RESUMO
Addressing the mononuclear phagocyte system (MPS) and macrophage M1/M2 activation is important in diagnosing hematological disorders and inflammatory pathologies and designing therapeutic tools. CSF1R is a reliable marker to identify all circulating MPS cells and tissue macrophages in humans using a single surface protein. CSF1R permits the quantification and isolation of monocyte and dendritic cell (DC) subsets in conjunction with CD14, CD16, and CD1c and is stable across the lifespan and sexes in the absence of overt pathology. Beyond cell detection, measuring M1/M2 activation in humans poses challenges due to response heterogeneity, transient signaling, and multiple regulation steps for transcripts and proteins. MPS cells respond in a conserved manner to M1/M2 pathways such as interleukin-4 (IL-4), steroids, interferon-γ (IFNγ), and lipopolysaccharide (LPS), for which we propose an ad hoc modular gene expression tool. Signature analysis highlights macrophage activation mosaicism in experimental samples, an emerging concept that points to mixed macrophage activation states in pathology.
Assuntos
Ativação de Macrófagos , Macrófagos , Receptores de Fator Estimulador das Colônias de Granulócitos e Macrófagos , Humanos , Ativação de Macrófagos/genética , Macrófagos/metabolismo , Macrófagos/imunologia , Receptores de Fator Estimulador das Colônias de Granulócitos e Macrófagos/metabolismo , Receptores de Fator Estimulador das Colônias de Granulócitos e Macrófagos/genética , Interferon gama/metabolismo , Lipopolissacarídeos/farmacologia , Feminino , Mosaicismo , Masculino , Monócitos/metabolismo , Receptores de Lipopolissacarídeos/metabolismo , Interleucina-4/metabolismo , Células Dendríticas/metabolismo , Células Dendríticas/imunologia , Receptores de IgG/metabolismo , Receptores de IgG/genética , Antígenos CD1/metabolismo , Antígenos CD1/genética , Sistema Fagocitário Mononuclear/metabolismo , Glicoproteínas , Receptor de Fator Estimulador de Colônias de MacrófagosRESUMO
Nanoparticle-based drug delivery systems have emerged as promising platforms for enhancing therapeutic efficacy while minimizing off-target effects. Among various strategies employed to optimize these systems, polyethylene glycol (PEG) modification, known as PEGylation-the covalent attachment of PEG to nanoparticles, has gained considerable attention for its ability to impart stealth properties to nanoparticles while also extending circulation time and improving biocompatibility. PEGylation extends to different drug delivery systems, in specific, nanoparticles for targeting cancer cells, where the concentration of drug in the cancer cells is improved by virtue of PEGylation. The primary challenge linked to PEGylation lies in its confirmation. Numerous research findings provide comprehensive insights into selecting PEG for various PEGylation methods. In this review, we have endeavored to consolidate the outcomes concerning the choice of PEG and diverse PEGylation techniques.
Assuntos
Lipídeos , Nanopartículas , Polietilenoglicóis , Polietilenoglicóis/química , Nanopartículas/química , Humanos , Lipídeos/química , Sistemas de Liberação de Medicamentos , AnimaisRESUMO
Most nanomedicines require efficient in vivo delivery to elicit diagnostic and therapeutic effects. However, en route to their intended tissues, systemically administered nanoparticles often encounter delivery barriers. To describe these barriers, we propose the term "nanoparticle blood removal pathways" (NBRP), which summarizes the interactions between nanoparticles and the body's various cell-dependent and cell-independent blood clearance mechanisms. We reviewed nanoparticle design and biological modulation strategies to mitigate nanoparticle-NBRP interactions. As these interactions affect nanoparticle delivery, we studied the preclinical literature from 2011-2021 and analyzed nanoparticle blood circulation and organ biodistribution data. Our findings revealed that nanoparticle surface chemistry affected the in vivo behavior more than other nanoparticle design parameters. Combinatory biological-PEG surface modification improved the blood area under the curve by ~418%, with a decrease in liver accumulation of up to 47%. A greater understanding of nanoparticle-NBRP interactions and associated delivery trends will provide new nanoparticle design and biological modulation strategies for safer, more effective, and more efficient nanomedicines.
