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Journal of Biomedical Materials... Jul 2024Approximately 5%-10% of fractures go on to delayed healing and nonunion, posing significant clinical, economic, and social challenges. Current treatment methods...
Approximately 5%-10% of fractures go on to delayed healing and nonunion, posing significant clinical, economic, and social challenges. Current treatment methods involving open bone harvesting and grafting are associated with considerable pain and potential morbidity at the donor site. Hence, there is growing interest in minimally invasive approaches such as bone marrow aspirate concentrate (BMAC), which contains mesenchymal stromal cells (MSCs), macrophages (Mφ), and T cells. However, the use of cultured or activated cells for treatment is not yet FDA-approved in the United States, necessitating further exploration of optimal cell types and proportions for effective bone formation. As our understanding of osteoimmunology advances, it has become apparent that factors from anti-inflammatory Mφ (M2) promote bone formation by MSCs. Additionally, M2 Mφ promote T helper 2 (Th2) cells and Treg cells, both of which enhance bone formation. In this study, we investigated the interactions among MSCs, Mφ, and T cells in bone formation and explored the potential of subsets of BMAC. Coculture experiments were conducted using primary MSCs, Mφ, and CD4+ T cells at specific ratios. Our results indicate that nonactivated T cells had no direct influence on osteogenesis by MSCs, while coculturing MSCs with Mφ and T cells at a ratio of 1:5:10 positively impacted bone formation. Furthermore, higher numbers of T cells led to increased M2 polarization and a higher proportion of Th2 cells in the early stages of coculture. These findings suggest the potential for enhancing bone formation by adjusting immune and mesenchymal cell ratios in BMAC. By understanding the interactions and effects of immune cells on bone formation, we can develop more effective strategies and protocols for treating bone defects and nonunions. Further studies are needed to investigate these interactions in vivo and explore additional factors influencing MSC-based therapies.
PubMed: 38963690
DOI: 10.1002/jbm.a.37771 -
Molecular Cancer Therapeutics Jul 2024Radioimmunotherapy (RIT) uses monoclonal antibodies to deliver radionuclides to cancer cells or the tumor microenvironment and has shown promise in treating localized...
Radioimmunotherapy (RIT) uses monoclonal antibodies to deliver radionuclides to cancer cells or the tumor microenvironment and has shown promise in treating localized and diffuse tumors. Although RIT agents have gained FDA/EMA approval for certain hematologic malignancies, effectiveness of RIT in treating solid tumors remains limited. In this study, we present PreTarg-it®, a novel approach for pretargeted RIT, providing optimized delivery of payloads in a two-step regimen. The effectiveness of PreTarg-it® is demonstrated by a powerful combination of ON105, a novel bispecific antibody against both oxidized macrophage migration inhibitory factor (oxMIF) and the histamine-succinyl-glycyl (HSG) hapten, as the first component and the radioactively labeled DOTA-di-HSG peptide as the second component in murine models of cancer. Mice bearing either subcutaneous mouse colorectal CT26 or human pancreatic CFPAC-1 tumors received an i.v. injection of ON105. After ON105 had accumulated in the tumor and cleared from circulation to approximately 1% to 3% of its peak concentration, 177Lu-DOTA-di-HSG peptide was administered. A single PreTarg-it® treatment cycle resulted in tumor regression when mice bearing CT26 tumors were given the highest treatment dose with a pretargeting delay of 3 days. Administered with a 5-day interval, the highest dose arrested tumor growth in both CT26 syngrafts and CFPAC-1 xenografts. In all cases, the highest treatment dose resulted in 100% survival at the study endpoint, whereas the control cohorts showed 0% and 60% survival in the CT26 and CFPAC-1 models, respectively. Therefore, PreTarg-it® holds potential as a novel and potent therapy for patients with hard-to-treat solid tumors, such as pancreatic cancer, as well as those with late-stage malignancies.
