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Search Results (369)

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Keywords = human THP-1 macrophages

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13 pages, 1842 KiB  
Article
Pro-Inflammatory and Lipid Metabolism Dysregulating Effects of ANGPTL3 in THP-1 Macrophages
by Ilenia Milani, Ilaria Rossi, Giorgia Marodin, Maria Giovanna Lupo, Maria Pia Adorni, Francesca Zimetti and Nicola Ferri
Lipidology 2025, 2(3), 14; https://doi.org/10.3390/lipidology2030014 - 26 Jul 2025
Viewed by 272
Abstract
Background and aim: ANGPTL3 is a hepatokine acting as a negative regulator of lipoprotein lipase (LPL) through its N-terminal domain. Besides this activity, the C-terminal domain of ANGPTL3 interacts with integrin αVβ3. Since integrins are involved in inflammation and in the initiation of [...] Read more.
Background and aim: ANGPTL3 is a hepatokine acting as a negative regulator of lipoprotein lipase (LPL) through its N-terminal domain. Besides this activity, the C-terminal domain of ANGPTL3 interacts with integrin αVβ3. Since integrins are involved in inflammation and in the initiation of atherosclerotic plaque, the aim of our study was to evaluate the potential direct pro-inflammatory action of ANGPTL3 through the interaction of the fibrinogen-like domain and integrin αVβ3. Methods: We utilized cultured THP-1 human-derived macrophages and evaluated their pro-inflammatory phenotype in response to treatment with human recombinant ANGPTL3 (hANGPTL3). By Western blot, RT-qPCR, biochemical analysis, and ELISA assays, we determined the expression of genes and proteins involved in lipid metabolism and inflammatory response as well as intracellular cholesterol and triglyceride levels. In addition, we evaluated the effect of hANGPTL3 on the cellular cholesterol efflux process. Results: Incubation of THP-1-derived macrophages with 100 ng/mL of hANGPTL3 increased the mRNA expression of the pro-inflammatory cytokines IL-1β, IL-6, and TNFα (respectively, 1.87 ± 0.08-fold, 1.35 ± 0.11-fold, and 2.49 ± 0.43-fold vs. control). The secretion of TNFα, determined by an ELISA assay, was also induced by hANGPTL3 (1.98 ± 0.4-fold vs. control). The pro-inflammatory effect of hANGPTL3 was partially counteracted by co-treatment with the integrin αVβ3 inhibitor RGD peptide, reducing the mRNA levels of IL-1β (3.35 ± 0.35-fold vs. 2.54 ± 0.25-fold for hANGPTL3 vs. hANGPTL3 + RGD, respectively). Moreover, hANGPTL3 reduced cholesterol efflux to apoA-I, with a parallel increase in the intracellular triglyceride and cholesterol contents by 31.2 ± 2.8% and 20.0 ± 4.1%, respectively, compared to the control. Conclusions: ANGPTL3 is an important liver-derived regulator of plasma lipoprotein metabolism, and overall, our results add a new important pro-inflammatory activity of this circulating protein. This new function of ANGPTL3 could also be related to triglyceride and cholesterol accumulation into macrophages. Full article
(This article belongs to the Special Issue Lipid Metabolism and Inflammation-Related Diseases)
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12 pages, 1243 KiB  
Article
The Pharmacological Evidences for the Involvement of AhR and GPR35 Receptors in Kynurenic Acid-Mediated Cytokine and Chemokine Secretion by THP-1-Derived Macrophages
by Katarzyna Sawa-Wejksza, Jolanta Parada-Turska and Waldemar Turski
Molecules 2025, 30(15), 3133; https://doi.org/10.3390/molecules30153133 - 26 Jul 2025
Viewed by 438
Abstract
Kynurenic acid (KYNA), a tryptophan metabolite, possesses immunomodulatory properties, although the molecular mechanism of this action has not yet been resolved. In the present study, the effects of KYNA on the secretion of selected cytokines and chemokines by macrophages derived from the human [...] Read more.