RESUMO
Histiocytic and dendritic cell neoplasms comprise diverse tumors originating from the mononuclear phagocytic system, which includes monocytes, macrophages, and dendritic cells. The 5th edition of the World Health Organization (WHO) classification updating the categorization of these tumors, reflecting a deeper understanding of their pathogenesis.In this updated classification system, tumors are categorized as Langerhans cell and other dendritic cell neoplasms, histiocyte/macrophage neoplasms, and plasmacytoid dendritic cell neoplasms. Follicular dendritic cell neoplasms are classified as mesenchymal dendritic cell neoplasms within the stroma-derived neoplasms of lymphoid tissues.Each subtype of histiocytic and dendritic cell neoplasms exhibits distinct morphological characteristics. They also show a characteristic immunophenotypic profile marked by various markers such as CD1a, CD207/langerin, S100, CD68, CD163, CD4, CD123, CD21, CD23, CD35, and ALK, and hematolymphoid markers such as CD45 and CD43. In situ hybridization for EBV-encoded small RNA (EBER) identifies a particular subtype. Immunoprofiling plays a critical role in determining the cell of origin and identifying the specific subtype of tumors. There are frequent genomic alterations in these neoplasms, especially in the mitogen-activated protein kinase pathway, including BRAF (notably BRAF V600E), MAP2K1, KRAS, and NRAS mutations, and ALK gene translocation.This review aims to offer a comprehensive and updated overview of histiocytic and dendritic cell neoplasms, focusing on their ontogeny, morphological aspects, immunophenotypic profiles, and molecular genetics. This comprehensive approach is essential for accurately differentiating and classifying neoplasms according to the updated WHO classification.
RESUMO
Nanoparticle-mediated drug delivery has emerged as a highly promising and effective therapeutic approach for addressing myocardial infarction. However, clinical translation tends to be a failure due to low cardiac retention as well as liver and spleen entrapment in previous therapies. Herein, we report a two-step exosome delivery system, which precludes internalization by the mononuclear phagocyte system before the delivery of therapeutic cardiac targeting exosomes (ExoCTP). Importantly, curcumin released by ExoCTP diminishes reactive oxygen species over-accumulation in ischemic myocardium, as well as serum levels of lactate dehydrogenase, malonyldialdehyde, superoxide dismutase and glutathione, indicating better antioxidant capacity than free curcumin. Finally, our strategy was proven to greatly potentiate the delivery and therapeutic efficacy of curcumin without systemic toxicity. Taken together, our smart exosome-mediated drug delivery strategy can serve either as therapeutics alone or in combination with other drugs for effective heart targeting and subsequent wound healing.
RESUMO
BACKGROUND: Recent research reported that mononuclear phagocyte system (MPS) can contribute to immune defense but the classification of head and neck squamous cell carcinoma (HNSCC) patients based on MPS-related multi-omics features using machine learning lacked. METHODS: In this study, we obtain marker genes for MPS through differential analysis at the single-cell level and utilize "similarity network fusion" and "MoCluster" algorithms to cluster patients' multi-omics features. Subsequently, based on the corresponding clinical information, we investigate the prognosis, drugs, immunotherapy, and biological differences between the subtypes. A total of 848 patients have been included in this study, and the results obtained from the training set can be verified by two independent validation sets using "the nearest template prediction". RESULTS: We identified two subtypes of HNSCC based on MPS-related multi-omics features, with CS2 exhibiting better predictive prognosis and drug response. CS2 represented better xenobiotic metabolism and higher levels of T and B cell infiltration, while the biological functions of CS1 were mainly enriched in coagulation function, extracellular matrix, and the JAK-STAT signaling pathway. Furthermore, we established a novel and stable classifier called "getMPsub" to classify HNSCC patients, demonstrating good consistency in the same training set. External validation sets classified by "getMPsub" also illustrated similar differences between the two subtypes. CONCLUSIONS: Our study identified two HNSCC subtypes by machine learning and explored their biological difference. Notably, we constructed a robust classifier that presented an excellent classifying prediction, providing new insight into the precision medicine of HNSCC.
