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Antibiotics (Basel, Switzerland) May 2024Gum arabic, a polysaccharide exudate from (L.) Willdenow trees, has already been used by African native people in natural medicine.
BACKGROUND
Gum arabic, a polysaccharide exudate from (L.) Willdenow trees, has already been used by African native people in natural medicine.
METHODS
Using whole-blood samples from young (20-35 years) and older (>80 years) healthy volunteers (each group n = 10), the effect of an aqueous solution of GA on phagocytosis of was examined with a gentamicin protection assay. Whole-blood samples of each volunteer were stimulated with GA and as a control with CpG oligodeoxynucleotides (Toll-like receptor -9 agonists) for 2 h, then co-incubated with for 30 min and thereafter treated with gentamicin for up to 240 min to kill extracellular bacteria. Then, whole-blood cells were lysed with distilled water, and colony-forming units were counted by quantitative plating. Cytokine enzyme-linked immunosorbent assay for the detection of TNF-α and IL-6 was performed using the blood supernatant.
RESULTS
The GA concentration tested (20 mg/mL) did not affect the viability of eukaryotic cells. Phagocytosis of by whole-blood leukocytes derived from young ( = 0.008) and older ( = 0.004) healthy volunteers was increased by 120.8% (young) and 39.2% (old) after stimulation with GA. In contrast, CpG only stimulated the bacterial phagocytosis by cells derived from young volunteers ( = 0.004). Stimulation of whole blood with GA increased the intracellular killing of in young ( = 0.045) and older volunteers ( = 0.008) and induced a TNF-α release in whole blood collected from older volunteers but not from younger ones ( = 0.008).
CONCLUSIONS
These data encourage the isolation of active compounds of GA and the initiation of clinical trials addressing the preventive effect of GA on bacterial infections.
PubMed: 38927149
DOI: 10.3390/antibiotics13060482 -
Biomolecules Jun 2024Intracerebral hemorrhage (ICH) is a life-threatening condition associated with significant morbidity and mortality. This study investigates transcriptomic alterations in...
Intracerebral hemorrhage (ICH) is a life-threatening condition associated with significant morbidity and mortality. This study investigates transcriptomic alterations in rodent models of ICH and severe ICH to shed light on the genetic pathways involved in hemorrhagic brain injury. We performed principal component analysis, revealing distinct principal component segments of normal rats compared to ICH and severe ICH rats. We employed heatmaps and volcano plots to identify differentially expressed genes and utilized bar plots and KEGG pathway analysis to elucidate the molecular pathways involved. We identified a multitude of differentially expressed genes in both the ICH and severe ICH models. Our results revealed 5679 common genes among the normal, ICH, and severe ICH groups in the upregulated genes group, and 1196 common genes in the downregulated genes, respectively. A volcano plot comparing these groups further highlighted common genes, including PDPN, TIMP1, SERPINE1, TUBB6, and CD44. These findings underscore the complex interplay of genes involved in inflammation, oxidative stress, and neuronal damage. Furthermore, pathway enrichment analysis uncovered key signaling pathways, including the TNF signaling pathway, protein processing in the endoplasmic reticulum, MAPK signaling pathway, and Fc gamma R-mediated phagocytosis, implicated in the pathogenesis of ICH.
Topics: Animals; Cerebral Hemorrhage; Rats; Disease Models, Animal; Transcriptome; Male; Rats, Sprague-Dawley; Gene Expression Profiling; Signal Transduction; Gene Expression Regulation; Principal Component Analysis
PubMed: 38927081
DOI: 10.3390/biom14060678 -
Journal For Immunotherapy of Cancer Jun 2024The majority of anti-programmed cell-death 1 (PD-1) monoclonal antibodies (mAbs) use SP mutation IgG4 as the structural basis to avoid the activation of immune cells or...
BACKGROUND
The majority of anti-programmed cell-death 1 (PD-1) monoclonal antibodies (mAbs) use SP mutation IgG4 as the structural basis to avoid the activation of immune cells or complement. However, little attention has been paid to the Fc-Fc interactions between IgG4 and other IgG Fc fragments that could result in adverse effects. Fc-null IgG1 framework is a potential safer alternative to avoid the undesirable Fc-Fc interactions and Fc receptor binding derived effects observed with IgG4. This study provides a comprehensive evaluation of anti-PD-1 mAbs of these two frameworks.