PubMed: 38963557
DOI: 10.1158/1535-7163.MCT-24-0083 -
Blood Research Jul 2024Histiocytic neoplasms are rare diseases involving macrophages, dendritic cells, and monocytes. They include Langerhans cell histiocytosis (LCH), Erdheim-Chester disease... (Review)
Review
Histiocytic neoplasms are rare diseases involving macrophages, dendritic cells, and monocytes. They include Langerhans cell histiocytosis (LCH), Erdheim-Chester disease (ECD), Rosai-Dorfman disease (RDD), juvenile xanthogranuloma (JXG), and histiocytic sarcoma. Histiocytic neoplasms are characterized by varied clinical courses and prognoses, necessitating a nuanced understanding of their classification, epidemiology, and clinical manifestations. Genetic studies have revealed somatic mutations, predominantly in the MAPK pathway, suggesting a clonal neoplastic nature. This review covers the current understanding of histiocytic neoplasms, molecular pathophysiology, with a particular focus on mutations in genes such as BRAF, MAP2K1, and the PI3K-AKT signaling pathways, and evolving treatment strategies, especially focusing on LCH, ECD, RDD, and JXG. The treatment landscape has evolved with advancements in targeted therapies. BRAF inhibitors, such as vemurafenib and dabrafenib, have shown efficacy, especially in high-risk LCH cases; however, challenges remain, including relapse post-treatment discontinuation, and adverse effects. MEK inhibitors have also demonstrated effectiveness, and cobimetinib has recently been approved for use in adults. Further research is required to determine the optimal treatment duration and strategies for managing therapy interruptions. Advancements in molecular genetics and targeted therapies have revolutionized the management of histiocytic neoplasms. However, ongoing research is crucial for optimizing patient outcomes.
PubMed: 38963520
DOI: 10.1007/s44313-024-00022-w -
Influence of the agrochemical benomyl on Cryptococcus gattii-plant interaction in vitro and in vivo.Brazilian Journal of Microbiology :... Jul 2024Cryptococcus gattii, an environmental fungus, is one of the agents of cryptococcosis. The influence of agrochemicals on fungal resistance to antifungals is widely...
Cryptococcus gattii, an environmental fungus, is one of the agents of cryptococcosis. The influence of agrochemicals on fungal resistance to antifungals is widely discussed. However, the effects of benomyl (BEN) on fungal interaction with different hosts is still to be understood. Here we studied the influence of adaptation to BEN in the interaction with a plant model, phagocytes and with Tenebrio molitor. First, the strain C. gattii L24/01 non-adapted (NA), adapted (A) to BEN, and adapted with further culture on drug-free media (10p) interact with Nicotiana benthamiana, with a peak in the yeast burden on the 7th day post-inoculation. C. gattii L24/01 A and 10p provided lower fungal burden, but these strains increased cell diameter and capsular thickness after the interaction, together with decreased fungal growth. The strains NA and A showed reduced ergosterol levels, while 10p exhibited increased activity of laccase and urease. L24/01 A recovered from N. benthamiana was less engulfed by murine macrophages, with lower production of reactive oxygen species. This phenotype was accompanied by increased ability of this strain to grow inside macrophages. Otherwise, L24/01 A showed reduced virulence in the T. molitor larvae model. Here, we demonstrate that the exposure to BEN, and interaction with plants interfere in the morphophysiology and virulence of the C. gattii.
PubMed: 38963475
DOI: 10.1007/s42770-024-01440-9 -
Digestive Diseases and Sciences Jul 2024In inflammatory bowel diseases (IBD), the most promising therapies targeting cytokines or immune cell trafficking demonstrate around 40% efficacy. As IBD is a... (Review)
Review
In inflammatory bowel diseases (IBD), the most promising therapies targeting cytokines or immune cell trafficking demonstrate around 40% efficacy. As IBD is a multifactorial inflammation of the intestinal tract, a single-target approach is unlikely to solve this problem, necessitating an alternative strategy that addresses its variability. One approach often overlooked by the pharmaceutically driven therapeutic options is to address the impact of environmental factors. This is somewhat surprising considering that IBD is increasingly viewed as a condition heavily influenced by such factors, including diet, stress, and environmental pollution-often referred to as the "Western lifestyle". In IBD, intestinal responses result from a complex interplay among the genetic background of the patient, molecules, cells, and the local inflammatory microenvironment where danger- and microbe-associated molecular patterns (D/MAMPs) provide an adjuvant-rich environment. Through activating DAMP receptors, this array of pro-inflammatory factors can stimulate, for example, the NLRP3 inflammasome-a major amplifier of the inflammatory response in IBD, and various immune cells via non-specific bystander activation of myeloid cells (e.g., macrophages) and lymphocytes (e.g., tissue-resident memory T cells). Current single-target biological treatment approaches can dampen the immune response, but without reducing exposure to environmental factors of IBD, e.g., by changing diet (reducing ultra-processed foods), the adjuvant-rich landscape is never resolved and continues to drive intestinal mucosal dysregulation. Thus, such treatment approaches are not enough to put out the inflammatory fire. The resultant smoldering, low-grade inflammation diminishes physiological resilience of the intestinal (micro)environment, perpetuating the state of chronic disease. Therefore, our hypothesis posits that successful interventions for IBD must address the complexity of the disease by simultaneously targeting all modifiable aspects: innate immunity cytokines and microbiota, adaptive immunity cells and cytokines, and factors that relate to the (micro)environment. Thus the disease can be comprehensively treated across the nano-, meso-, and microscales, rather than with a focus on single targets. A broader perspective on IBD treatment that also includes options to adapt the DAMPing (micro)environment is warranted.
