Sites Of Inflammation Research Articles

Abstract 4129709: Aspirin-Nanoparticle for Dual Therapies: Targeted Anti-Inflammatory and Prolonged Anti-Platelet Effects for Atherosclerosis

Background: The current unmet needs for aspirin usage in atherosclerosis lie in its short half-life and narrow indication for anti-platelet effects. Daily aspirin intake is mandatory, and the anti-inflammatory effects of aspirin for atherosclerosis have not successfully translated to clinical practice. Nanoparticles remain in circulation for 2-3 days, with a large portion being cleared by splenic monocytes, which are known to inherently target inflamed sites. Hypothesis: By altering the pharmacokinetics of aspirin through loading into nanoparticles, aspirin-nanoparticles can exert prolonged anti-platelet effects and target atherosclerosis sites via monocyte carriers for anti-inflammatory effects, resulting in dual therapies. Methods: Splenic monocytes were loaded with aspirin-liposomes and co-cultured with endothelial cells or platelets to examine the interactions between them using high-resolution time-series microscopy. Prolonged anti-platelet effects and targeted anti-inflammatory effects of aspirin were validated in intact mice and hindlimb ischemia models, respectively. Furthermore, the dual therapies of aspirin-liposomes were validated in an atherosclerotic mouse model created by partial carotid ligation and a western diet in apoE gene knock-out mice. Results: When splenic monocytes were loaded with aspirin-liposomes, they emitted extracellular vesicles (EVs) loaded with aspirin towards endothelial cells or platelets. As inflamed cells upregulate caveolin expression, they uptake an increased amount of transferred EVs compared to non-inflamed cells. Additionally, aspirin-liposomes showed prolonged circulation time and increased splenic accumulation compared to aspirin itself, resulting in prolonged anti-platelet effects (>7 days) and targeted anti-inflammatory effects at inflamed sites. Compared to the daily oral aspirin group in the atherosclerosis model, the weekly intravenous aspirin-liposome group showed superior therapeutic effects, including attenuated systemic and local inflammation and patent lumen in atherosclerotic sites. Conclusion: Aspirin-nanoparticles can exert prolonged anti-platelet effects combined with targeted anti-inflammatory effects, resulting in superior therapeutic effects on atherosclerosis.

Brain Abscess Causes Brain Damage With Long-Lasting Focal Cerebral Hypoactivity that Correlates With Abscess Size: A Cross-Sectional 18F-Fluoro-Deoxyglucose Positron Emission Tomography Study

BACKGROUND AND OBJECTIVES: Bacterial brain abscesses may have long-term clinical consequences, eg, mental fatigue or epilepsy, but long-term structural consequences to the brain remain underexplored. We asked if brain abscesses damage brain activity long term, if the extent of such damage depends on the size of the abscess, and if the abscess capsule, which is often left in place during neurosurgery, remains a site of inflammation, which could explain long-lasting symptoms in patients with brain abscess. METHODS: 2-[18F]-fluoro-2-deoxy-D-glucose positron emission tomography/computed tomography (FDG-PET/CT), electroencephalography, and MRI were performed 2 days to 9 years after neurosurgery for bacterial brain abscess. RESULTS: FDG-PET/CT revealed hypometabolism in the neocortex or cerebellum overlying the previous bacterial abscess in 38 of 40 patients. The larger the abscess, the greater was the extent of the subsequent hypometabolism (r = 0.63; p = 3 × 10−5). In 9 patients, the extent of subsequent hypometabolism seemed to coincide with the extent of peri-abscess edema in the acute phase. Follow-up MRI after ≥1 year in 9 patients showed focal tissue loss and gliosis. In 13 patients with abnormal electroencephalography recordings, abnormalities extended beyond the cerebral lobe affected by the abscess, indicating damage to wider brain networks. The abscess capsule had an FDG signal indicating inflammation only during the first week after neurosurgical pus drainage. CONCLUSION: The bigger a brain abscess is allowed to grow, the more extensive is the long-term focal reduction in brain activity. This finding emphasizes the need for rapid neurosurgical intervention. The abscess capsule does not display long-lasting inflammation and probably does not explain long-term symptoms after brain abscess.

