curve (ROC) and Cox analysis. The molecular mechanism underlying the function of GSEC was investigated in RAW264.7 cell with luciferase reporter assay and cell transfection. ResultsSignificant upregulation of GSEC was observed in sepsis patients’ plasma, which could discriminate sepsis patients from healthy and non-sepsis individuals. Upregulation of GSEC was positively correlated with inflammation cytokine levels and adverse prognosis of sepsis patients. In vitro, GSEC was found to modulate the expression level of miR-873-3p, which mediated the regulatory effect of GSEC on the inflammation and proliferation of RAW264.7. ConclusionUpregulated GSEC could serve as a biomarker of sepsis pathogenesis and development. GSEC regulates the inflammation and proliferation of macrophage cells through modulating miR-873-3p.

Tantalum nanoparticles reinforced polyetheretherketone coatings on titanium substrates: Bio-tribological and cell behaviour

As a biomaterial for bone repair, the application of polyetheretherketone (PEEK) has been limited by its poor wear resistance and cell behaviour. Inspired by the double ‘soft-hard’ phase structure, tantalum (Ta)/PEEK composite coating was fabricated on a titanium surface. All composite coatings had a lower friction coefficient and wear resistance under fetal bovine serum conditions. The adhesion, proliferation, and osteogenic differentiation of rat bone osteoblastic cells (MC3T3-E1) and mononuclear macrophage cells (RAW264.7) on the Ta/PEEK composite coating was enhanced. In particular, composite coatings effectively reduced inflammatory markers, with cytokines TGF-β and IL-10 released. As a result, titanium alloys with Ta reinforced PEEK coatings could exhibit improved bioactivity and tribology.

GAS6-mediated dialogue between decidual stromal cells and macrophages is essential for early pregnancy maintenance by inducing M2-like polarization and cell proliferation of decidual macrophages.

Maternal immunotolerance towards the semi-allogeneic foetus is critical for normal pregnancy (NP). As a secretory protein, growth arrest-specific factor 6 (GAS6) promotes cancer progression by inducing the conversion of tumour-associated macrophages to an immunosuppressive M2-like phenotype. However, little is known about whether GAS6 regulates decidual macrophages (dMφs) in the early maternal-foetal interface. In this study, first-trimester decidual tissues were obtained from normal pregnant women undergoing elective terminations and patients with miscarriages. The expression of GAS6 and its receptors (AXL, TYRO3 and MERTK) in decidua and GAS6 secretion by decidual stromal cells (DSCs) was measured. Then, we investigated the effect of recombinant human GAS6 (rhGAS6) on dMφs isolated from NP and THP-1 cells, and revealed the underlying mechanism. Both the expression of GAS6 in DSCs and MERTK in dMφs, in addition to GAS6 secretion by DSCs, was found to be significantly decreased in miscarriage patients compared to that in NPs. Additionally, we observed that rhGAS6 polarized dMφs and THP-1 cells towards an M2-like phenotype, as evidenced by the up-regulated CD163 expression. Moreover, rhGAS6 enhanced the clearance of toxic cell-free haemoglobin by dMφs by up-regulating CD163 expression, and rhGAS6 also boosted cell proliferation of dMφs and THP-1 cells. Finally, we demonstrated that rhGAS6 stimulated CD163 expression and cell proliferation by activating the PI3K/Akt signalling pathway. Collectively, these findings suggest that GAS6-mediated dialogue between DSCs and dMφs is crucial for the establishment and maintenance of maternal-foetal immunotolerance, and decreased GAS6 secretion by DSCs may lead to the occurrence of miscarriage in the first trimester.

In situ delivery of apoptotic bodies derived from mesenchymal stem cells via a hyaluronic acid hydrogel: A therapy for intrauterine adhesions

Stem cell-based and stem cell-derived exosome-based therapies have shown promising potential for endometrial regeneration and the clinical treatment of intrauterine adhesions (IUAs). Evidence shows that apoptosis occurs in a majority of grafted stem cells, and apoptotic bodies (ABs) play a critical role in compensatory tissue regeneration. However, the therapeutic potential of AB-based therapy and its mechanism have not been explored in detail. Here, a cell-free therapeutic strategy was developed by incorporating mesenchymal stem cell-derived ABs into a hyaluronic acid (HA) hydrogel to achieve endometrial regeneration and fertility restoration. Specifically, we found that the ABs could induce macrophage immunomodulation, cell proliferation, and angiogenesis in vitro. The HA hydrogel promoted the retention of ABs and facilitated their continuous release. In a murine model of acute endometrial damage and a rat model of IUAs, in situ injection of the AB-laden HA hydrogel could efficiently reduce fibrosis and promote endometrial regeneration, resulting in the fertility restoration. Consequently, ABs show good potential as therapeutic vesicles, and the AB-laden HA hydrogel appears to be a clinically feasible and cell-free alternative for endometrial regeneration and IUA treatment.

HSPB1 inhibitor J2 attenuates lung inflammation through direct modulation of Ym1 production and paracrine signaling

Heat shock protein beta-1 (HSPB1) is a multifaceted protein that controls cellular stress, modulates cell differentiation and development, and inhibits apoptosis of cancer cells. Increased HSPB1 expression is highly associated with poor outcomes in lung cancer by enhancing cell migration and invasion; therefore, targeting HSPB1 may be a promising therapeutic for lung cancer and fibrosis. Although the HSPB1 inhibitor J2 has been reported to exhibit potent antifibrotic effects, it remains unclear whether and how J2 directly modulates inflammatory immune responses in pulmonary fibrosis. In this study, we found that J2 potently attenuated irradiation or bleomycin-induced pulmonary fibrosis by significantly inhibiting the infiltration and activation of T cells and macrophages. J2 inhibited T-cell proliferation and subsequently suppressed T helper cell development. Although there was no significant effect of J2 on cell proliferation of M1 and M2 macrophages, J2 specifically increased the expression of Ym1 in M2 macrophages without affecting the expression of other M2 markers. Interestingly, J2 increased lysosomal degradation of HSPB1 and inhibited HSPB1-induced repression of signal transducer and activator of transcription 6 (STAT6), which simultaneously increased STAT6 and Ym1 expression. Ym1 production and secretion by J2-treated M2 macrophages substantially decreased IL-8 production by airway epithelial cells in vitro and in vivo, resulting in attenuation of airway inflammation. Taken together, we suggest that J2 has potential as a therapeutic agent for pulmonary fibrosis with increased HSPB1 expression through direct immune suppression by Ym1 production by M2 macrophages as well as T-cell suppression.