METHODS
Trastuzumab and rituximab (both IgG1), wildtype IgG1 and IgG4 were immobilized on nitrocellulose membranes, coated to microplates and biosensor chips, and bound to tumor cells as targets for Fc-Fc interactions. Wildtype IgG1 and IgG4, anti-PD-1 mAb nivolumab (IgG4 SP), penpulimab (Fc-null IgG1), and tislelizumab (Fc-null IgG4 SP-RK) were assessed for their binding reactions to the immobilized IgG proteins and quantitative kinetic data were obtained. To evaluate the effects of the two anti-PD-1 mAbs on immune responses mediated by trastuzumab and rituximab in the context of combination therapy, we employed classic immune models for antibody-dependent cellular cytotoxicity, antibody-dependent cellular phagocytosis, and complement dependent cytotoxicity. Tumor-bearing mouse models, both wildtype and humanized, were used for in vivo investigation. Furthermore, we also examined the effects of IgG1 and IgG4 on diverse immune cell populations RESULTS: Experiments demonstrated that wildtype IgG4 and nivolumab bound to immobilized IgG through Fc-Fc interactions, diminishing antibody-dependent cell-mediated cytotoxicity and phagocytosis reactions. Quantitative analysis of kinetic parameters suggests that nivolumab and wildtype IgG4 exhibit comparable binding affinities to immobilized IgG1 in both non-denatured and denatured states. IgG4 exerted inhibitory effects on various immune cell types. Wildtype IgG4 and nivolumab both promoted tumor growth in wildtype mouse models. Conversely, wildtype IgG1, penpulimab, and tislelizumab did not show similar adverse effects.
CONCLUSIONS
Fc-null IgG1 represents a safer choice for anti-PD-1 immunotherapies by avoiding both the adverse Fc-Fc interactions and Fc-related immune inhibitory effects of IgG4. Fc-null IgG4 SP-RK and Fc-null IgG1 displayed similar structural properties and benefits. This study contributes to the understanding of immunotherapy resistance and the advancement of safer immune therapies for cancer.
Topics: Immunoglobulin G; Animals; Mice; Humans; Immunotherapy; Immunoglobulin Fc Fragments; Female; Programmed Cell Death 1 Receptor
PubMed: 38925680
DOI: 10.1136/jitc-2024-009034 -
Developmental and Comparative Immunology Jun 2024An infection induces the migration of immune cells called hemocytes to the insect heart, where they aggregate around heart valves called ostia and phagocytose pathogens...
An infection induces the migration of immune cells called hemocytes to the insect heart, where they aggregate around heart valves called ostia and phagocytose pathogens in areas of high hemolymph flow. Here, we investigated whether the cardiac extracellular matrix proteins, pericardin (Prc) and lonely heart (Loh), regulate the infection-induced aggregation of periostial hemocytes in the mosquito, An. gambiae. We discovered that RNAi-based post-transcriptional silencing of Prc or Loh did not affect the resident population of periostial hemocytes in uninfected mosquitoes, but that knocking down these genes decreases the infection-induced migration of hemocytes to the heart. Knocking down Prc or Loh did not affect the proportional distribution of periostial hemocytes along the periostial regions. Moreover, knocking down Prc or Loh did not affect the number of sessile hemocytes outside the periostial regions, suggesting that the role of these proteins is cardiac-specific. Finally, knocking down Prc or Loh did not affect the amount of melanin at the periostial regions, or the intensity of an infection at 24 hr after challenge. Overall, we demonstrate that Prc and Loh are positive regulators of the infection-induced migration of hemocytes to the heart of mosquitoes.
PubMed: 38925431
DOI: 10.1016/j.dci.2024.105219 -
Proceedings of the National Academy of... Jul 2024The non-neural cholinergic system plays a critical role in regulating immune equilibrium and tissue homeostasis. While the expression of choline acetyltransferase...