PubMed: 38963463
DOI: 10.1007/s10620-024-08523-5 -
Journal of Cellular and Molecular... Jul 2024Interleukin-5 (IL-5) has been reported to be involved in cardiovascular diseases, such as atherosclerosis and cardiac injury. This study aimed to investigate the effects...
Interleukin-5 (IL-5) has been reported to be involved in cardiovascular diseases, such as atherosclerosis and cardiac injury. This study aimed to investigate the effects of IL-5 on cardiac remodelling. Mice were infused with angiotensin II (Ang II), and the expression and source of cardiac IL-5 were analysed. The results showed that cardiac IL-5 expression was time- and dose-dependently decreased after Ang II infusion, and was mainly derived from cardiac macrophages. Additionally, IL-5-knockout (IL-5-/-) mice were used to observe the effects of IL-5 knockout on Ang II-induced cardiac remodelling. We found knockout of IL-5 significantly increased the expression of cardiac hypertrophy markers, elevated myocardial cell cross-sectional areas and worsened cardiac dysfunction in Ang II-infused mice. IL-5 deletion also promoted M2 macrophage differentiation and exacerbated cardiac fibrosis. Furthermore, the effects of IL-5 deletion on cardiac remodelling was detected after the STAT3 pathway was inhibited by S31-201. The effects of IL-5 on cardiac remodelling and M2 macrophage differentiation were reversed by S31-201. Finally, the effects of IL-5 on macrophage differentiation and macrophage-related cardiac hypertrophy and fibrosis were analysed in vitro. IL-5 knockout significantly increased the Ang II-induced mRNA expression of cardiac hypertrophy markers in myocardial cells that were co-cultured with macrophages, and this effect was reversed by S31-201. Similar trends in the mRNA levels of fibrosis markers were observed when cardiac fibroblasts and macrophages were co-cultured. In conclusions, IL-5 deficiency promote the differentiation of M2 macrophages by activating the STAT3 pathway, thereby exacerbating cardiac remodelling in Ang II-infused mice. IL-5 may be a potential target for the clinical prevention of cardiac remodelling.
Topics: Animals; Angiotensin II; STAT3 Transcription Factor; Mice, Knockout; Ventricular Remodeling; Signal Transduction; Mice; Macrophages; Fibrosis; Interleukin-5; Cardiomegaly; Male; Mice, Inbred C57BL; Cell Differentiation; Myocardium
PubMed: 38963241
DOI: 10.1111/jcmm.18493 -
Journal of Obstetrics and Gynaecology :... Dec 2024The expression and function of coexpression genes of M1 macrophage in cervical cancer have not been identified. And the CXCL9-expressing tumour-associated macrophage has...
BACKGROUND
The expression and function of coexpression genes of M1 macrophage in cervical cancer have not been identified. And the CXCL9-expressing tumour-associated macrophage has been poorly reported in cervical cancer.
