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Journal of Materials Science. Materials... Jun 2024Calcium phosphate cements, primarily brushite cements, require the addition of setting retarders to ensure adequate processing time and processability. So far, citric...
Calcium phosphate cements, primarily brushite cements, require the addition of setting retarders to ensure adequate processing time and processability. So far, citric acid has been the primary setting retarder used in this context. Due to the poor biocompatibility, it is crucial to explore alternative options for better processing. In recent years, the setting retarder phytic acid (IP6) has been increasingly investigated. This study investigates the biological behaviour of calcium phosphate cements with varying concentrations of IP6, in addition to their physical properties. Therefore cytocompatibility in vitro testing was performed using osteoblastic (MG-63) and osteoclastic (RAW 264.7 differentiated with RANKL) cells. We could demonstrate that the physical properties like the compressive strength of specimens formed with IP6 (brushite_IP6_5 = 11.2 MPa) were improved compared to the reference (brushite = 9.8 MPa). In osteoblast and osteoclast assays, IP6 exhibited significantly better cytocompatibility in terms of cell activity and cell number for brushite cements up to 11 times compared to the brushite reference. In contrast, the calcium-deficient hydroxyapatite (CDHA) cements produced similar results for IP6 (CDHA_IP6_0.25 = 27.0 MPa) when compared to their reference (CDHA = 21.2 MPa). Interestingly, lower doses of IP6 were found to be more effective than higher doses with up to 3 times higher. Additionally, IP6 significantly increased degradation in both passive and active resorption. For these reasons, IP6 is emerging as a strong new competitor to established setting retarders such as citric acid. These cements have potential applications in bone augmentation, the stabilisation of non-load bearing fractures (craniofacial), or the cementation of metal implants.
Topics: Phytic Acid; Animals; Calcium Phosphates; Mice; Materials Testing; Bone Cements; Osteoblasts; RAW 264.7 Cells; Humans; Osteoclasts; Compressive Strength; Biocompatible Materials; Durapatite
PubMed: 38900219
DOI: 10.1007/s10856-024-06805-y -
Cell Communication and Signaling : CCS Jun 2024Excessive scar formation such as hypertrophic scars and keloids, resulting from trauma or surgical procedures, present a widespread concern for causing disfigurement,...
Excessive scar formation such as hypertrophic scars and keloids, resulting from trauma or surgical procedures, present a widespread concern for causing disfigurement, discomfort, and functional limitations. Macrophages play pivotal roles in maintaining tissue homeostasis, orchestrating tissue development, repair, and immune responses, and its transition of function and phenotype plays a critical role in regulating the balance between inflammation and tissue regeneration, which is central to cutaneous scar formation. Recent evidence suggests the involvement of Sonic Hedgehog (SHH) in the induction of anti-inflammatory M2-like macrophage phenotypes within tumor microenvironments. In our study, we observed increased SHH expression in human hypertrophic scars, prompting an investigation into its influence on macrophage polarization, efferocytosis, and cutaneous scar formation. Our findings reveal that SHH can enhance oxidative phosphorylation (OXPHOS) in macrophages, augment macrophage efferocytosis, and promote M2 polarization, finally contributing to the progression of cutaneous scar formation. Notably, targeting SHH signaling with vismodegib exhibited promising potential in mitigating scar formation by reversing the effects of enhanced OXPHOS and M2 polarization in macrophages. In conclusion, this study underscores the critical roles of macrophage metabolism, particularly OXPHOS, efferocytosis and SHH signaling in cutaneous scar formation. Understanding these mechanisms provides new avenues for potential interventions and scar prevention strategies.
Topics: Hedgehog Proteins; Macrophages; Humans; Oxidative Phosphorylation; Animals; Phagocytosis; Cicatrix, Hypertrophic; Mice; Signal Transduction; Cicatrix; Mice, Inbred C57BL; Anilides; Pyridines; Efferocytosis
PubMed: 38898530
DOI: 10.1186/s12964-024-01692-w -
Journal of Translational Medicine Jun 2024The importance of the immune microenvironment in poorly cohesive carcinoma (PCC) has been highlighted due to its limited response rate to conventional therapy and...
