Cationic Nanostructures for the Treatment of Inflammatory Bone Loss

Abstract Periodontitis is a common type of inflammatory bone loss and is a risk factor for systemic diseases. The pathogenesis of periodontitis relies on inflammatory dysregulation, which represents a target for new therapeutic strategies to treat periodontitis. Here we demonstrate that cell-free DNA (cfDNA) is correlated with periodontitis in patient samples, and that cfDNA/TLR9 interactions participate in the immune response of periodontitis. We then tested the hypothesis that removing cfDNA would benefit periodontitis treatment. To create nucleic acid-binding nanoparticles (NABNs) specific for periodontitis, we coated bone-mimicking selenium-doped hydroxyapatite nanoparticles with cationic polyamidoamine dendrimers (PAMAM-G3), and compared the activities of these NABNs with those of soluble PAMAM-G3 polymers. Both NABNs and PAMAM-G3 inhibited periodontitis-related inflammation in vitro by scavenging cfDNA, and alleviated inflammatory bone loss in a mouse model of ligature-induced periodontitis. Both cfDNA scavengers also regulated the mononuclear phagocyte system in a periodontitis environment, promoting the M1 over the M2 macrophage phenotype. However, NABNs showed greater therapeutic effects than PAMAM-G3 in terms of scavenging and reducing inflammation and bone loss in vivo. Our findings demonstrate the importance of cfDNA in periodontitis and the potential for using cfDNA-scavenging and hydroxyapatite-based NABNs to ameliorate inflammation and bone loss in periodontitis.

Download Full-text

Exosomes secreted by FNDC5-BMMSCs protect myocardial infarction by anti-inflammation and macrophage polarization via NF-κB signaling pathway and Nrf2/HO-1 Axis

10.21203/rs.3.rs-754264/v1 ◽

2021 ◽

Author(s):

Hogjuan Ning ◽

Haixu Chen ◽

Jingyu Deng ◽

Chun Xiao ◽

Lina Shan ◽

...

Keyword(s):

Myocardial Infarction ◽

Signaling Pathway ◽

Transmembrane Protein ◽

Macrophage Polarization ◽

M2 Macrophage ◽

Therapeutic Effects ◽

Cell Based Therapy ◽

Anti Inflammation

Abstract Background Exosomes are considered a substitute for stem cell-based therapy for myocardial infarction (MI). FNDC5, a transmembrane protein located in the cytoplasm, plays a crucial role in inflammation diseases and MI repair. Furthermore, our previous study found that FNDC5 pre-conditioning bone marrow-derived mesenchymal stem cells (BMMSCs) could secreted more exosomes, but little was known on MI repair. Methods Exosomes isolated from BMMSCs with or without FNDC5-OV were injected into infarcted hearts. Then, cardiomyocytes apoptosis, and inflammation responses were detected. Furthermore, exosomes were administrated to RAW264.7 macrophage with LPS treatment to investigate its effect on inflammation and macrophage polarization. Results Compared with MSCs-Exo, FNDC5-MSCs-Exo had superior therapeutic effects on anti-inflammation and anti-apoptosis, as well as polarizing M2 macrophage in vivo. Meanwhile, the in vitro results also showed that FNDC5-MSCs–Exo decreased pro-inflammatory secretion and increased anti-inflammatory secretion under LPS stimulation, which partly depressed NF-κB signaling pathway and upregulated Nrf2/HO-1 Axis. Conclusions FNDC5-BMMSCs-derived exosomes play anti-inflammation effects and promote M2 macrophage polarization via NF-κB signaling pathway and Nrf2/HO-1 Axis, which may develop a promising cell-free therapy for MI.

Download Full-text

Contribution of Thrombospondin-1 and -2 to Lipopolysaccharide-Induced Acute Respiratory Distress Syndrome

Mediators of Inflammation ◽

10.1155/2021/8876484 ◽

2021 ◽

Vol 2021 ◽

pp. 1-22

Author(s):

Qiang Li ◽

Xiaoxiao Fu ◽

Jiang Yuan ◽

Shu Han

Keyword(s):