Kynurenic acid (KYNA), a tryptophan metabolite, possesses immunomodulatory properties, although the molecular mechanism of this action has not yet been resolved. In the present study, the effects of KYNA on the secretion of selected cytokines and chemokines by macrophages derived from the human THP-1 cell line are investigated. Furthermore, the involvement of the aryl hydrocarbon receptor (AhR) and the G protein-coupled receptor 35 (GPR35) in mediating the effects of KYNA was examined. In lipopolysaccharide (LPS)-stimulated THP-1-derived macrophages, KYNA significantly reduced IL-6 and CCL-2, but increased IL-10 and M-CSF levels. AhR antagonist CH-223191 reduced the KYNA influence on IL-6, CCL-2, and M-CSF production, while the GPR35 antagonist, ML-145, blocked KYNA-induced IL-10 production. Furthermore, it was shown that THP-1 derived macrophages were capable of synthesizing and releasing KYNA and that its production was increased in the presence of LPS. These findings suggest that THP-1-derived macrophages are a source of KYNA and that KYNA modulates inflammatory responses predominantly through AhR and GPR35 receptors. Our study provides further evidence for the involvement of macrophages in immunomodulatory processes that are dependent on AhR and GPR35 receptors, as well as the potential role of KYNA in these phenomena. Full article
(This article belongs to the Section Medicinal Chemistry)
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13 pages, 1228 KiB  
Brief Report
Lipopolysaccharide-Activated Macrophages Suppress Cellular Senescence and Promote Rejuvenation in Human Dermal Fibroblasts
by Hiroyuki Inagawa, Chie Kohchi, Miyuki Uehiro and Gen-Ichiro Soma
Int. J. Mol. Sci. 2025, 26(15), 7061; https://doi.org/10.3390/ijms26157061 - 22 Jul 2025
Viewed by 297
Abstract
Tissue-resident macrophages are essential for skin homeostasis. This study investigated whether lipopolysaccharide (LPS)-activated macrophages affect senescence and rejuvenation in human dermal fibroblasts. Human monocytic THP-1 cells were stimulated with Pantoea agglomerans–derived LPS (1–1000 ng/mL), and culture supernatants were collected. These were applied [...] Read more.
Tissue-resident macrophages are essential for skin homeostasis. This study investigated whether lipopolysaccharide (LPS)-activated macrophages affect senescence and rejuvenation in human dermal fibroblasts. Human monocytic THP-1 cells were stimulated with Pantoea agglomerans–derived LPS (1–1000 ng/mL), and culture supernatants were collected. These were applied to two NB1RGB fibroblast populations: young, actively dividing cells (Young cells) and senescent cells with high population doubling levels and reduced proliferation (Old cells). Senescence markers P16, P21, and Ki-67 were analyzed at gene and protein levels. Conditioned medium from Old cells induced senescence in Young cells, increasing P16 and P21 expression levels. This effect was suppressed by cotreatment with LPS-activated THP-1 supernatant. Old cells treated with the LPS-activated supernatant exhibited decreased P16 and P21 levels as well as increased Ki-67 expression, indicating partial rejuvenation. These effects were not observed following treatment with unstimulated THP-1 supernatants or LPS alone. Overall, these findings suggest that secretory factors from LPS-activated macrophages can suppress cellular senescence and promote human dermal fibroblast rejuvenation, highlighting the potential role of macrophage activation in regulating cellular aging and offering a promising strategy for skin aging intervention. Full article
(This article belongs to the Special Issue Lipopolysaccharide in the Health and Disease)
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19 pages, 2792 KiB  
Article
Opposite Responses of Interferon and Proinflammatory Cytokines Induced by Human Metapneumovirus and Respiratory Syncytial Virus in Macrophages
by Iván Martínez-Espinoza and Antonieta Guerrero-Plata
Pathogens 2025, 14(7), 694; https://doi.org/10.3390/pathogens14070694 - 14 Jul 2025
Viewed by 444
Abstract
Macrophages are a principal pulmonary source of type I and III interferons (IFNs), initiating and coordinating the early antiviral response to respiratory viral infections. Yet the contribution of macrophage-derived IFNs to host defense during human metapneumovirus (HMPV) infection remains poorly defined. Here, we [...] Read more.
Macrophages are a principal pulmonary source of type I and III interferons (IFNs), initiating and coordinating the early antiviral response to respiratory viral infections. Yet the contribution of macrophage-derived IFNs to host defense during human metapneumovirus (HMPV) infection remains poorly defined. Here, we use human primary monocyte-derived macrophages (MDMs) and THP-1-derived macrophages to analyze the IFN responses induced by HMPV compared to its closely related human pneumovirus, respiratory syncytial virus (RSV). We show that HMPV induced a robust response of type I and type III IFNs and ISGs, whereas RSV elicited only a modest, delayed IFN response despite strong IRF activation; instead, RSV preferentially activates NF-κB and exhibits a pronounced proinflammatory cytokine output. Our results highlight the role of macrophages as key modulators of the IFN and proinflammatory responses during HMPV and RSV infection. Full article
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14 pages, 2845 KiB  
Article
Heparin-Binding Hemagglutinin-Induced Trained Immunity in Macrophages: Implications for Antimycobacterial Defense
by Yongqiang Li, Xiuping Jia, Jinhua Tang, Huilian Qiao, Jiani Zhou and Yueyun Ma
Biomolecules 2025, 15(7), 959; https://doi.org/10.3390/biom15070959 - 4 Jul 2025
Viewed by 404
Abstract
Tuberculosis (TB) is a major global health threat, with the current Bacillus Calmette–Guérin (BCG) vaccine having limited efficacy against adult pulmonary disease. Trained immunity (TI) is a form of innate immune memory that enhances antimicrobial defense. It is characterized by the epigenetic and [...] Read more.