Engineered self-regulating macrophages for targeted anti-inflammatory drug delivery

BackgroundRheumatoid arthritis (RA) is a systemic autoimmune disease characterized by increased levels of inflammation that primarily manifests in the joints. Macrophages act as key drivers for the progression of RA, contributing to the perpetuation of chronic inflammation and dysregulation of pro-inflammatory cytokines such as interleukin 1 (IL-1). The goal of this study was to develop a macrophage-based cell therapy for biologic drug delivery in an autoregulated manner.MethodsFor proof-of-concept, we developed “smart” macrophages to mitigate the effects of IL-1 by delivering its inhibitor, IL-1 receptor antagonist (IL-1Ra). Bone marrow-derived macrophages were lentivirally transduced with a synthetic gene circuit that uses an NF-κB inducible promoter upstream of either the Il1rn or firefly luciferase transgenes. Two types of joint like cells were utilized to examine therapeutic protection in vitro, miPSCs derived cartilage and isolated primary mouse synovial fibroblasts while the K/BxN mouse model of RA was utilized to examine in vivo therapeutic protection.ResultsThese engineered macrophages were able to repeatably produce therapeutic levels of IL-1Ra that could successfully mitigate inflammatory activation in co-culture with both tissue-engineered cartilage constructs and synovial fibroblasts. Following injection in vivo, macrophages homed to sites of inflammation and mitigated disease severity in the K/BxN mouse model of RA.ConclusionThese findings demonstrate the successful development of engineered macrophages that possess the ability for controlled, autoregulated production of IL-1 based on inflammatory signaling such as via the NF-κB pathway to mitigate the effects of this cytokine for applications in RA or other inflammatory diseases. This system provides proof of concept for applications in other immune cell types as self-regulating delivery systems for therapeutic applications in a range of diseases.

Influence of methods of treatment of the periimplantit on chemiluminescent activity of neutrophil granulocytes in vitro.

Abstract AIMS: Evaluation of the biocompatibility of implants removed from the site of inflammation and treated with air-flow and laser. MATERIALS AND METHODS: Three types of implant were investigated: anodized titanium dioxide surface (TiO2), coarse sandblasting and acid etching (Sand-blasted, Large grit, Acid-etched - SLA), RBM (Resorbable Blast Media). Implants were removed from the jaw of patients diagnosed with periimplantitis and the implant surface was treated with Air-flow air-abrasive mixture and chlorhexidine (first experimental group) and YSGG 2780 nm laser (second experimental group). New, out-of-package implants were used as controls. Biocompatibility was assessed by the level of synthesis of primary and secondary reactive oxygen species (ROS) by neutrophils, the intensity and kinetics of synthesis of which were determined by chemiluminescence analysis. RESULTS: Lucigenin- and luminol-dependent chemiluminescence of neutrophils was studied in vitro after incubation with SLA, RMB and TiO2 implants removed from the jaws of patients diagnosed with periimplantitis and treated with air-flow and chlorhexidine-air-abrasive mixture. It was found that, regardless of the type of implant studied, the time to reach maximum was reduced and the values of maximum intensity and area under the curve of spontaneous and zymosan-induced chemiluminescence of neutrophils were increased. The change in the values of zymosan-induced chemiluminescence activity indices of neutrophils during incubation with implants is much higher than the values of spontaneous chemiluminescence, leading to an increase in the values of the activation index. Incubation of neutrophils in vitro with laser-treated SLA, RMB and TiO2 implants does not cause significant changes in the values of neutrophil chemiluminescence indices. CONCLUSIONS: SLA, RMB and TiO2 implants removed from the jaws of patients with periimplantitis and treated with air-flow and chlorhexidine have a low biocompatibility. However, implants with the RBM surface after air-flow treatment have relatively higher biocompatibility in comparison with ..... продложение не влезло, находится в файле.