The importance of the immune microenvironment in poorly cohesive carcinoma (PCC) has been highlighted due to its limited response rate to conventional therapy and emerging treatment resistance. A combination of clinical cohorts, bioinformatics analyses, and functional/molecular experiments revealed that high infiltration of Interferon Induced Protein with Tetratricopeptide Repeats 1 (IFIT1) + tumor-associated neutrophils (TANs) is a distinguishing feature of PCC patients. Upregulation of IFIT1 + TANs promote migration and invasion of gastric cancer (GC) cell lines (MKN45 and MKN74) and stimulates the growth of cell-derived xenograft models. Besides, by promoting macrophage secreted phosphoprotein 1 (SPP1) expression and facilitating cancer-associated fibroblast and endothelial cell recruitment and activation through TANs, IFIT1 promotes a mesenchymal phenotype, which is associated with a poor prognosis. Importantly, compared to non-PCC (NPCC), PCC tumors is more immunosuppressive. Mechanistically, IFIT1 can be stimulated by IFN-γ and contributes to the expression of Programmed Cell Death 1 Ligand (PDL1) in TANs. We demonstrated in mouse models that IFIT1 + PDL1 + TANs can induce acquired resistance to anti-PD-1 immunotherapy, which may be responsible for the difficulty of PCC patients to benefit from immunotherapy. This work highlights the role of IFIT1 + TANs in mediating the remodeling of the tumor immune microenvironment and immunotherapeutic resistance and introduces IFIT1 + TANs as a promising target for precision therapy of PCC.
Topics: Humans; Neutrophils; Animals; RNA-Binding Proteins; Cell Line, Tumor; Adaptor Proteins, Signal Transducing; Tumor Microenvironment; Female; B7-H1 Antigen; Stomach Neoplasms; Male; Mice; Drug Resistance, Neoplasm; Cell Movement; Immune Tolerance; Immunosuppression Therapy; Gene Expression Regulation, Neoplastic; Neoplasm Invasiveness; Mice, Nude; Immunotherapy; Middle Aged
PubMed: 38898490
DOI: 10.1186/s12967-024-05389-z -
Journal of Nanobiotechnology Jun 2024Tumor-associated macrophages (TAMs) are a promising target for cancer immunotherapy, but delivering therapeutic agents to TAMs within the tumor microenvironment (TME) is...
Tumor-associated macrophages (TAMs) are a promising target for cancer immunotherapy, but delivering therapeutic agents to TAMs within the tumor microenvironment (TME) is challenging. In this study, a photosensitive, dual-targeting nanoparticle system (M.RGD@Cr-CTS-siYTHDF1 NPs) was developed. The structure includes a shell of DSPE-modified RGD peptides targeting integrin receptors on tumor cells and carboxymethyl mannose targeting CD206 receptors on macrophages, with a core of chitosan adsorbing m6A reading protein YTHDF1 siRNA and chromium nanoparticles (Cr NPs). The approach is specifically designed to target TAM and cancer cells, utilizing the photothermal effect of Cr NPs to disrupt the TME and deliver siYTHDF1 to TAM. In experiments with tumor-bearing mice, M.RGD@Cr-CTS-siYTHDF1 NPs, when exposed to laser irradiation, effectively killed tumor cells, disrupted the TME, delivered siYTHDF1 to TAMs, silenced the YTHDF1 gene, and shifted the STAT3-STAT1 equilibrium by reducing STAT3 and enhancing STAT1 expression. This reprogramming of TAMs towards an anti-tumor phenotype led to a pro-immunogenic TME state. The strategy also suppressed immunosuppressive IL-10 production, increased expression of immunostimulatory factors (IL-12 and IFN-γ), boosted CD8 + T cell infiltration and M1-type TAMs, and reduced Tregs and M2-type TAMs within the TME. In conclusion, the dual-targeting M.RGD@Cr-CTS-siYTHDF1 NPs, integrating dual-targeting capabilities with photothermal therapy (PTT) and RNA interference, offer a promising approach for molecular targeted cancer immunotherapy with potential for clinical application.