Tuberculosis (TB) is a major global health threat, with the current Bacillus Calmette–Guérin (BCG) vaccine having limited efficacy against adult pulmonary disease. Trained immunity (TI) is a form of innate immune memory that enhances antimicrobial defense. It is characterized by the epigenetic and metabolic reprogramming of innate immune cells and holds promise as a promising approach to prevent TB. In this study, we investigated the capacity of heparin-binding hemagglutinin (HBHA), a methylated antigen of Mycobacterium tuberculosis, to induce TI in murine RAW264.7 macrophages, human-derived THP-1 macrophages, and human peripheral blood mononuclear cells (hPBMCs). HBHA-trained macrophages exhibited the enhanced expression of pro-inflammatory cytokines (IL-1β, IL-6, TNF-α) following secondary lipopolysaccharide stimulation. The epigenetic profiling indicated elevated levels of H3K4me1 and H3K4me3 histone marks at cytokine gene loci. Further, metabolic analysis revealed heightened lactate production and the increased expression of glycolytic enzymes. Functionally, HBHA-trained macrophages exhibited improved control of intracellular mycobacteria, as evidenced by a significant reduction in colony-forming units following BCG infection. These findings elucidate that HBHA induces a functional TI phenotype via coordinated epigenetic and metabolic changes, and suggest HBHA may serve as a valuable tool for studying TI and its relevance to host defense against mycobacterial infections, pending further in vivo and clinical validation. Full article
(This article belongs to the Section Biomacromolecules: Proteins, Nucleic Acids and Carbohydrates)
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21 pages, 2642 KiB  
Article
Membrane Vesicles of Enterococcus faecalis: In Vitro Composition Analysis and Macrophage Inflammatory Response Under Different pH Conditions
by Zijian Yuan, Wenling Huang, Poukei Chan, Jiani Zhou, Jingheng Liang and Lihong Guo
Microorganisms 2025, 13(6), 1344; https://doi.org/10.3390/microorganisms13061344 - 10 Jun 2025
Viewed by 601
Abstract
Enterococcus faecalis (E. faecalis) is one of the most detected bacteria in persistent apical periodontitis (PAP), with alkaline tolerance enabling post-treatment survival. In this study, we will investigate how alkaline conditions alter proteomic and metabolomic profiles of E. faecalis membrane vesicles [...] Read more.
Enterococcus faecalis (E. faecalis) is one of the most detected bacteria in persistent apical periodontitis (PAP), with alkaline tolerance enabling post-treatment survival. In this study, we will investigate how alkaline conditions alter proteomic and metabolomic profiles of E. faecalis membrane vesicles (MVs) and preliminarily investigate the role of MVs of E. faecalis in the regulation of macrophage inflammatory response. E. faecalis MVs were characterized using transmission electron microscopy and nanoparticle tracking analysis under varying pH conditions. MVs’ proteomic and metabolomic profiling across pH levels was compared. The effects of E. faecalis MVs on human dTHP-1 macrophages were evaluated using CCK-8 metabolic activity assays and ELISA-based quantitative analysis of inflammatory cytokines. In this study, the presence of E. faecalis MVs was verified, and the alkaline environment of pH 9.0 did not alter their production. Through proteomic and metabolomic analysis, we observed that ATP synthase and stress proteins, as well as lysine degradation and tryptophan metabolism pathways, were significantly enriched in the MVs at pH 9.0. Finally, we observed that both E. faecalis MVs at pH 7.0 and pH 9.0 could dose-dependently inhibit the activity of dTHP-1 cells. E. faecalis MVs promote the secretion of IL-6, TNF-α, IL-1β, IL-1ra, and TGF-β by macrophages. Compared to pH 7.0, pH 9.0 E. faecalis MVs have a reduced effect on IL-1ra and TGF-β secretion. Additionally, we observed a significant increase in the IL-1β/IL-1ra ratio after treatment with E. faecalis MVs. Our study indicated that E. faecalis can produce MVs in pH 7.0 and pH 9.0 environments. ATP synthase, stress proteins, as well as lysine degradation and tryptophan metabolism pathways, were significantly enriched in pH 9.0 MVs. Furthermore, E. faecalis MVs could promote inflammatory responses in macrophages and dose-dependently inhibit the viability of dTHP-1 cells. Full article
(This article belongs to the Section Molecular Microbiology and Immunology)
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23 pages, 4349 KiB  
Article
The RXR Agonist MSU-42011 Reduces Tumor Burden in a Murine Preclinical NF1-Deficient Model
by Pei-Yu Hung, Jessica A. Moerland, Ana S. Leal, Bilal Aleiwi, Edmund Ellsworth, D. Wade Clapp, Verena Staedtke, Renyuan Bai and Karen T. Liby
Cancers 2025, 17(12), 1920; https://doi.org/10.3390/cancers17121920 - 9 Jun 2025
Viewed by 675
Abstract
Background/Objectives: Neurofibromatosis type 1 (NF1) is a prevalent inherited disorder, with approximately 50% of affected individuals developing plexiform neurofibromas (PNFs), which can progress to highly aggressive malignant peripheral nerve sheath tumors (MPNSTs). While selumetinib is FDA-approved for PNFs, its efficacy in MPNSTs is [...] Read more.