T Regulatory Cells ◽

Inflammatory Diseases ◽

Macrophage Polarization ◽

Endothelial Permeability ◽

M2 Macrophage ◽

Vascular Endothelial ◽

Macrophage Phenotype ◽

Thrombospondin 1

Thrombospondin (TSP) proteins have been shown to impact T-cell adhesion, migration, differentiation, and apoptosis. Thrombospondin-1 (TSP-1) is specifically upregulated in several inflammatory diseases and can effectively promote lipopolysaccharide- (LPS-) induced inflammation. In contrast, thrombospondin-2 (TSP-2) has been associated with activation of “anti-inflammatory” T-regulatory cells (Tregs). In this study, we investigated the effects of both TSP-1 and TSP-2 overexpression on macrophage polarization and activation in vitro and in vivo. We analyzed the effects of TSP-1 and TSP-2 on inflammation, vascular endothelial permeability, edema, ultrastructural morphology, and apoptosis in lung tissues of an ARDS mouse model and cultured macrophages. Our results demonstrated that TSP-2 overexpression effectively attenuated LPS-induced ARDS in vivo and promoted M2 macrophage phenotype polarization in vitro. Furthermore, TSP-2 played a role in regulating pulmonary vascular barrier leakage by activating the PI3K/Akt pathway. Overall, our findings indicate that TSP-2 can modulate inflammation and could therefore be a potential therapeutic target against LPS-induced ARDS.

Download Full-text

Exosomes secreted by FNDC5-BMMSCs protect myocardial infarction by anti-inflammation and macrophage polarization via NF-κB signaling pathway and Nrf2/HO-1 axis

Stem Cell Research & Therapy ◽

10.1186/s13287-021-02591-4 ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Hongjuan Ning ◽

Haixu Chen ◽

Jingyu Deng ◽

Chun Xiao ◽

Moyan Xu ◽

...

Keyword(s):

Myocardial Infarction ◽

Signaling Pathway ◽

Transmembrane Protein ◽

Macrophage Polarization ◽

M2 Macrophage ◽

Therapeutic Effects ◽

Cell Based Therapy ◽

Anti Inflammation

Abstract Background Exosomes are considered a substitute for stem cell-based therapy for myocardial infarction (MI). FNDC5, a transmembrane protein located in the cytoplasm, plays a crucial role in inflammation diseases and MI repair. Furthermore, our previous study found that FNDC5 pre-conditioning bone marrow-derived mesenchymal stem cells (BMMSCs) could secrete more exosomes, but little was known on MI repair. Methods Exosomes isolated from BMMSCs with or without FNDC5-OV were injected into infarcted hearts. Then, cardiomyocytes apoptosis and inflammation responses were detected. Furthermore, exosomes were administrated to RAW264.7 macrophage with LPS treatment to investigate its effect on inflammation and macrophage polarization. Results Compared with MSCs-Exo, FNDC5-MSCs-Exo had superior therapeutic effects on anti-inflammation and anti-apoptosis, as well as polarizing M2 macrophage in vivo. Meanwhile, the in vitro results also showed that FNDC5-MSCs-Exo decreased pro-inflammatory secretion and increased anti-inflammatory secretion under LPS stimulation, which partly depressed NF‐κB signaling pathway and upregulated Nrf2/HO-1 Axis. Conclusions FNDC5-BMMSCs-derived exosomes play anti-inflammation effects and promote M2 macrophage polarization via NF-κB signaling pathway and Nrf2/HO-1 Axis, which may develop a promising cell-free therapy for MI.

Download Full-text

Silicone Implants Immobilized with Interleukin-4 Promote the M2 Polarization of Macrophages and Inhibit the Formation of Fibrous Capsules

Polymers ◽

10.3390/polym13162630 ◽

2021 ◽

Vol 13 (16) ◽

pp. 2630

Author(s):

Hyun-Seok Kim ◽

Seongsoo Kim ◽

Byung-Ho Shin ◽

Chan-Yeong Heo ◽

Omar Faruq ◽

...

Keyword(s):

Tissue Regeneration ◽

Capsular Contracture ◽

Silicone Implant ◽

Interleukin 4 ◽

Silicone Implants ◽

M2 Macrophage ◽

Macrophage Phenotype ◽

Arginase 1

Breast augmentations with silicone implants can have adverse effects on tissues that, in turn, lead to capsular contracture (CC). One of the potential ways of overcoming CC is to control the implant/host interaction using immunomodulatory agents. Recently, a high ratio of anti-inflammatory (M2) macrophages to pro-inflammatory (M1) macrophages has been reported to be an effective tissue regeneration approach at the implant site. In this study, a biofunctionalized implant was coated with interleukin (IL)-4 to inhibit an adverse immune reaction and promoted tissue regeneration by promoting polarization of macrophages into the M2 pro-healing phenotype in the long term. Surface wettability, nitrogen content, and atomic force microscopy data clearly showed the successful immobilization of IL-4 on the silicone implant. Furthermore, in vitro results revealed that IL-4-coated implants were able to decrease the secretion of inflammatory cytokines (IL-6 and tumor necrosis factor-α) and induced the production of IL-10 and the upregulation of arginase-1 (mannose receptor expressed by M2 macrophage). The efficacy of this immunomodulatory implant was further demonstrated in an in vivo rat model. The animal study showed that the presence of IL-4 diminished the capsule thickness, the amount of collagen, tissue inflammation, and the infiltration of fibroblasts and myofibroblasts. These results suggest that macrophage phenotype modulation can effectively reduce inflammation and fibrous CC on a silicone implant conjugated with IL-4.