Assuntos
Neoplasias de Cabeça e Pescoço , Multiômica , Humanos , Carcinoma de Células Escamosas de Cabeça e Pescoço/genética , Carcinoma de Células Escamosas de Cabeça e Pescoço/terapia , Sistema Fagocitário Mononuclear , Imunoterapia , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Neoplasias de Cabeça e Pescoço/genética , Prognóstico , Microambiente TumoralRESUMO
Objective To explore the cell subsets and characteristics related to the prognosis of osteosarcoma by analyzing the cellular composition of tumor tissue samples from different osteosarcoma patients.Methods The single-cell sequencing data and bulk sequencing data of different osteosarcoma patients were downloaded.We extracted the information of cell samples for dimensionality reduction,annotation,and cell function analysis,so as to identify the cell subsets and clarify the cell characteristics related to the prognosis of osteosarcoma.The development trajectory of macrophages with prognostic significance was analyzed,and the prognostic model of osteosarcoma was established based on the differentially expressed genes of macrophage differentiation.Results The cellular composition presented heterogeneity in the patients with osteosarcoma.The infiltration of mononuclear phagocytes in osteosarcoma had prognostic significance(P=0.003).Four macrophage subsets were associated with prognosis,and their signature transcription factors included RUNX3(+),ETS1(+),HOXD11(+),ZNF281(+),and PRRX1(+).Prog_Macro2 and Prog_Macro4 were located at the end of the developmental trajectory,and the prognostic ability of macrophage subsets increased with the progression of osteosarcoma.The prognostic model established based on the differentially expressed genes involved in macrophage differentiation can distinguish the survival rate of osteosarcoma patients with different risks(P<0.001).Conclusion Macrophage subsets are closely related to the prognosis of osteosarcoma and can be used as the key target cells for the immunotherapy of osteosarcoma.
Assuntos
Neoplasias Ósseas , Osteossarcoma , Humanos , Prognóstico , Osteossarcoma/genética , Imunoterapia , Macrófagos , Fatores de Transcrição , Neoplasias Ósseas/genética , Proteínas de Homeodomínio , Proteínas RepressorasRESUMO
Dynamin II (dynII) plays a significant role in the internalization pathways of endocytic cells, by allowing membrane invaginations to "bud off". An important class of dynII inhibitors that are used clinically are phenothiazines, such as prochlorperazine (PCZ). PCZ is an antipsychotic drug but is also currently in clinical trials at higher concentrations as an adjuvant in cancer patients that increases the efficacy of monoclonal antibodies at high intravenous doses. It is unknown, however, whether high-dose dynII inhibitors have the potential to alter the pharmacokinetics of co-administered chemotherapeutic nanomedicines that are largely cleared via the mononuclear phagocyte system. This work therefore sought to investigate the impact of clinically relevant concentrations of phenothiazines, PCZ and thioridazine, on in vitro liposome endocytosis and in vivo liposome pharmacokinetics after PCZ infusion in rats. The uptake of fluorescently labeled PEGylated liposomes into differentiated and undifferentiated THP-1 and RAW246.7 cells, and primary human peripheral white blood cells, was investigated via flow cytometry after co-incubation with dynII inhibitors. The IV pharmacokinetics of PEGylated liposomes were also investigated in rats after a 20 min infusion with PCZ. Phenothiazines and dyngo4a reduced the uptake of PEGylated liposomes by THP-1 and RAW264.7 cells in a concentration-dependent manner in vitro. However, dynII inhibitors did not alter the mean uptake of liposomes by human peripheral white blood cells, but endocytic white cells from some donors exhibited sensitivity to phenothiazine exposure. When a clinically relevant dose of PCZ was co-administered with PEGylated liposomal doxorubicin (Caelyx/Doxil) in rats, the pharmacokinetics and biodistribution of liposomes were unaltered. These data suggest that while clinically relevant doses of dynII inhibitors can inhibit the uptake of liposomes by endocytic cells in vitro, they are unlikely to significantly affect the pharmacokinetics of long-circulating, co-administered liposomes.