Nanomotors as Therapeutic Agents: Advancing Treatment Strategies for Inflammation-Related Diseases.

Inflammation is a physiological response of the body to harmful stimuli such as pathogens, damaged cells, or irritants, involving a series of cellular and molecular events. It is associated with various diseases including neurodegenerative disorders, cancer, and atherosclerosis, and is a leading cause of global mortality. Key inflammatory factors, such as Tumor Necrosis Factor-alpha (TNF-α), Interleukin-1 (IL-1), Interleukin-6 (IL-6), Monocyte Chemoattractant Protein-1 (MCP-1/CCL2), RANTES (CCL5), and prostaglandins, play central roles in inflammation and disease progression. Traditional treatments such as NSAIDs, steroids, biologic agents, and antioxidants have limitations. Recent advancements in nanomaterials present promising solutions for treating inflammation-related diseases. Unlike nanomaterials that rely on passive targeting and face challenges in precise drug delivery, nanomotors, driven by chemical or optical stimuli, offer a more dynamic approach by actively navigating to inflammation sites, thereby enhancing drug delivery efficiency and therapeutic outcomes. Nanomotors allow for controlled drug release in response to specific environmental changes, such as pH and inflammatory factors, ensuring effective drug concentrations at disease sites. This active targeting capability enables the use of smaller drug doses, which reduces overall drug usage, costs, and potential side effects compared to traditional treatments. By improving precision and efficiency, nanomotors address the limitations of conventional therapies and represent a significant advancement in the treatment of inflammation-related diseases. This review summarizes the latest research on nanomotor-mediated treatment of inflammation-related diseases and discusses the challenges and future directions for optimizing their clinical translation.

IP-10 acts early in CV-A16 infection to induce BBB destruction and promote virus entry into the CNS by increasing TNF-α expression

The mechanisms underlying pathological changes in the central nervous system (CNS) following Coxsackievirus A16 (CV-A16) infection have not yet been elucidated. IFN-γ-inducible protein-10 (IP-10) is often used as a predictive factor to monitor early virus infection. It has also been reported that IP-10 plays a pivotal role in neuroinflammation. In this study, we aimed to explore the role of IP-10 in the neuropathogenesis of CV-A16 infection. We observed that the level of IP-10, as well as the TLR3-TRIF-TRAF3-TBK1-NF-κB and RIG-I/MDA5-MAVS-TRAFS-TBK1-NF-κB pathways, which are the upstream of IP-10, were significantly elevated during the course of CV-A16 infection. This increase was accompanied by an increase in a series of inflammatory cytokines at different time-points during CV-A16 infection. To determine whether IP-10 influences BBB integrity, we examined junctional complexes. Our results revealed that the expression levels of Claudin5, Occludin, ZO-1 and VE-Cadherin were notably decreased in CV-A16-infected HUVECs, but these indicators were restored in CV-A16-infected HUVECs with Eldelumab treatment. Nevertheless, IP-10 is only a chemokine that primarily traffics CXCR3-positive immune cells to inflammatory sites or promotes the production of inflammatory cytokines. Therefore, the interactions between IP-10 and inflammatory cytokines were evaluated. Our data revealed that IP-10 mediated the production of TNF-α, which was also observed to change the junctional complexes. Moreover, in a suckling mouse model, IP-10 and TNF-α treatments exacerbated clinical symptoms, mortality and pathological changes in the brain of CV-A16-infected mice, but Anti-IP-10 and Anti-TNF-α treatments alleviated these changes. Our data also revealed that IP-10 may be detected early in CV-A16 infection, whereas TNF-α was detected late in CV-A16 infection, and the production of TNF-α was also found to be positively correlated with IP-10. In addition, IP-10 and TNF-α were observed to reduce junctional complexes and enhance virus entry into the CNS. Taken together, this study provides the first evidence that CV-A16 activates the IP-10/TNF-α regulatory axis to cause BBB damage and accelerate the formation of neuroinflammation in infected hosts, which not only provides a new understanding of the neuropathogenesis caused by CV-A16, but also offers a promising target for the development of CV-A16 antiviral drugs.