Background/Objectives: Neurofibromatosis type 1 (NF1) is a prevalent inherited disorder, with approximately 50% of affected individuals developing plexiform neurofibromas (PNFs), which can progress to highly aggressive malignant peripheral nerve sheath tumors (MPNSTs). While selumetinib is FDA-approved for PNFs, its efficacy in MPNSTs is limited and associated with dose-limiting toxicities. NF1 deficiency drives tumorigenesis and alters immune dynamics via RAS hyperactivation. Given the substantial macrophage infiltration in NF1 lesions and its association with disease progression, we hypothesized that targeting tumor-promoting immune cells with the retinoid X receptor (RXR) agonist MSU-42011 could be an alternative therapeutic strategy, as it has shown promise in KRAS-driven cancers by decreasing pERK levels and reducing tumor-promoting immune cells. Methods: We examined the effects of MSU-42011 and selumetinib, alone and in combination, on NF1-deficient cells and in a syngeneic MPNST model. Results: In vivo, the combination of MSU-42011 and selumetinib significantly reduced tumor growth, pERK levels, and tumor-promoting macrophages and increased activated CD8+ T cells in syngeneic MPNST models. In NF1-deficient cells, MSU-42011 or selumetinib reduced pERK levels, with combination treatment achieving greater reductions. Conditioned media (CM) from NF1-deficient cells increased the protein and mRNA levels of several cytokines and chemokines in human THP1 cells and bone marrow-derived macrophages (BMDMs). MSU-42011 and selumetinib, alone or in combination, partially reversed this induction. Conclusions: These findings suggest RXR agonists may have therapeutic potential against NF1, and their combination with MEK inhibitors could represent a promising strategy for NF1-associated tumors. Further studies are needed to validate these results and assess their translational relevance. Full article
(This article belongs to the Special Issue Neurofibromatosis)
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17 pages, 3651 KiB  
Article
Polarization of THP-1-Derived Human M0 to M1 Macrophages Exposed to Flavored E-Liquids
by Raivat Shah, Emily D. Luo, Carly A. Shaffer, Maya Tabakha, Sophie Tomov, Siara H. Minton, Mikaela K. Brown, Dominic L. Palazzolo and Giancarlo A. Cuadra
Toxics 2025, 13(6), 451; https://doi.org/10.3390/toxics13060451 - 29 May 2025
Viewed by 1081
Abstract
Electronic cigarettes (ECIGs) are widely used but their effects on the immune system need to be further investigated. Macrophages are white blood cells central to the immune response. Using THP-1-derived M0 macrophages, this study aims to determine the effects of ECIG liquids (E-liquids) [...] Read more.
Electronic cigarettes (ECIGs) are widely used but their effects on the immune system need to be further investigated. Macrophages are white blood cells central to the immune response. Using THP-1-derived M0 macrophages, this study aims to determine the effects of ECIG liquids (E-liquids) on the polarization of M0 to the pro-inflammatory M1 macrophage subtype. THP-1 cells were cultured and differentiated to M0 macrophages using RPMI media. E-liquids ± cinnamon, menthol, strawberry and tobacco flavors were added to cell cultures at 1% (v/v) during polarization with lipopolysaccharides and interferon γ for 24 to 72 h. Morphology, viability, gene expression and cytokine production were measured using light microscopy, the LDH cytotoxicity assay, qPCR and ELISA, respectively. The results show that cells present little to no LDH activity under any treatments. In addition, cinnamon-flavored E-liquid severely affects morphology (i.e., abolishing pseudopodia formation), gene expression of all genes tested, and cytokine production. Other E-liquid flavors also affect some of these parameters, but to a lesser extent. Our data suggest that E-liquids can affect the polarization from M0 to M1, thus affecting the immune response in ECIG-exposed tissues such as the mucosa in the oral cavity and airways, ultimately mitigating the health status. Full article
(This article belongs to the Special Issue Health Risk Assessment of Exposure to Emerging Contaminants)
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20 pages, 4072 KiB  
Article
Impact of Black Soldier Fly Larvae Oil on Immunometabolic Processes
by Hadas Inbart Richter, Ofer Gover, Amit Hamburg, Keren Bendalak, Tamar Ziv and Betty Schwartz
Int. J. Mol. Sci. 2025, 26(10), 4855; https://doi.org/10.3390/ijms26104855 - 19 May 2025
Viewed by 622
Abstract
The oil extract derived from black soldier fly (Hermetia illucens) larvae (BSFL) is characterized by a distinctive fatty acid composition and bioactive compounds with demonstrated anti-inflammatory properties, as shown in our previous work. The present study aims to mechanistically explore the [...] Read more.