Download Full-text

The mmu_circ_0000335 inhibits M1 microglial-induced hippocampal neuronal apoptosis via the miR-19b-3p/SOCS1 axis in a mouse epilepsy model

10.21203/rs.2.16568/v1 ◽

2019 ◽

Author(s):

Yong Zhu ◽

Qiong Li ◽

Weiping Kuang ◽

Jun Lu ◽

Qin Wang ◽

...

Keyword(s):

In Vivo Studies ◽

Luciferase Reporter ◽

Circular Rnas ◽

Cytokine Signaling ◽

M2 Macrophage ◽

Macrophage Phenotype ◽

Bioinformatics Analyses ◽

M1 Macrophage

Abstract Background : Increasing evidence has demonstrated that circular RNAs (circRNAs) participate in epileptogenesis, but the expression profile and role of circRNAs in epilepsy remain unknown. A circRNA microarray was performed to examine epilepsy-related circRNAs. Bioinformatics analyses, luciferin reporter experiments and real-time quantitative PCR (Rt-qPCR) in vitro experiments were performed to demonstrate the mechanism of circRNA-mediated gene regulation of the microglial phenotype under epileptic conditions. Then, to further confirm the effect of circRNAs on nerve damage in the hippocampus, a mouse model of epilepsy was established by intraperitoneal injection of lithium chloride and pilocarpine. Results: The data indicated that 364 circRNAs were differentially expressed comparing epilepsy and control tissues. In particular, mmu_circ_0000335 expression was significantly downregulated in epileptic mice which was confirmed by Rt-qPCR. Overexpression of mmu_circ_0000335 promoted BV2 cell transformation into the M2 macrophage phenotype by increasing expression of CD206, Arg1, Ym1 and IL-10 while decreasing M1 macrophage markers IL-1β, IL-6, TNF-α and IFN-γ expressions under epileptic conditions. mmu_circ_0000335 expression triggered upregulation of Suppressor of Cytokine Signaling 1 (SOCS1) by decreasing miR-19b-3p levels, as determined by luciferase reporter assay. In vivo studies found that mmu_circ_0000335 overexpression decreased epilepsy-induced neural cell apoptosis in the hippocampus by reducing inflammatory cytokine expression. Immunofluorescence detection showed that mmu_circ_0000335 overexpression promoted microglial transformation into the M2 phenotype which had an anti-inflammatory effect. Conclusions: These results collectively indicated that mmu_circ_0000335 was involved in epilepsy progression by functioning as a miR-19b-3p sponge to enhance SOCS1 expression. Thus, mmu_circ_0000335 may be a candidate therapeutic target for epilepsy patients.

Download Full-text

Human monocytes lose 5-lipoxygenase and FLAP as they mature into monocyte-derived macrophages in vitro

AJP Cell Physiology ◽

10.1152/ajpcell.1996.271.1.c372 ◽

1996 ◽

Vol 271 (1) ◽

pp. C372-C377 ◽

Cited By ~ 9

Author(s):

W. L. Ring ◽

C. A. Riddick ◽

J. R. Baker ◽

D. A. Munafo ◽

T. D. Bigby

Keyword(s):

Northern Blot Analysis ◽

Mononuclear Phagocyte ◽

Lipoxygenase Activity ◽

Mononuclear Phagocytes ◽

Macrophage Phenotype ◽

Lipoxygenase Pathway ◽

Maturation In Vitro ◽

Enhanced Expression

Previous studies in mononuclear phagocytes have shown that macrophages have substantially greater 5-lipoxygenase activity than monocytes and that this is associated with greater amounts of 5-lipoxygenase and its activating protein (FLAP). The aim of this study was to examine the effect of mononuclear phagocyte maturation in vitro on 5-lipoxygenase expression. At baseline, monocytes had significant 5-lipoxygenase activity, but then lost all detectable 5-lipoxygenase activity over 7 days. Immunoblot and Northern blot analysis revealed that immunoreactive protein and mRNA for both 5-lipoxygenase and FLAP were significantly decreased over time. These studies demonstrate that in vitro differentiation of monocytes into a macrophage phenotype is not accompanied by the enhanced expression of 5-lipoxygenase and FLAP seen in macrophages derived from in vivo sources. In fact, baseline expression of 5-lipoxygenase and FLAP by monocytes is lost in vitro. These studies have clear implications for the use of cultured monocytes as a model of macrophages, and they also further our understanding of the regulation of the 5-lipoxygenase pathway.