The non-neural cholinergic system plays a critical role in regulating immune equilibrium and tissue homeostasis. While the expression of choline acetyltransferase (ChAT), the enzyme catalyzing acetylcholine biosynthesis, has been well documented in lymphocytes, its role in the myeloid compartment is less understood. Here, we identify a significant population of macrophages (Mϕs) expressing ChAT and synthesizing acetylcholine in the resolution phase of acute peritonitis. Using -GFP reporter mice, we observed marked upregulation of ChAT in monocyte-derived small peritoneal Mϕs (SmPMs) in response to Toll-like receptor agonists and bacterial infections. These SmPMs, phenotypically and transcriptionally distinct from tissue-resident large peritoneal macrophages, up-regulated ChAT expression through a MyD88-dependent pathway involving MAPK signaling. Notably, this process was attenuated by the TRIF-dependent TLR signaling pathway, and our tests with a range of neurotransmitters and cytokines failed to induce a similar response. Functionally, deficiency in Mϕs led to significantly decreased peritoneal acetylcholine levels, reduced efferocytosis of apoptotic neutrophils, and a delayed resolution of peritonitis, which were reversible with exogenous ACh supplementation. Intriguingly, despite B lymphocytes being a notable ChAT-expressing population within the peritoneal cavity, deletion in B cells did not significantly alter the resolution process. Collectively, these findings underscore the crucial role of Mϕ-derived acetylcholine in the resolution of inflammation and highlight the importance of the non-neuronal cholinergic system in immune regulation.
Topics: Animals; Choline O-Acetyltransferase; Peritonitis; Mice; Macrophages, Peritoneal; Acetylcholine; Myeloid Differentiation Factor 88; Mice, Inbred C57BL; Signal Transduction; Inflammation; B-Lymphocytes; Toll-Like Receptors; Phagocytosis; Macrophages; Mice, Knockout
PubMed: 38923993
DOI: 10.1073/pnas.2402143121 -
Cancer Communications (London, England) Jun 2024Phagocytosis, a vital defense mechanism, involves the recognition and elimination of foreign substances by cells. Phagocytes, such as neutrophils and macrophages,... (Review)
Review
Phagocytosis, a vital defense mechanism, involves the recognition and elimination of foreign substances by cells. Phagocytes, such as neutrophils and macrophages, rapidly respond to invaders; macrophages are especially important in later stages of the immune response. They detect "find me" signals to locate apoptotic cells and migrate toward them. Apoptotic cells then send "eat me" signals that are recognized by phagocytes via specific receptors. "Find me" and "eat me" signals can be strategically harnessed to modulate antitumor immunity in support of cancer therapy. These signals, such as calreticulin and phosphatidylserine, mediate potent pro-phagocytic effects, thereby promoting the engulfment of dying cells or their remnants by macrophages, neutrophils, and dendritic cells and inducing tumor cell death. This review summarizes the phagocytic "find me" and "eat me" signals, including their concepts, signaling mechanisms, involved ligands, and functions. Furthermore, we delineate the relationships between "find me" and "eat me" signaling molecules and tumors, especially the roles of these molecules in tumor initiation, progression, diagnosis, and patient prognosis. The interplay of these signals with tumor biology is elucidated, and specific approaches to modulate "find me" and "eat me" signals and enhance antitumor immunity are explored. Additionally, novel therapeutic strategies that combine "find me" and "eat me" signals to better bridge innate and adaptive immunity in the treatment of cancer patients are discussed.
PubMed: 38923737
DOI: 10.1002/cac2.12579 -
Traffic (Copenhagen, Denmark) Jun 2024Processes such as cell migration, phagocytosis, endocytosis, and exocytosis refer to the intense exchange of information between the internal and external environment in... (Review)
Review
Processes such as cell migration, phagocytosis, endocytosis, and exocytosis refer to the intense exchange of information between the internal and external environment in the cells, known as vesicular trafficking. In eukaryotic cells, these essential cellular crosstalks are controlled by Rab GTPases proteins through diverse adaptor proteins like SNAREs complex, coat proteins, phospholipids, kinases, phosphatases, molecular motors, actin, or tubulin cytoskeleton, among others, all necessary for appropriate mobilization of vesicles and distribution of molecules. Considering these molecular events, Rab GTPases are critical components in specific biological processes of immune cells, and many reports refer primarily to macrophages; therefore, in this review, we address specific functions in immune cells, concretely in the mechanism by which the GTPase contributes in dendritic cells (DCs) and, T/B lymphocytes.