The oil extract derived from black soldier fly (Hermetia illucens) larvae (BSFL) is characterized by a distinctive fatty acid composition and bioactive compounds with demonstrated anti-inflammatory properties, as shown in our previous work. The present study aims to mechanistically explore the immunomodulatory effects of a saponified form of BSFL oil (MBSFL) and its potential interaction with metabolic signaling pathways. Using Pam3CSK4-polarized M1 primary human peripheral blood mononuclear cells (PBMCs), we demonstrate that MBSFL phenotypically suppressed the secretion of pro-inflammatory cytokines TNFα, IL-6, IL-17, and GM-CSF (p < 0.01) without altering anti-inflammatory cytokine levels (TGFβ1, IL-13, and IL-4). A phosphoproteomic analysis of Pam3CSK4-stimulated THP-1 macrophages revealed MBSFL-mediated downregulation of CK2 and ERK kinases (p < 0.05), key regulators of NF-κB signaling activation. We confirmed that MBSFL directly inhibits NF-κB p65 nuclear translocation (p < 0.05), using both immunofluorescence staining and a western blot analysis of nuclear and cytoplasmic fractions. In the context of metabolism, using a luciferase reporter assay, we demonstrate that MBSFL functions as a weak agonist of PPARγ and PPARδ (p < 0.05), which are nuclear receptors involved in lipid metabolism and immune regulation. However, subsequent immunoblotting revealed a macrophage polarization-dependent regulation: MBSFL upregulated PPARγ in M0 macrophages but did not prevent its suppression upon Pam3CSK4 stimulation, whereas it specifically enhanced PPARδ expression during M1 polarization (p < 0.05). This study provides novel experimental evidence supporting our hypothesis of MBSFL’s role in immunometabolism. We demonstrate for the first time that MBSFL acts as a dual regulator by suppressing NF-κB-mediated inflammation while promoting PPARδ activity—an inverse relationship with potential relevance to immunometabolic disorders. Full article
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21 pages, 4422 KiB  
Article
The Regulation of the NF-κB p65 and Nrf2/HO-1 Signaling Pathways by Fucoxanthin in Human THP-1 Monocyte Macrophages Under a Lipopolysaccharide-Induced Inflammation Model
by Linyi Zhang, Tong Li, Jingyi Liu, Jiyan Sun, Jinkun Niu, Dandan Ren, Yichao Ma, Yunhai He, Shu Liu and Qiukuan Wang
Foods 2025, 14(10), 1746; https://doi.org/10.3390/foods14101746 - 14 May 2025
Cited by 1 | Viewed by 797
Abstract
Fucoxanthin (Fx), a natural carotenoid predominantly found in brown algae and certain microalgae, has garnered significant attention in recent years for its potent antioxidant and anti-inflammatory properties. As inflammation and oxidative stress represent fundamental physiological responses that play pivotal roles in disease pathogenesis, [...] Read more.