Assuntos
Dinamina II , Lipossomos , Ratos , Humanos , Animais , Distribuição Tecidual , Doxorrubicina , Polietilenoglicóis , Fenotiazinas , ProclorperazinaRESUMO
Although the "multiple hits" theory is a widely accepted pathogenesis in IgA nephropathy (IgAN), increasing evidence suggests that the mononuclear/macrophage system plays important roles in the progression of IgAN; however, the exact mechanism is unclear. In the present study, we explored 1,067 patients in 15 studies and found that the number of macrophages per glomerulus was positively related with the degree of hematuria, and the macrophages in the glomeruli were mainly related to mesangial proliferation (M) in renal biopsy. In the tubulointerstitium, macrophages were significantly paralleled to tubulointerstitial α-SMA and NF-kB expression, tubulointerstitial lesion, tubule atrophy/interstitial fibrosis (T), and segmental glomerulosclerosis (S). In the glomeruli and tubulointerstitium, M1 accounted for 85.41% in the M classification according to the Oxford MEST-C, while in the blood, M1 accounted for 100%, and the patients with low CD89+ monocyte mean fluorescence intensity displayed more severe pathological characteristics (S1 and T1-2) and clinical symptoms. M1 (CD80+) macrophages were associated with proinflammation in the acute phase; however, M2 (CD163+) macrophages participated in tissue repair and remodeling, which correlated with chronic inflammation. In the glomeruli, M2 macrophages activated glomerular matrix expansion by secreting cytokines such as IL-10 and tumor necrosis factor-ß (TGF-ß), and M0 (CD68+) macrophages stimulated glomerular hypercellularity. In the tubulointerstitium, M2 macrophages played pivotal roles in renal fibrosis and sclerosis. It is assumed that macrophages acted as antigen-presenting cells to activate T cells and released diverse cytokines to stimulate an inflammatory response. Macrophages infiltrating glomeruli destroy the integrity of podocytes through the mesangio-podocytic-tubular crosstalk as well as the injury of the tubule.
Assuntos
Glomerulonefrite por IGA , Glomerulosclerose Segmentar e Focal , Humanos , Glomerulonefrite por IGA/patologia , Glomerulosclerose Segmentar e Focal/patologia , Prognóstico , Macrófagos/metabolismo , CitocinasRESUMO
At present, extracellular vesicles (EVs) are considered key candidates for cell-free therapies, including treatment of allergic and autoimmune diseases. However, their therapeutic effectiveness, dependent on proper targeting to the desired cells, is significantly limited due to the reduced bioavailability resulting from their rapid clearance by the cells of the mononuclear phagocyte system (MPS). Thus, developing strategies to avoid EV elimination is essential when applying them in clinical practice. On the other hand, malfunctioning MPS contributes to various immune-related pathologies. Therapeutic reversal of these effects with EVs would be beneficial and could be achieved, for example, by modulating the macrophage phenotype or regulating antigen presentation by dendritic cells. Additionally, intended targeting of EVs to MPS macrophages for replication and repackaging of their molecules into new vesicle subtype can allow for their specific targeting to appropriate populations of acceptor cells. Herein, we briefly discuss the under-explored aspects of the MPS-EV interactions that undoubtedly require further research in order to accelerate the therapeutic use of EVs.
RESUMO
BACKGROUND: The "mononuclear phagocyte system" (MPS) refers to dispersed mononuclear monocytes and macrophages and is used to distinguish them from polymorphonuclear cells. The term "histiocyte" indicates large cells with voluminous granulated cytoplasm, sometimes containing engulfed particles, recognized as fully differentiated end cells of the MPS. Dendritic cells (DC) represent another diversified population whose inclusion in the MPS is still debated. The diverse cells of the MPS cannot all be characterized by single antigen markers or unique functions expressed at all stages of cell differentiation or activation. Nevertheless, in a diagnostic setting, their reliable identification plays a major role when a specific therapy must be established. Understanding the heterogeneity among MPS cell populations is indeed relevant to define different therapeutic approaches that can range from the use of antibiotics to immunomodulatory agents. For this reason, we attempted to establish a protocol to reliably identify the proportion of macrophages within the mononuclear phagocyte system in a tissue and/or in a given inflammatory population. METHODS: the Tafuri method was used in different double immunofluorescence protocols using an anti-Iba-1, anti-MAC387, and anti-CD11b-CD68-CD163-CD14-CD16 antibody. RESULTS AND DISCUSSION: in normal canine skin the anti-Iba-1 antibody stained an epidermal cell population (i.e. Langerhans cells) and scattered cells within the dermal compartment. MAC387 was unable to stain cells containing Leishmania amastigotes in leishmaniasis-diagnosed samples as the anti-CD11b-CD68-CD163-CD14-CD16 antibody did. By using a combination of staining protocols to differentiate macrophages within the whole histiocytic infiltrate we validated the use of a cocktail of rabbit monoclonal antibodies raised against CD11b, CD68, CD163, CD14, CD16 to stain skin macrophages.