Hyaluronic acid modified prussian blue analogs/TiO₂ janus nanostructures through efficient charge separation to enhance photocatalytic-driven dual gas for achieve multimodal treatment of rheumatoid arthritis

Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by the abnormal proliferation of fibroblast-like synoviocytes and changes in the joint synovium, including elevated reactive oxygen species, decreased pH, and reduced oxygen content. In this study, we synthesized a novel nanocomposite material, namely HA-PBA-TiO2 Janus nanocomposite, by in situ etching in prussian blue analogs doped with Co and Ni, followed by the growth of TiO2 nano-flowers and encapsulation in hyaluronic acid. When these janus nanoparticles diffused to the inflammatory sites of RA, they exhibited outstanding photocatalytic water-splitting ability under 660 nm laser irradiation, generating H2 and O2. This capability helps ameliorate the hypoxic microenvironment at RA inflammatory sites by eliminating reactive oxygen species (ROS) and enhancing antioxidation and oxygenation. Furthermore, owing to the doping of Co and Ni, HA-PBA-TiO2 exhibits photothermal conversion capability, which significant damage to FLS upon exposure to 660 nm laser irradiation, thereby controlling their aberrant proliferation. Through a series of in vitro and in vivo experiments, we validated the significant therapeutic efficacy of HA-PBA-TiO2 in treating RA, highlighting its broad prospects for application.

Lysophosphatidylcholine Acyltransferase 2 Contributes to Increased Allergic and Irritant Inflammation in Mice.

Platelet-activating factor (PAF) is an important chemical mediator in the field of inflammation, but its function in the skin is unclear. To unravel the role of PAF, we focused on lysophosphatidylcholine acyltransferase 2 (LPCAT2 also called LPLAT9), a biosynthetic enzyme involved in PAF production, and investigated the role of PAF in allergic contact dermatitis (ACD) and irritant contact dermatitis (ICD). We measured the amount of PAF in the skin and investigated the ear swelling responses and leukocyte infiltration into the skin following the application of 2,4,6-trinitro-1-chlorobenzene (TNCB) or croton oil in wild-type (WT) and LPCAT2 knockout (LPCAT2-KO) mice. The amount of PAF was increased in the skin of WT mice after TNCB or croton oil application but not detected in LPCAT2-KO mice. The ear swelling response was decreased in LPCAT2-KO mice compared with that in WT mice. In the ACD model, the numbers of lymphocytes, eosinophils, macrophages, mast cells and neutrophils were smaller in LPCAT2-KO mice than in WT mice. In the ICD model, the ear swelling response was also decreased in LPCAT2-KO mice compared with that in WT mice. When double staining of each inflammatory cell type and LPCAT2 was performed in ACD tissue, marked co-staining of the eosinophil marker and LPCAT2 was observed. In addition, LPCAT2 expression was observed in the epidermis. These results indicate that PAF is involved in the infiltration of several cell types into the sites of allergic and non-allergic skin inflammation. Furthermore, eosinophils and keratinocytes are primarily responsible for PAF production in skin inflammation.

Antimicrobial peptide LyeTx I mn∆K labeled with 68Ga is a potential PET radiopharmaceutical for molecular imaging of infections