Topics: Humans; rab GTP-Binding Proteins; Animals; T-Lymphocytes; Dendritic Cells; Antigen-Presenting Cells
PubMed: 38923715
DOI: 10.1111/tra.12950 -
Microbiology and Immunology Jun 2024The tumor microenvironment of hepatoblastoma (HB), the most common pediatric liver tumor, predominantly exhibits a myeloid immune landscape. in which tumor-associated... (Review)
Review
The tumor microenvironment of hepatoblastoma (HB), the most common pediatric liver tumor, predominantly exhibits a myeloid immune landscape. in which tumor-associated macrophages (TAMs) are considered the core component. The crosstalk between TAMs and HB cells markedly influences tumor behavior. TAM-derived factors are involved in tumor proliferation and vascular invasion. On the other hand, HB cell secretome attracts, stimulates, and reprograms TAMs to be immunosuppressive in favor of tumor invasion, rather than their innate role in combating tumor growth, such crosstalk sometimes forms bidirectional feedback loops, making the tumor more virulent and resistant to routine therapeutics. Consequently, TAMs are the common denominator of most suggested HB immunotherapeutic strategies. Macrophage immune checkpoint inhibitors, macrophage-mediated antibody-dependent cellular phagocytosis, and the novel chimeric antigen receptor macrophage therapy (CAR Mφ) are currently under trial. In this review, we will summarize the significance of TAMs and their potential role as a therapeutic target in HB.
PubMed: 38923004
DOI: 10.1111/1348-0421.13162 -
Pathogens (Basel, Switzerland) May 2024Coronavirus frequently infects humans and animals, showing the ability to recombine and cross over to different species. Cats can be considered a model for studying...
Coronavirus frequently infects humans and animals, showing the ability to recombine and cross over to different species. Cats can be considered a model for studying coronavirus infection, in which feline coronavirus (FCoV) represents a major enteric pathogen related to gastroenteric disease. In this animal, the virus can acquire tropism for macrophage cells, leading to a deadly disease called feline infectious peritonitis (FIP). In this study, monocyte-derived macrophages were isolated by CD14-positive selection in venous whole blood from 26 cats with FIP and 32 FCoV-positive healthy cats. Phagocytosis and respiratory burst activities were investigated and compared between the groups. This is the first study comparing macrophage activity in cats affected by FIP and healthy cats positive for FCoV infection. Our results showed that in cats with FIP, the phagocytic and respiratory burst activities were significantly lower. Our results support the possible role of host immunity in Coronaviridae pathogenesis in cats, supporting future research on the immune defense against this systemic disease.
PubMed: 38921735
DOI: 10.3390/pathogens13060437 -
Metabolites May 2024Acute inflammation is the body's first defense in response to pathogens or injury that is partially governed by a novel genus of endogenous lipid mediators that... (Review)
Review
Acute inflammation is the body's first defense in response to pathogens or injury that is partially governed by a novel genus of endogenous lipid mediators that orchestrate the resolution of inflammation, coined specialized pro-resolving mediators (SPMs). SPMs, derived from omega-3-polyunstaturated fatty acids (PUFAs), include the eicosapentaenoic acid-derived and docosahexaenoic acid-derived Resolvins, Protectins, and Maresins. Herein, we review their biosynthesis, structural characteristics, and therapeutic effectiveness in various diseases such as ischemia, viral infections, periodontitis, neuroinflammatory diseases, cystic fibrosis, lung inflammation, herpes virus, and cancer, especially focusing on therapeutic effectiveness in respiratory inflammation and ischemia-related injuries. Resolvins are sub-nanomolar potent agonists that accelerate the resolution of inflammation by reducing excessive neutrophil infiltration, stimulating macrophage functions including phagocytosis, efferocytosis, and tissue repair. In addition to regulating neutrophils and macrophages, Resolvins control dendritic cell migration and T cell responses, and they also reduce the pro-inflammatory cytokines, proliferation, and metastasis of cancer cells. Importantly, several lines of evidence have demonstrated that Resolvins reduce tumor progression in melanoma, oral squamous cell carcinoma, lung cancer, and liver cancer. In addition, Resolvins enhance tumor cell debris clearance by macrophages in the tumor's microenvironment. Resolvins, with their unique stereochemical structure, receptors, and biosynthetic pathways, provide a novel therapeutical approach to activating resolution mechanisms during cancer progression.
PubMed: 38921449
DOI: 10.3390/metabo14060314