Topics: Animals; Mice; Immunotherapy; RNA, Small Interfering; Humans; Liver Neoplasms; Cell Line, Tumor; Tumor Microenvironment; Tumor-Associated Macrophages; RNA-Binding Proteins; Nanoparticles; Metal Nanoparticles; Photosensitizing Agents
PubMed: 38898486
DOI: 10.1186/s12951-024-02612-3 -
Scientific Reports Jun 2024Cancer cells recruit neutrophils from the bloodstream into the tumor tissue, where these immune cells promote the progression of numerous solid tumors. Studies in mice...
Cancer cells recruit neutrophils from the bloodstream into the tumor tissue, where these immune cells promote the progression of numerous solid tumors. Studies in mice suggest that blocking neutrophil recruitment to tumors by inhibition of neutrophil chemokine receptor CXCR2 could be a potential immunotherapy for pancreatic cancer. Yet, the mechanisms by which neutrophils promote tumor progression in humans, as well as how CXCR2 inhibition could potentially serve as a cancer therapy, remain elusive. In this study, we developed a human cell-based microphysiological system to quantify neutrophil-tumor spheroid interactions in both "separated" and "contact" scenarios. We found that neutrophils promote the invasion of tumor spheroids through the secretion of soluble factors and direct contact with cancer cells. However, they promote the proliferation of tumor spheroids solely through direct contact. Interestingly, treatment with AZD-5069, a CXCR2 inhibitor, attenuates invasion and proliferation of tumor spheroids by blocking direct contact with neutrophils. Our findings also show that CXCR2 inhibition reduces neutrophil migration toward tumor spheroids. These results shed new light on the tumor-promoting mechanisms of human neutrophils and the tumor-suppressive mechanisms of CXCR2 inhibition in pancreatic cancer and may aid in the design and optimization of novel immunotherapeutic strategies based on neutrophils.
Topics: Receptors, Interleukin-8B; Humans; Pancreatic Neoplasms; Neutrophils; Immunotherapy; Cell Line, Tumor; Spheroids, Cellular; Cell Proliferation; Disease Progression; Neutrophil Infiltration; Microphysiological Systems; Benzamides; Cyclobutanes
PubMed: 38898176
DOI: 10.1038/s41598-024-64780-4 -
Journal of Nippon Medical School =... Jun 2024Mixed connective tissue disease (MCTD) is characterized by mixed features of systemic lupus erythematosus, systemic sclerosis, and polymyositis/dermatomyositis and is...
Mixed connective tissue disease (MCTD) is characterized by mixed features of systemic lupus erythematosus, systemic sclerosis, and polymyositis/dermatomyositis and is rare in children. Here, we report a case of MCTD in a 10-year-old girl who presented at our hospital with arthralgia, Raynaud's phenomenon, and fatigue. Blood tests were positive for anti-U1-ribonucleoprotein (RNP) antibodies and for rheumatoid factors (RFs) IgG-RF and anti-galactose-deficient IgG. Levels of myogenic enzymes and hypergammaglobulinemia were elevated. Macrophages were prominent in bone marrow, with scattered phagocytic macrophages. MCTD was diagnosed based on the patient's symptoms and laboratory findings. Methylprednisolone pulse therapy combined with oral tacrolimus was administered, which led to resolution of symptoms. Three months after pulse therapy, arthralgia worsened and methotrexate was administered. Arthralgia improved but did not resolve. Magnetic resonance imaging performed to investigate the hip pain revealed a mature ovarian teratoma, which was surgically removed. Because the pain persisted and interfered with her daily life, she was treated with tocilizumab for joint pain relief, which decreased the pain level. Tocilizumab is a candidate for additional treatment of juvenile idiopathic arthritis-like arthritis associated with childhood-onset MCTD.