Fucoxanthin (Fx), a natural carotenoid predominantly found in brown algae and certain microalgae, has garnered significant attention in recent years for its potent antioxidant and anti-inflammatory properties. As inflammation and oxidative stress represent fundamental physiological responses that play pivotal roles in disease pathogenesis, their intricate interplay has become a focus of scientific investigation. This study employed an LPS-induced THP-1 cell inflammation model to elucidate the anti-inflammatory mechanisms of fucoxanthin and its interaction with oxidative stress pathways. Our findings demonstrate that fucoxanthin effectively suppresses the LPS-induced secretion of pro-inflammatory mediators, including IL-1β, IL-6, iNOS, COX-2, and TNF-α, in THP-1 cells. Mechanistically, this effect is achieved through the inhibition of IκB-α phosphorylation, thereby blocking the activation of the NF-κB p65 signaling pathway. Concurrently, fucoxanthin exhibits robust antioxidant activity, as evidenced by enhanced catalase (CAT) and superoxide dismutase (SOD) activities coupled with reduced malondialdehyde (MDA) production. Furthermore, fucoxanthin activates the Nrf2 signaling pathway, leading to upregulated heme oxygenase-1 (HO-1) expression and the consequent attenuation of reactive oxygen species (ROS) generation. These results collectively indicate that fucoxanthin exerts dual protective effects through anti-inflammatory action mediated by NF-κB pathway inhibition and antioxidant activity via Nrf2/HO-1 pathway activation. The observed crosstalk between these pathways suggests that fucoxanthin’s therapeutic potential stems from its ability to simultaneously modulate interconnected inflammatory and oxidative stress responses. Our study provides compelling evidence that fucoxanthin’s antioxidant and anti-inflammatory activities are functionally interrelated, with the Nrf2 signaling pathway serving as a critical node in this protective mechanism against LPS-induced cellular damage. Full article
(This article belongs to the Section Nutraceuticals, Functional Foods, and Novel Foods)
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9 pages, 2102 KiB  
Article
Engagement of CD300c by a Novel Monoclonal Antibody Ameliorates Behavioral Deficits in a 5xFAD Mouse Model of Alzheimer’s Disease
by Suin Lee, Chang Ki Lim, Jongyeob Kim, Joon Kim, Hee Kyung Jin, Jae-sung Bae and Jae-Won Jeon
Biomedicines 2025, 13(5), 1169; https://doi.org/10.3390/biomedicines13051169 - 10 May 2025
Cited by 1 | Viewed by 562
Abstract
Background: Current treatment modalities for Alzheimer’s disease (AD), which is characterized by the accumulation of amyloid β (Aβ), have limitations with regard to their efficacy and safety, posing significant challenges for advances in healthcare. However, recent studies indicated that AD can be [...] Read more.
Background: Current treatment modalities for Alzheimer’s disease (AD), which is characterized by the accumulation of amyloid β (Aβ), have limitations with regard to their efficacy and safety, posing significant challenges for advances in healthcare. However, recent studies indicated that AD can be treated using monocyte-derived macrophages (MDMs). Reportedly, the protein CD300c regulates monocyte differentiation, indicating that targeting CD300c could offer a treatment for AD. Methods: To confirm this, we developed CB201, a fully human anti-CD300c antibody, and demonstrated its strong and specific binding to CD300c using surface plasmon resonance and binding ELISAs. Results: Treatment of THP-1 and human peripheral blood mononuclear cells with CB201 led to increased levels of pro-inflammatory cytokines and the differentiation of macrophages to MDMs. Moreover, the CB201-differentiated macrophages expressed cytokines and chemokines in a pattern that alleviates AD symptoms. In a 5xFAD mouse model, CB201 treatment improved memory and behavior in both the early and late stages of AD and reduced cerebral Aβ plaque load. Conclusions: These results indicate that CB201 promotes the differentiation of macrophages to MDMs and modulates AD-related inflammatory responses, thereby ameliorating the pathological features of AD. These findings identify CD300c as a potential therapeutic target for AD and indicate that CB201 is a promising candidate for its treatment. Full article
(This article belongs to the Section Neurobiology and Clinical Neuroscience)
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20 pages, 13618 KiB  
Article
Naringenin Targets PI3K p85alpha to Suppress PI3K/AKT Signaling Pathway and Ameliorate Disordered MMP-9 Secretion in Cigarette Smoke Extract-Induced Alveolar Macrophages In Vitro
by Weiyang Fan, Ziyan Xu, Mengli Zhong, Xiao Wu, Pan Chen, Zhen Chen, Weiwei Su, Hao Wu and Peibo Li
Cells 2025, 14(10), 678; https://doi.org/10.3390/cells14100678 - 8 May 2025
Viewed by 776
Abstract
Background: Naringenin has demonstrated potential therapeutic effects against cigarette smoke-induced lung injury; however, its underlying mechanisms of regulating matrix metalloproteinase-9 (MMP-9) in alveolar macrophages remain unclear. Methods: The regulatory mechanisms of naringenin in cigarette smoke extract (CSE)-induced alveolar macrophages were investigated using proteomics, [...] Read more.