Download Full-text

Exosomes Secreted from Hypoxia-Preconditioned Mesenchymal Stem Cells Prevent Steroid-Induced Osteonecrosis of the Femoral Head by Promoting Angiogenesis in Rats

BioMed Research International ◽

10.1155/2021/6655225 ◽

2021 ◽

Vol 2021 ◽

pp. 1-13

Author(s):

Na Yuan ◽

Zhaogang Ge ◽

Wenchen Ji ◽

Jia Li

Keyword(s):

Stem Cells ◽

Mesenchymal Stem Cells ◽

Femoral Head ◽

Bone Loss ◽

Umbilical Vein ◽

Tube Formation ◽

Therapeutic Effects ◽

Umbilical Vein Endothelial Cells

Recent studies have suggested that exosomes exert similar therapeutic effects to those of mesenchymal stem cells (MSCs) in regenerative medicine and MSCs-derived exosomes exhibit therapeutic effects on steroid-induced osteonecrosis of the femoral head (ONFH). Furthermore, reparative functions of exosomes from MSCs are enhanced by hypoxia treatment of the cells. However, there are no related reports about whether exosomes derived from hypoxia-preconditioned MSCs could show better therapeutic effects on steroid-induced ONFH. In vitro, we investigated the effects of hypoxia precondition on exosomes derived from bone marrow mesenchymal stem cells (BMMSCs) from rats and the proangiogenic ability of exosomes derived from hypoxia-preconditioned BMMSCs. In vivo, we investigated the role of exosomes from hypoxia-preconditioned BMMSCs on angiogenesis and protecting osteonecrosis in a rat ONFH model. We found that the potential of the proangiogenic ability of exosomes derived from hypoxia-preconditioned BMMSCs was higher than exosomes derived from BMMSCs cultured under normoxia. Exosomes derived from hypoxia-preconditioned BMMSCs significantly promoted proliferation, migration, vascular endothelial growth factor (VEGF) expression, and tube formation of human umbilical vein endothelial cells (HUVECs) compared with exosomes derived from BMMSCs cultured under normoxia. Administration of exosomes derived from hypoxia-preconditioned BMMSCs significantly prevented bone loss and increased vessel volume in the femoral head compared with exosomes derived from BMMSCs cultured under normoxia. Taken together, our data suggest that exosomes derived from hypoxia-preconditioned BMMSCs exert better therapeutic effects on steroid-induced ONFH by promoting angiogenesis and preventing bone loss.

Download Full-text

Clinical Trials in Thrombosis: Secondary Prevention of Myocardial Infarction

Thrombosis and Haemostasis ◽

10.1055/s-0038-1647910 ◽

1976 ◽

Vol 35 (01) ◽

pp. 049-056 ◽

Cited By ~ 4

Author(s):

Christian R Klimt ◽

P. H Doub ◽

Nancy H Doub

Keyword(s):

Myocardial Infarction ◽

Secondary Prevention ◽

Case Control ◽

Therapeutic Effects ◽

Case Control Studies ◽

Definitive Answer ◽

Inhibition Of Platelet Aggregation ◽

Prospective Trials

SummaryNumerous in vivo and in vitro experiments, investigating the inhibition of platelet aggregation and the prevention of experimentally-induced thrombosis, suggest that anti-platelet drugs, such as aspirin or the combination of aspirin and dipyridamole or sulfinpyrazone, may be effective anti-thrombotic agents in man. Since 1971, seven randomized prospective trials and two case-control studies have been referenced in the literature or are currently being conducted, which evaluate the effects of aspirin, sulfinpyrazone, or dipyridamole in combination with aspirin in the secondary prevention of myocardial infarction. A critical review of these trials indicates a range of evidence from no difference to a favorable trend that antiplatelet drugs may serve as anti-thrombotic agents in man. To date, a definitive answer concerning the therapeutic effects of these drugs in the secondary prevention of coronary heart disease is not available.