Assuntos
Macrófagos , Monócitos , Animais , Cães , Diferenciação Celular , Anticorpos Monoclonais , ImunofluorescênciaRESUMO
Extended circulation of anticancer nanodrugs in blood stream is essential for their clinical applications. However, administered nanoparticles are rapidly sequestered and cleared by cells of the mononuclear phagocyte system (MPS). In this study, we developed a biomimetic nanosystem that is able to efficiently escape MPS and target tumor tissues. The fabricated nanoparticles (TM-CQ/NPs) were coated with fibroblast cell membrane expressing tumor necrosis factor (TNF)-related apoptosis inducing ligand (TRAIL). Coating with this functionalized membrane reduced the endocytosis of nanoparticles by macrophages, but increased the nanoparticle uptake in tumor cells. Importantly, this membrane coating specifically induced tumor cell apoptosis via the interaction of TRAIL and its cognate death receptors. Meanwhile, the encapsulated chloroquine (CQ) further suppressed the uptake of nanoparticles by macrophages, and synergized with TRAIL to induce tumor cell apoptosis. The vigorous antitumor efficacy in two mice tumor models confirmed our nanosystem was an effective approach to address the MPS challenge for cancer therapy. Together, our TM-CQ/NPs nanosystem provides a feasible approach to precisely target tumor tissues and improve anticancer efficacy.
RESUMO
Ischemic stroke (IS) is a major cause of disability and death in adults, and the immune response plays an indispensable role in its pathological process. After the onset of IS, an inflammatory storm, with the infiltration and mobilization of the mononuclear phagocyte system (MPS), is triggered in the brain. Microglia are rapidly activated in situ, followed by waves of circulating monocytes into the ischemic area. Activated microglia and monocytes/macrophages are mainly distributed in the peri-infarct area. These cells have similar morphology and functions, such as secreting cytokines and phagocytosis. Previously, the presence of the MPS was considered a marker of an exacerbated inflammatory response that contributes to brain damage. However, recent studies have suggested a rather complicated role of the MPS in IS. Here, we reviewed articles focusing on various functions of the MPS among different phases of IS, including recruitment, polarization, phagocytosis, angiogenesis, and interaction with other types of cells. Moreover, due to the characteristics of the MPS, we also noted clinical research addressing alterations in the MPS as potential biomarkers for IS patients for the purposes of predicting prognosis and developing novel therapeutic strategies.
Assuntos
AVC Isquêmico , Acidente Vascular Cerebral , Humanos , AVC Isquêmico/metabolismo , Sistema Fagocitário Mononuclear/metabolismo , Sistema Fagocitário Mononuclear/patologia , Macrófagos/metabolismo , Microglia/patologia , Monócitos , Acidente Vascular Cerebral/patologiaRESUMO
Targeted delivery of oligonucleotides or small molecular drugs to hepatocytes, the liver's parenchymal cells, is challenging without targeting moiety due to the highly efficient mononuclear phagocyte system (MPS) of the liver. The MPS comprises Kupffer cells and specialized sinusoidal endothelial cells, efficiently clearing nanocarriers regardless of their size and surface properties. Physiologically, this non-parenchymal shield protects hepatocytes; however, these local barriers must be overcome for drug delivery. Nanocarrier structural properties strongly influence tissue penetration, in vivo pharmacokinetics, and biodistribution profile. Here we demonstrate the in vivo biodistribution of polyplex micelles formed by polyion complexation of short interfering (si)RNA with modified poly(ethylene glycol)-block-poly(allyl glycidyl ether) (PEG-b-PAGE) diblock copolymer that carries amino moieties in the side chain. The ratio between PEG corona and siRNA complexed PAGE core of polyplex micelles was chemically varied by altering the degree of polymerization of PAGE. Applying Raman-spectroscopy and dynamic in silico modeling on the polyplex micelles, we determined the corona-core ratio (CCR) and visualized the possible micellar structure with varying CCR. The results for this model system reveal that polyplex micelles with higher CCR, i.e., better PEG coverage, exclusively accumulate and thus allow passive cell-type-specific targeting towards hepatocytes, overcoming the macrophage-rich reticuloendothelial barrier of the liver.