METHODS
To clarify the regulatory gene network of M1 macrophage in cervical cancer, we downloaded gene expression profiles of cervical cancer patients in TCGA database to identify M1 macrophage coexpression genes. Then we constructed the protein-protein interaction networks by STRING database and performed functional enrichment analysis to investigate the biological effects of the coexpression genes. Next, we used multiple bioinformatics databases and experiments to overall investigate coexpression gene CXCL9, including western blot assay and immunohistochemistry assay, GeneMANIA, Kaplan-Meier Plotter, Xenashiny, TISCH2, ACLBI, HPA, TISIDB, GSCA and cBioPortal databases.
RESULTS
There were 77 positive coexpression genes and 5 negative coexpression genes in M1 macrophage. The coexpression genes in M1 macrophage participated in the production and function of chemokines and chemokine receptors. Especially, CXCL9 was positively correlated with M1 macrophage infiltration levels in cervical cancer. CXCL9 expression would significantly decrease and high CXCL9 levels were linked to good prognosis in the cervical cancer tumour patients, it manifestly expressed in blood immune cells, and was positively related to immune checkpoints. CXCL9 amplification was the most common type of mutation. The CXCL9 gene interaction network could regulate immune-related signalling pathways, and CXCL9 amplification was the most common mutation type in cervical cancer. Meanwhile, CXCL9 may had clinical significance for the drug response in cervical cancer, possibly mediating resistance to chemotherapy and targeted drug therapy.
CONCLUSION
Our findings may provide new insight into the M1 macrophage coexpression gene network and molecular mechanisms in cervical cancer, and indicated that M1 macrophage association gene CXCL9 may serve as a good prognostic gene and a potential therapeutic target for cervical cancer therapies.
Topics: Uterine Cervical Neoplasms; Humans; Female; Chemokine CXCL9; Gene Expression Regulation, Neoplastic; Macrophages; Prognosis; Gene Regulatory Networks; Protein Interaction Maps; Computational Biology; Tumor-Associated Macrophages; Gene Expression Profiling; Databases, Genetic
PubMed: 38963237
DOI: 10.1080/01443615.2024.2373951 -
Molecular Medicine Reports Sep 2024Cirrhosis impairs macrophage function and disrupts bile acid homeostasis. Although bile acids affect macrophage function in patients with sepsis, whether and how the...
Cirrhosis impairs macrophage function and disrupts bile acid homeostasis. Although bile acids affect macrophage function in patients with sepsis, whether and how the bile acid profile is changed by infection in patients with cirrhosis to modulate macrophage function remains unclear. The present study aimed to investigate the changes in the bile acid profile of patients with cirrhosis and infection and their effects on macrophage function. Serum was collected from 20 healthy subjects, 18 patients with cirrhosis and 39 patients with cirrhosis and infection. Bile acid profiles were detected using high‑performance liquid chromatography‑triple time‑of‑flight mass spectrometer. The association between bile acid changes and infection was analysed using receiver operating characteristic (ROC) curves. Infection‑altered bile acids were used in combination with lipopolysaccharides (LPS) to stimulate RAW264.7/THP‑1 cells . The migratory capacity was evaluated using wound healing and Transwell migration assays. The expression of Arg‑1, iNOS, IκBα, phosphorylated (p‑)IκBα and p65 was examined with western blotting and immunofluorescence, , and mRNA was examined with RT‑qPCR, and CD86, CD163 and phagocytosis was measured with flow cytometry. The ROC curves showed that decreased hyodeoxycholic acid (HDCA) and deoxycholic acid (DCA) levels were associated with infection. HDCA or DCA combined with LPS enhanced the phagocytic and migratory ability of macrophages, accompanied by upregulation of iNOS and CD86 protein expression as well as , , and mRNA expression. However, neither HDCA nor DCA alone showed an effect on these phenotypes. In addition, DCA and HDCA acted synergistically with LPS to increase the expression of p‑IκBα and the intranuclear migration of p65. Infection changed the bile acid profile in patients with cirrhosis, among which the reduction of DCA and HDCA associated most strongly with infection. HDCA and DCA enhanced the sensitivity of macrophage function loss to LPS stimulation. These findings suggested a potential role for monitoring the bile acid profile that could help manage patients with cirrhosis and infection.