Download Full-text

Reprogrammed M1 macrophages with inhibited STAT3, STAT6 and/or SMAD3 extends lifespan of mice with experimental carcinoma

ZHurnal «Patologicheskaia fiziologiia i eksperimental`naia terapiia» ◽

10.25557/0031-2991.2017.02.4-9 ◽

2017 ◽

pp. 4-9

Author(s):

С.В. Калиш ◽

С.В. Лямина ◽

А.А. Раецкая ◽

И.Ю. Малышев

Keyword(s):

Tumor Growth ◽

Culture Medium ◽

Ehrlich Carcinoma ◽

Macrophage Phenotype ◽

M1 Macrophages ◽

M1 Macrophage ◽

Ec Cells ◽

Experimental Carcinoma

Цель исследования. Репрограммирование М1 фенотипа макрофагов с ингибированными факторами транскрипции М2 фенотипа STAT3, STAТ6 и SMAD и оценка их влияния на развитие карциномы Эрлиха (КЭ) in vitro и in vivo. Методика. Рост опухоли иницировали in vitro путем добавления клеток КЭ в среду культивирования RPMI-1640 и in vivo путем внутрибрюшинной инъекции клеток КЭ мышам. Результаты. Установлено, что M1макрофаги и in vitro, и in vivo оказывают выраженный противоопухолевый эффект, который превосходит антиопухолевые эффекты М1, M1, M1 макрофагов и цисплатина. Заключение. М1 макрофаги с ингибированными STAT3, STAT6 и/или SMAD3 эффективно ограничивают рост опухоли. Полученные данные обосновывают разработку новой технологии противоопухолевой клеточной терапии. Objective. Reprogramming of M1 macrophage phenotype with inhibited M2 phenotype transcription factors, such as STAT3, STAT6 and SMAD and assess their impact on the development of Ehrlich carcinoma (EC) in vitro and in vivo . Methods. Tumor growth in vitro was initiated by addition of EC cells in RPMI-1640 culture medium and in vivo by intraperitoneal of EC cell injection into mice. Results. It was found that M1 macrophages have a pronounced anti-tumor effect in vitro , and in vivo , which was greater than anti-tumor effects of M1, M1, M1 macrophages and cisplatin. Conclusion. M1 macrophages with inhibited STAT3, STAT6 and/or SMAD3 effectively restrict tumor growth. The findings justify the development of new anti-tumor cell therapy technology.

Download Full-text

A novel BRD4 inhibitor suppresses osteoclastogenesis and ovariectomized osteoporosis by blocking RANKL-mediated MAPK and NF-κB pathways

Cell Death and Disease ◽

10.1038/s41419-021-03939-7 ◽

2021 ◽

Vol 12 (7) ◽

Author(s):

Ying Liu ◽

Wenjie Liu ◽

Ziqiang Yu ◽

Yan Zhang ◽

Yinghua Li ◽

...

Keyword(s):

Bone Loss ◽

Osteoporosis Treatment ◽

Inhibitory Effect ◽

Specific Gene ◽

Actin Ring ◽

Treatment Target ◽

Significant Inhibitory Effect ◽

Promising Treatment

AbstractBromodomain-containing protein 4 (BRD4) has emerged as a promising treatment target for bone-related disorders. (+)-JQ1, a thienotriazolodiazepine compound, has been shown to inhibit pro-osteoclastic activity in a BRD4-dependent approach and impede bone loss caused by ovariectomy (OVX) in vivo. However, clinical trials of (+)-JQ1 are limited because of its poor druggability. In this study, we synthesized a new (+)-JQ1 derivative differing in structure and chirality. One such derivative, (+)-ND, exhibited higher solubility and excellent inhibitory activity against BRD4 compared with its analogue (+)-JQ1. Interestingly, (-)-JQ1 and (-)-ND exhibited low anti-proliferative activity and had no significant inhibitory effect on RANKL-induced osteoclastogenesis as compared with (+)-JQ1 and (+)-ND, suggesting the importance of chirality in the biological activity of compounds. Among these compounds, (+)-ND displayed the most prominent inhibitory effect on RANKL-induced osteoclastogenesis. Moreover, (+)-ND could inhibit osteoclast-specific gene expression, F‐actin ring generation, and bone resorption in vitro and prevent bone loss in OVX mice. Collectively, these findings indicated that (+)-ND represses RANKL‐stimulated osteoclastogenesis and averts OVX-triggered osteoporosis by suppressing MAPK and NF-κB signalling cascades, suggesting that it may be a prospective candidate for osteoporosis treatment.

Download Full-text