Assuntos
Micelas , Oligonucleotídeos , Distribuição Tecidual , Células Endoteliais , Polietilenoglicóis/química , RNA Interferente Pequeno/genética , HepatócitosRESUMO
Purpose: To study the uptake capacity of cells from the reticuloendothelial system after irradiation with high-energy X-rays. Methods: Eighteen male Wistar rats were distributed in three groups: group A (n = 6): control, unirradiated animals studied alongside animals from group B; group B (n = 6) and group C (n = 6): animals irradiated and studied after 24 and 48 hours, respectively. The rats were anesthetized and placed on a 10 MV linear accelerator. Next, they were irradiated in the abdominal region, with 8 Gy. Twenty-four (groups A and B) and 48 hours later (group C), a colloidal carbon solution (1 mL/kg) was intravenously injected in the tail vein. Fifty minutes later, the spleens and livers were withdrawn and prepared to be studied. Kupffer cells and splenic macrophages containing carbon pigments were counted in an optical microscope. Arithmetic means were calculated for each group and compared among them. Results: X-rays were associated with a reduced number of Kupffer cells containing colloidal carbon, proliferation and enlargement of biliary ducts, hypoplasia, and hepatocyte necrosis. In the irradiated spleen, the colloidal carbon uptake was concentrated in the marginal zone around the white pulp, with an inexpressive uptake of pigments by macrophages from white and red pulps. Conclusions: The X-rays in the rat abdomen are associated with a reduction in the Kupffer cells uptake of colloidal carbon, hepatocyte disorders, bile duct proliferation, and splenic uptake of colloidal carbon concentrated in the marginal zone.
Assuntos
Animais , Ratos , Sistema Fagocitário Mononuclear , Radioterapia de Alta Energia , Células de KupfferRESUMO
Objective To explore the cell subsets and characteristics related to the prognosis of osteosarcoma by analyzing the cellular composition of tumor tissue samples from different osteosarcoma patients.Methods The single-cell sequencing data and bulk sequencing data of different osteosarcoma patients were downloaded.We extracted the information of cell samples for dimensionality reduction,annotation,and cell function analysis,so as to identify the cell subsets and clarify the cell characteristics related to the prognosis of osteosarcoma.The development trajectory of macrophages with prognostic significance was analyzed,and the prognostic model of osteosarcoma was established based on the differentially expressed genes of macrophage differentiation.Results The cellular composition presented heterogeneity in the patients with osteosarcoma.The infiltration of mononuclear phagocytes in osteosarcoma had prognostic significance(P=0.003).Four macrophage subsets were associated with prognosis,and their signature transcription factors included RUNX3(+),ETS1(+),HOXD11(+),ZNF281(+),and PRRX1(+).Prog_Macro2 and Prog_Macro4 were located at the end of the developmental trajectory,and the prognostic ability of macrophage subsets increased with the progression of osteosarcoma.The prognostic model established based on the differentially expressed genes involved in macrophage differentiation can distinguish the survival rate of osteosarcoma patients with different risks(P<0.001).Conclusion Macrophage subsets are closely related to the prognosis of osteosarcoma and can be used as the key target cells for the immunotherapy of osteosarcoma.