Topics: Humans; Liver Cirrhosis; Macrophage Activation; Bile Acids and Salts; Male; Female; Middle Aged; Mice; RAW 264.7 Cells; Animals; Macrophages; Lipopolysaccharides; THP-1 Cells; Adult; Aged; Phagocytosis; Cytokines; Cell Movement
PubMed: 38963032
DOI: 10.3892/mmr.2024.13274 -
Advanced Science (Weinheim,... Jul 2024Novel antimicrobial strategies are urgently needed to treat extensively drug-resistant (XDR) bacterial infections due to the high mortality rate and lack of effective...
Novel antimicrobial strategies are urgently needed to treat extensively drug-resistant (XDR) bacterial infections due to the high mortality rate and lack of effective therapeutic agents. Herein, nanoengineered human umbilical cord mesenchymal stem cells (hUC-MSCs), named PMZMU, are designed as a sonosensitizer for synergistic sonodynamic-nano-antimicrobial therapy against gram-negative XDR bacteria. PMZMU is composed of a bacterial targeting peptide (UBI) modified hUC-MSCs membrane (MSCm), a sonosensitizer meso-tetra(4-car-boxyphenyl) porphine doped mesoporous organo-silica nanoparticle and an acidity-responsive metal-organic framework ZIF-8. This innovative formulation enables efficient loading of polymyxin B, reduces off-target drug release, increases circulation and targeting efficacy, and generates reactive oxygen species upon ultrasound irradiation. PMZMU exhibits remarkable in vitro inhibitory activity against four XDR bacteria: Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa (PA), and Escherichia coli. Taking advantage of the bacterial targeting ability of UBI and the inflammatory chemotaxis of hUC-MSC, PMZMU can be precisely delivered to lung infection sites thereby augmenting polymyxin B concentration. PMZMU-mediated sonodynamic therapy significantly reduces bacterial burden, relieves inflammatory damage by promoting the polarization of macrophages toward M phenotype, and improves survival rates without introducing adverse events. Overall, this study offers promising strategies for treating deep-tissue XDR bacterial infections, and guides the design and optimization of biomimetic nanomedicine.
PubMed: 38962911
DOI: 10.1002/advs.202402473 -
Frontiers in Veterinary Science 2024Porcine reproductive and respiratory syndrome (PRRS) caused by the PRRS virus (PRRSV) has been harming the pig industry worldwide for nearly 40 years. Although...
Porcine reproductive and respiratory syndrome (PRRS) caused by the PRRS virus (PRRSV) has been harming the pig industry worldwide for nearly 40 years. Although scientific researchers have made substantial efforts to explore PRRSV pathogenesis, the immune factors influencing PRRSV infection still need to be better understood. Infectious virus-antibody immune complexes (ICs) formed by PRRSV and sub-or non-neutralizing antibodies specific for PRRSV may significantly promote the development of PRRS by enhancing PRRSV replication through antibody-dependent enhancement. However, nothing is known about whether PRRSV infection is affected by non-infectious ICs (NICs) formed by non-pathogenic/infectious antigens and corresponding specific antibodies. Here, we found that PRRSV significantly induced the transcripts and proteins of interferon-α (IFN-α), IFN-β, IFN-γ, IFN-λ1, and tumor necrosis factor-α (TNF-α) primary porcine alveolar macrophages (PAMs) in the early stage of infection. Our results showed that NICs formed by rabbit-negative IgG (RNI) and pig anti-RNI specific IgG significantly reduced the transcripts and proteins of IFN-α, IFN-β, IFN-γ, IFN-λ1, and TNF-α PAMs and significantly elevated the transcripts and proteins of interleukine-10 (IL-10) and transforming growth factor-β1 (TGF-β1) PAMs. NICs-mediated PRRSV infection showed that NICs not only significantly decreased the induction of IFN-α, IFN-β, IFN-γ, IFN-λ1, and TNF-α by PRRSV but also significantly increased the induction of IL-10 and TGF-β1 by PRRSV and considerably enhanced PRRSV replication PAMs. Our data suggested that NICs could downregulate the production of antiviral cytokines (IFN-α/β/γ/λ1 and TNF-α) during PRRSV infection and facilitated PRRSV proliferation in its host cells by inhibiting innate antiviral immune response. This study elucidated one novel immune response to PRRSV infection, which would enhance our understanding of the pathogenesis of PRRSV.
PubMed: 38962699
DOI: 10.3389/fvets.2024.1420466