BackgroundAntimicrobial peptides have been radiolabeled and investigated as molecular diagnostic probes due to their propensity to accumulate in infectious sites rather than aseptic inflammatory lesions. LyeTx I is a cationic peptide from the venom of Lycosa erythrognatha, exhibiting significant antimicrobial activity. LyeTx I mn∆K is a shortened derivative of LyeTx I, with an optimized balance between antimicrobial and hemolytic activities. This study reports the first 68Ga-radiolabeling of the DOTA-modified LyeTx I mn∆K and primarily preclinical evaluations of [68Ga]Ga-DOTA(K)-LyeTx I mn∆K as a PET radiopharmaceutical for infection imaging. MethodsDOTA(K)-LyeTx I mn∆K was radiolabeled with freshly eluted 68Ga. Radiochemical yield (RCY), radiochemical purity (RCP), and radiochemical stability (in saline and serum) were evaluated using ascending thin-layer chromatography (TLC) and reversed-phase high-performance liquid chromatography (RP-HPLC). The radiopeptide's lipophilicity was assessed by determining the logarithm of the partition coefficient (Log P). Serum protein binding (SBP) and binding to Staphylococcus aureus (S. aureus) cells were determined in vitro. Ex vivo biodistribution studies and PET/CT imaging were conducted in healthy mice (control) and mice with infection and aseptic inflammation to evaluate the potential of [68Ga]Ga-DOTA(K)-LyeTx I mn∆K as a specific PET radiopharmaceutical for infections. Results[68Ga]Ga-DOTA(K)-LyeTx I mn∆K was obtained with a high RCY (>90 %), and after purification through a Sep-Pak C18 cartridge, the RCP exceeded 99 %. Ascending TLC and RP-HPLC showed that the radiopeptide remained stable for up to 3.0 h in saline solution and up to 1.5 h in murine serum. [68Ga]Ga-DOTA(K)-LyeTx I mn∆K exhibited hydrophilic characteristics (Log P = −2.4 ± 0.1) and low SPB (ranging from 23.3 ± 0.4 % at 5 min of incubation to 10.5 ± 1.1 % at 60 min of incubation). The binding of [68Ga]Ga-DOTA(K)-LyeTx I mn∆K to S. aureus cells was proportional to bacterial concentration, with binding percentages of 8.8 ± 0.5 % (0.5 × 109 CFU.mL−1), 16.2 ± 1.4 % (1.0 × 109 CFU.mL−1), and 62.2 ± 0.6 % (5.0 × 109 CFU.mL−1). Ex vivo biodistribution studies and PET/CT images showed higher radiopeptide uptake at the infection site compared to the aseptic inflammation site; the latter was similar to the control group. Target-to-non-target (T/NT) ratios obtained by ex vivo biodistribution data were approximately 1.0, 1.3, and 3.0 at all investigated time intervals for the control, aseptic inflammation, and infection groups, respectively. Furthermore, T/NT ratios obtained from PET/CT images were 1.1 ± 0.1 for the control group and 1.4 ± 0.1 for the aseptic inflammation group. For the infection group, T/NT ratio was 5.0 ± 0.3, approximately 5 times greater compared to the former groups. ConclusionsThe results suggest the potential of [68Ga]Ga-DOTA(K)-LyeTx I mn∆K as a PET radiopharmaceutical for molecular imaging of infections.

Possible involvement of Toll-like receptor 8-positive monocytes/macrophages in the pathogenesis of Sjögren’s disease

BackgroundSjögren’s disease (SjD) is an autoimmune disease marked by lymphocytic infiltration of salivary and lacrimal glands, leading to glandular dysfunction, where CD4-positive helper T (Th) cells and their cytokines are crucial in the pathogenesis. Recent studies have demonstrated that Toll-like receptors (TLRs), particularly those recognizing immune complexes containing DNA and RNA, contribute to Th cell activation in various autoimmune diseases. This study explores the expression and function of these TLRs in SjD.MethodsDNA microarray analysis of salivary gland tissue from six SjD patients and real-time PCR (n = 32) was used to identify overexpressed TLRs. Single-cell RNA sequencing (scRNA-seq) was performed using tissue lesions and integrated with published scRNA-seq data from tissues and peripheral blood mononuclear cells to examine gene expression in macrophages and monocytes. Finally, multi-color immunofluorescence staining was conducted to confirm TLR8 expression and function in SjD lesions (n = 19).ResultsDNA microarray analysis revealed the up-regulation of TLR8, along with other TLRs and innate immune response genes in SjD. Real-time PCR showed significant up-regulation of TLR7 and TLR8. TLR8 up-regulated in both analyses. In scRNA-seq analysis, the TLR8-expressing cluster comprised macrophages and monocytes, which also produced T cell activation genes like CD86. TLR8-positive macrophages infiltrated inflammatory sites and frequently expressed CD86 in quantitative imaging approaches.ConclusionsThese results suggest that infiltrating monocytes and macrophages may produce cytokines and chemokines through TLR8 stimulation, potentially enhancing B7 molecule expression, promoting the adaptive immune response, and contributing to SjD pathogenesis.