Assuntos
Humanos , Prognóstico , Osteossarcoma/genética , Imunoterapia , Macrófagos , Fatores de Transcrição , Neoplasias Ósseas/genética , Proteínas de Homeodomínio , Proteínas RepressorasRESUMO
Extended circulation of anticancer nanodrugs in blood stream is essential for their clinical applications. However, administered nanoparticles are rapidly sequestered and cleared by cells of the mononuclear phagocyte system (MPS). In this study, we developed a biomimetic nanosystem that is able to efficiently escape MPS and target tumor tissues. The fabricated nanoparticles (TM-CQ/NPs) were coated with fibroblast cell membrane expressing tumor necrosis factor (TNF)-related apoptosis inducing ligand (TRAIL). Coating with this functionalized membrane reduced the endocytosis of nanoparticles by macrophages, but increased the nanoparticle uptake in tumor cells. Importantly, this membrane coating specifically induced tumor cell apoptosis via the interaction of TRAIL and its cognate death receptors. Meanwhile, the encapsulated chloroquine (CQ) further suppressed the uptake of nanoparticles by macrophages, and synergized with TRAIL to induce tumor cell apoptosis. The vigorous antitumor efficacy in two mice tumor models confirmed our nanosystem was an effective approach to address the MPS challenge for cancer therapy. Together, our TM-CQ/NPs nanosystem provides a feasible approach to precisely target tumor tissues and improve anticancer efficacy.
RESUMO
The mononuclear phagocyte system (MPS) consists of monocytes, dendritic cells and macrophages, which play vital roles in innate immune defense against cancer. Hepatocellular carcinoma (HCC) is a complex disease that is affected or initiated by many factors, including chronic hepatitis B virus infection, hepatitis C virus infection, metabolic disorders or alcohol consumption. Liver function, tumor stage and the performance status of patients affect HCC clinical outcomes. Studies have shown that targeted treatment of tumor microenvironment disorders may improve the efficacy of HCC treatments. Cytokines derived from the innate immune response can regulate T-cell differentiation, thereby shaping adaptive immunity, which is associated with the prognosis of HCC. Therefore, it is important to elucidate the function of the MPS in the progression of HCC. In this review, we outline the impact of HCC on the MPS. We illustrate how HCC reshapes MPS cell phenotype remodeling and the production of associated cytokines and characterize the function and impairment of the MPS in HCC.
Assuntos
Carcinoma Hepatocelular , Hepatite B Crônica , Neoplasias Hepáticas , Humanos , Carcinoma Hepatocelular/patologia , Neoplasias Hepáticas/patologia , Hepatite B Crônica/complicações , Sistema Fagocitário Mononuclear , Citocinas , Microambiente TumoralRESUMO
Magnetic nanoparticles are widely used in biomedicine for MRI imaging and anemia treatment. The aging of these nanomaterials in vivo may lead to gradual diminishing of their contrast properties and inducing toxicity. Here, we describe observation of the full lifecycle of 40-nm magnetic particles from their injection to the complete degradation in vivo and associated impact on the organism. We found that in 2 h the nanoparticles were eliminated from the bloodstream, but their initial biodistribution changed over time. In 1 week, a major part of the nanoparticles was transferred to the liver and spleen, where they degraded with a half-life of 21 days. MRI and a magnetic spectral approach revealed preservation of contrast in these organs for more than 1 month. The particle degradation led to the increased number of red blood cells and blood hemoglobin level due to released iron without causing any toxicity in tissues. We also observed an increase in gene expression level of Fe-associated proteins such as transferrin, DMT1, and ferroportin in the liver in response to the iron particle degradation. A deeper understanding of the organism response to the particle degradation can bring new directions to the field of MRI contrast agent design.
Assuntos
Nanopartículas de Magnetita , Nanopartículas de Magnetita/toxicidade , Distribuição Tecidual , Magnetismo , Ferro , Imageamento por Ressonância Magnética/métodos , Biotransformação , Meios de ContrasteRESUMO
The activation of monocytes and their trans-differentiation into macrophages are critical processes of the immune response. Prior work has characterized the differences in the expression between monocytes and macrophages, but the transitional process between these cells is poorly detailed. Here, we analyzed the temporal changes of the transcriptome during trans-differentiation of primary human monocytes into M0 macrophages. We find changes with many transcription factors throughout the process, the vast majority of which exhibit a maximally different expression at the intermediate stages. A few factors, including AP-1, were previously known to play a role in immunological transitions, but most were not. Thus, these findings indicate that this trans-differentiation requires the dynamic expression of many transcription factors not previously discussed in immunology, and provide a foundation for the delineation of the molecular mechanisms associated with healthy or pathological responses that involve this transition.