Background: Naringenin has demonstrated potential therapeutic effects against cigarette smoke-induced lung injury; however, its underlying mechanisms of regulating matrix metalloproteinase-9 (MMP-9) in alveolar macrophages remain unclear. Methods: The regulatory mechanisms of naringenin in cigarette smoke extract (CSE)-induced alveolar macrophages were investigated using proteomics, and then, naringenin’s targets were further validated by Western blot, molecular docking, molecular dynamics (MD) simulations, cellular thermal shift assay (CETSA), and enzyme activity assay. Results: The proteomics revealed that the PI3K/AKT signaling pathway might play a crucial role in naringenin’s inhibition of MMP-9. Western blot analysis confirmed that naringenin significantly inhibited CSE-upregulated PI3K/AKT signaling pathway and reduced MMP-9 expression in MH-S cells. Notably, the PI3K activator 740Y-P reversed naringenin’s effects on MMP-9. Additionally, molecular docking, MD simulations, and CETSA identified PI3K p85alpha as the potential binding site for naringenin, and naringenin markedly inhibited CSE-induced PI3K activity. In in vitro experiments, naringenin inhibiting MMP-9 secretion in alveolar macrophages contributed to alleviating elastin and E-cadherin damage in alveolar epithelial cells. Furthermore, naringenin effectively suppressed CSE-induced MMP-9 secretion in primary mouse alveolar macrophages and human THP-1-differentiated macrophages. Conclusions: Our findings revealed that naringenin, a potential candidate for treating smoking-induced lung injury, directly targeted PI3K p85alpha, inhibiting PI3K activity and MMP-9 expression in CSE-induced alveolar macrophages via suppressing the PI3K/AKT signaling pathway. Full article
(This article belongs to the Section Cell Motility and Adhesion)
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21 pages, 2561 KiB  
Article
Indole-3-Carbinol Enhances Alternative Activation of Macrophages via AHR Pathway and Glucose Transporter Regulation
by Delara Omrani, Saeed Mohammadi, Moein Malekzadeh, Mohsen Saeidi, Fakhri Sadat Seyedhosseini, Ahmed Al-Harrasi and Yaghoub Yazdani
Immuno 2025, 5(2), 15; https://doi.org/10.3390/immuno5020015 - 2 May 2025
Viewed by 724
Abstract
Disruption in macrophage polarization is linked to inflammatory diseases and metabolic disorders. Our study aimed to investigate how AHR activation by I3C and TCDD could impact glucose transporters and macrophage phenotypes and functions in human macrophages. Human monocyte-derived macrophages (hMDMs) and THP-1 cell-derived [...] Read more.
Disruption in macrophage polarization is linked to inflammatory diseases and metabolic disorders. Our study aimed to investigate how AHR activation by I3C and TCDD could impact glucose transporters and macrophage phenotypes and functions in human macrophages. Human monocyte-derived macrophages (hMDMs) and THP-1 cell-derived macrophage-like cells were treated for 24 h with 100 ng/mL LPS, 100 nM TCDD, and 10 ng/µL I3C. CYP1A1 and CYP1B1 expression was significantly increased in the I3C and TCDD treatments, with CYP1B1 showing a higher fold change in I3C compared to TCDD. The AHRR expression was the highest in the TCDD group. For macrophage polarization, I3C significantly elevated CD163 expression while reducing CD16 and CD86, indicative of M2-like polarization. Additionally, I3C promoted ARG1 expression and reduced NOS2 levels, while TCDD increased NOS2. A cytokine analysis revealed I3C-induced upregulation of IL-10 and TGF-β, while TCDD significantly elevated TNF-α and IL-12. I3C upregulated glucose transporter genes (GLUT1, GLUT3, GLUT6), in contrast to the downregulation observed in TCDD-treated cells. Our findings demonstrated that I3C distinctly modulates AHR activation genes, macrophage polarization, cytokine expression, and glucose transporter levels in THP-1 cells compared to the TCDD and LPS treatments. Our findings suggest that I3C favors an anti-inflammatory M2-like macrophage polarization coupled with enhanced metabolic activity. Full article
(This article belongs to the Section Innate Immunity and Inflammation)
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27 pages, 7477 KiB  
Article
Synthesis of Tricyclic and Tetracyclic Lactone Derivatives of Thieno[2,3-b]pyrazine or Thieno[2,3-b]quinoline: Preliminary Antitumor and Antiparasitic Activity Evaluation
by Maria F. Martins, Francisco Ribeiro, Ana Borges, Ricardo C. Calhelha, Nuno Santarém, Anabela Cordeiro-da-Silva and Maria-João R. P. Queiroz
Molecules 2025, 30(9), 1999; https://doi.org/10.3390/molecules30091999 - 30 Apr 2025
Viewed by 1045
Abstract
Tricyclic and tetracyclic lactone derivatives of thieno[2,3-b]pyrazine or thieno[2,3-b]quinoline, and 2H-pyrones were prepared using different methodologies. Pd/Cu-catalyzed Sonogashira coupling using Et3N as a base, of methyl 7-bromothieno[2,3-b]pyrazine-6-carboxylate and (het)arylalkynes to yield the Sonogashira [...] Read more.