PubMed: 38897945
DOI: 10.1272/jnms.JNMS.2025_92-303 -
Science Advances Jun 2024Precision management of fibrotic lung diseases is challenging due to their diverse clinical trajectories and lack of reliable biomarkers for risk stratification and...
Precision management of fibrotic lung diseases is challenging due to their diverse clinical trajectories and lack of reliable biomarkers for risk stratification and therapeutic monitoring. Here, we validated the accuracy of CMKLR1 as an imaging biomarker of the lung inflammation-fibrosis axis. By analyzing single-cell RNA sequencing datasets, we demonstrated expression as a transient signature of monocyte-derived macrophages (MDMφ) enriched in patients with idiopathic pulmonary fibrosis (IPF). Consistently, we identified MDMφ as the major driver of the uptake of CMKLR1-targeting peptides in a murine model of bleomycin-induced lung fibrosis. Furthermore, CMKLR1-targeted positron emission tomography in the murine model enabled quantification and spatial mapping of inflamed lung regions infiltrated by CMKLR1-expressing macrophages and emerged as a robust predictor of subsequent lung fibrosis. Last, high expression by bronchoalveolar lavage cells identified an inflammatory endotype of IPF with poor survival. Our investigation supports the potential of CMKLR1 as an imaging biomarker for endotyping and risk stratification of fibrotic lung diseases.
Topics: Animals; Humans; Mice; Idiopathic Pulmonary Fibrosis; Pneumonia; Macrophages; Biomarkers; Disease Models, Animal; Positron-Emission Tomography; Pulmonary Fibrosis; Bleomycin; Lung; Male; Female; Mice, Inbred C57BL
PubMed: 38896611
DOI: 10.1126/sciadv.adm9817 -
ELife Jun 2024Tuberculosis is a major global health problem and is one of the top 10 causes of death worldwide. There is a pressing need for new treatments that circumvent emerging...
Tuberculosis is a major global health problem and is one of the top 10 causes of death worldwide. There is a pressing need for new treatments that circumvent emerging antibiotic resistance. parasitises macrophages, reprogramming them to establish a niche in which to proliferate, therefore macrophage manipulation is a potential host-directed therapy if druggable molecular targets could be identified. The pseudokinase Tribbles1 (Trib1) regulates multiple innate immune processes and inflammatory profiles making it a potential drug target in infections. Trib1 controls macrophage function, cytokine production, and macrophage polarisation. Despite wide-ranging effects on leukocyte biology, data exploring the roles of Tribbles in infection in vivo are limited. Here, we identify that human Tribbles1 is expressed in monocytes and is upregulated at the transcript level after stimulation with mycobacterial antigen. To investigate the mechanistic roles of Tribbles in the host response to mycobacteria in vivo, we used a zebrafish (Mm) infection tuberculosis model. Zebrafish Tribbles family members were characterised and shown to have substantial mRNA and protein sequence homology to their human orthologues. overexpression was host-protective against Mm infection, reducing burden by approximately 50%. Conversely, knockdown/knockout exhibited increased infection. Mechanistically, overexpression significantly increased the levels of proinflammatory factors and nitric oxide. The host-protective effect of was found to be dependent on the E3 ubiquitin kinase Cop1. These findings highlight the importance of Trib1 and Cop1 as immune regulators during infection in vivo and suggest that enhancing macrophage TRIB1 levels may provide a tractable therapeutic intervention to improve bacterial infection outcomes in tuberculosis.