Tricyclic and tetracyclic lactone derivatives of thieno[2,3-b]pyrazine or thieno[2,3-b]quinoline, and 2H-pyrones were prepared using different methodologies. Pd/Cu-catalyzed Sonogashira coupling using Et3N as a base, of methyl 7-bromothieno[2,3-b]pyrazine-6-carboxylate and (het)arylalkynes to yield the Sonogashira ester products, gave also the corresponding tricyclic lactones as minor products. However, the major products did not cyclize with TFA. Tricyclic lactones were then obtained by a tandem one-pot Sonogashira coupling and 6-endo-dig lactonization of 7-bromothieno[2,3-b]pyrazine-6-carboxylic acid with (het)arylalkynes, in good yields. Halogenated tricyclic lactones were synthesized by halocyclization using CuX and NXS. Tetracyclic lactones were synthesized through a Rh(III)-catalyzed formal [4+2] cycloaddition, between thieno[2,3-b]quinoline-2-carboxylic acid and internal alkynes, triggered by C-H activation, with the carboxylic group acting as a directing group. Using the SRB assay, the antitumor activity of both Sonogashira products and lactones was evaluated across five human cancer cell lines (CaCo-2, MCF-7, AGS, HeLa, NCI-H460). The best-performing compound was a Sonogashira product showing a GI50 < 10 µM in all tumor cell lines and low toxicity in PLP2 cells. Additionally, antiparasitic testing against Trypanosoma brucei and Leishmania infantum revealed some compounds with IC50 < 11 µM, though some level of cytotoxicity was observed in THP-1—derived macrophages. Full article
(This article belongs to the Section Organic Chemistry)
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24 pages, 8389 KiB  
Article
Low Fluoride Regulates Macrophage Polarization Through Mitochondrial Autophagy Mediated by PINK1/Parkin Axis
by Fengyu Xie, Jing Zhou, Bingshu Liu, Lijun Zhao, Cunqi Lv, Qiong Zhang, Lin Yuan, Dianjun Sun and Wei Wei
Biomolecules 2025, 15(5), 647; https://doi.org/10.3390/biom15050647 - 30 Apr 2025
Cited by 1 | Viewed by 885
Abstract
Fluoride exposure has been shown to affect immune cell subsets and immune function, but its impact on macrophage polarization remains unclear. This study investigates the effects of low fluoride exposure on macrophage polarization and its underlying mechanisms through epidemiological surveys, animal experiments, and [...] Read more.
Fluoride exposure has been shown to affect immune cell subsets and immune function, but its impact on macrophage polarization remains unclear. This study investigates the effects of low fluoride exposure on macrophage polarization and its underlying mechanisms through epidemiological surveys, animal experiments, and in vitro cell experiments. In the population-based epidemiological survey, we used mass cytometry to assess the impact of low fluoride exposure (0.570–2.027 mg/L) in the environment on human immune cell populations following the current water improvement and fluoride reduction measures. A rat fluorosis model was established by treating rats with sodium fluoride (NaF) in drinking water at concentrations of 0 mg/L, 5 mg/L, 10 mg/L, 25 mg/L, and 50 mg/L for 90 days., and morphological changes were assessed by hematoxylin–eosin (H&E) staining and transmission electron microscopy in the spleen of rats. Flow cytometry was used to analyze the proportion of macrophage subtypes in the spleen, while Western blot and immunofluorescence were performed to detect the expression of mitochondrial autophagy-related proteins. An M1 macrophage model was constructed in vitro by inducing THP-1 cells, and the effects of fluoride on macrophage-related cell markers and cytokines were assessed using flow cytometry and ELISA, respectively, following intervention with an autophagy inhibitor. Mitochondrial membrane potential and mitochondrial–lysosomal colocalization are analyzed through flow cytometry and confocal microscopy. The study aims to investigate the role of mitophagy in sodium fluoride-induced macrophage polarization. Epidemiological investigations revealed that low fluoride increases the proportion of blood monocytes, as well as the expression levels of CD68 (a macrophage surface marker), CD86 (an M1 macrophage marker), and the inflammatory cytokine IFN-γ in peripheral blood mononuclear cells (PBMCs). In the rats of NaF-treated groups, splenic tissues exhibited inflammatory infiltration, mitochondrial swelling, and increased autophagosome formation. Moreover, low fluoride activated the PINK1/Parkin-mediated mitophagy pathway, promoting an increase in the M2/M1 macrophage ratio. In vitro experiments further confirmed that autophagy inhibitors reversed the NaF-induced increase in the M2/M1 macrophage ratio. This study demonstrates that low fluoride induces inflammatory responses in the body and drives M1 macrophage polarization toward M2 macrophages via mitophagy. These findings highlight the potential immunological risks associated with low fluoride and provide mechanistic insights into the interplay among fluoride, mitophagy, and macrophage polarization. Full article
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