Topics: Animals; Protein Serine-Threonine Kinases; Zebrafish; Humans; Intracellular Signaling Peptides and Proteins; Mycobacterium marinum; Disease Models, Animal; Mycobacterium Infections, Nontuberculous; Monocytes; Macrophages; Host-Pathogen Interactions
PubMed: 38896446
DOI: 10.7554/eLife.95980 -
Journal of Cellular and Molecular... Jun 2024Takotsubo syndrome (TTS) is a particular form of acute heart failure that can be challenging to distinguish from acute coronary syndrome at presentation. TTS was... (Review)
Review
Takotsubo syndrome (TTS) is a particular form of acute heart failure that can be challenging to distinguish from acute coronary syndrome at presentation. TTS was previously considered a benign self-limiting condition, but it is now known to be associated with substantial short- and long-term morbidity and mortality. Because of the poor understanding of its underlying pathophysiology, there are few evidence-based interventions to treat TTS. The hypotheses formulated so far can be grouped into endogenous adrenergic surge, psychological stress or preexisting psychiatric illness, coronary vasospasm with microvascular dysfunction, metabolic and energetic alterations, and inflammatory mechanisms. Current evidence demonstrates that the infiltration of immune cells such as macrophages and neutrophils play a pivotal role in TTS. At baseline, resident macrophages were the dominant subset in cardiac macrophages, however, it underwent a shift from resident macrophages to monocyte-derived infiltrating macrophages in TTS. Depletion of macrophages and monocytes in mice strongly protected them from isoprenaline-induced cardiac dysfunction. It is probable that immune cells, especially macrophages, may be new targets for the treatment of TTS.
Topics: Takotsubo Cardiomyopathy; Humans; Inflammation; Animals; Macrophages
PubMed: 38896112
DOI: 10.1111/jcmm.18503 -
Hepatology Communications Jul 2024Neutrophils are key mediators of inflammation during acute liver injury (ALI). Emerging evidence suggests that they also contribute to injury resolution and tissue...
BACKGROUND
Neutrophils are key mediators of inflammation during acute liver injury (ALI). Emerging evidence suggests that they also contribute to injury resolution and tissue repair. However, the different neutrophil subsets involved in these processes and their kinetics are undefined. Herein, we characterized neutrophil kinetics and heterogeneity during ALI.
METHODS
We used the carbon tetrachloride model of ALI and employed flow cytometry, tissue imaging, and quantitative RT-PCR to characterize intrahepatic neutrophils during the necroinflammatory early and late repair phases of the wound healing response to ALI. We FACS sorted intrahepatic neutrophils at key time points and examined their transcriptional profiles using RNA-sequencing. Finally, we evaluated neutrophil protein translation, mitochondrial function and metabolism, reactive oxygen species content, and neutrophil extracellular traps generation.
RESULTS
We detected 2 temporarily distinct waves of neutrophils during (1) necroinflammation (at 24 hours after injury) and (2) late repair (at 72 hours). Early neutrophils were proinflammatory, characterized by: (1) upregulation of inflammatory cytokines, (2) activation of the noncanonical NF-κB pathway, (3) reduction of protein translation, (4) decreased oxidative phosphorylation, and (5) higher propensity to generate reactive oxygen species and neutrophil extracellular traps. In contrast, late neutrophils were prorepair and enriched in genes and pathways associated with tissue repair and angiogenesis. Finally, early proinflammatory neutrophils were characterized by the expression of a short isoform of C-X-C chemokine receptor 5, while the late prorepair neutrophils were characterized by the expression of C-X-C chemokine receptor 4.
CONCLUSIONS
This study underscores the phenotypic and functional heterogeneity of neutrophils and their dual role in inflammation and tissue repair during ALI.
Topics: Animals; Neutrophils; Mice; Disease Models, Animal; Mice, Inbred C57BL; Male; Reactive Oxygen Species; Liver; Chemical and Drug Induced Liver Injury; Cytokines; Extracellular Traps
PubMed: 38896080
DOI: 10.1097/HC9.0000000000000459