Spatial transcriptomics of meningeal inflammation reveals inflammatory gene signatures in adjacent brain parenchyma.

While modern high efficacy disease modifying therapies have revolutionized the treatment of relapsing-remitting multiple sclerosis, they are less effective at controlling progressive forms of the disease. Meningeal inflammation is a recognized risk factor for cortical gray matter pathology which can result in disabling symptoms such as cognitive impairment and depression, but the mechanisms linking meningeal inflammation and gray matter pathology remain unclear. Here, we performed magnetic resonance imaging (MRI)-guided spatial transcriptomics in a mouse model of autoimmune meningeal inflammation to characterize the transcriptional signature in areas of meningeal inflammation and the underlying brain parenchyma. We found broadly increased activity of inflammatory signaling pathways at sites of meningeal inflammation, but only a subset of these pathways active in the adjacent brain parenchyma. Subclustering of regions adjacent to meningeal inflammation revealed the subset of immune programs induced in brain parenchyma, notably complement signaling and antigen processing/presentation. Trajectory gene and gene set modeling analysis confirmed variable penetration of immune signatures originating from meningeal inflammation into the adjacent brain tissue. This work contributes a valuable data resource to the field, provides the first detailed spatial transcriptomic characterization in a model of meningeal inflammation, and highlights several candidate pathways in the pathogenesis of gray matter pathology.

Spatial transcriptomics of meningeal inflammation reveals inflammatory gene signatures in adjacent brain parenchyma

While modern high efficacy disease modifying therapies have revolutionized the treatment of relapsing-remitting multiple sclerosis, they are less effective at controlling progressive forms of the disease. Meningeal inflammation is a recognized risk factor for cortical gray matter pathology which can result in disabling symptoms such as cognitive impairment and depression, but the mechanisms linking meningeal inflammation and gray matter pathology remain unclear. Here, we performed magnetic resonance imaging (MRI)-guided spatial transcriptomics in a mouse model of autoimmune meningeal inflammation to characterize the transcriptional signature in areas of meningeal inflammation and the underlying brain parenchyma. We found broadly increased activity of inflammatory signaling pathways at sites of meningeal inflammation, but only a subset of these pathways active in the adjacent brain parenchyma. Subclustering of regions adjacent to meningeal inflammation revealed the subset of immune programs induced in brain parenchyma, notably complement signaling and antigen processing/presentation. Trajectory gene and gene set modeling analysis confirmed variable penetration of immune signatures originating from meningeal inflammation into the adjacent brain tissue. This work contributes a valuable data resource to the field, provides the first detailed spatial transcriptomic characterization in a model of meningeal inflammation, and highlights several candidate pathways in the pathogenesis of gray matter pathology.

Investigating T Cell Immune Dynamics and IL-6's Duality in a Microfluidic Lung Tumor Model.

Interleukin 6 (IL-6), produced by immune cells, is crucial in promoting T cell trafficking to infection and inflammation sites, influencing various physiological and pathological processes. Concentrations of IL-6 and other cytokines and chemokines can influence T cell differentiation and activation. Understanding the dual faces of IL-6 within the tumor microenvironment is crucial to understanding its role. A flow-based microsystem was designed to investigate CD4+ T cell activation in response to different IL-6 gradients in an under-control 3D culture. The study found that cancer cells' response to varying IL-6 concentrations was dynamic and dose-sensitive, with immune cell migration rates showing sensitivity to the IL-6 gradient. A549 cell expansion increases gradually and time-dependently with 50 ng of IL-6, while Jurkat cell migration follows a time-dependent pattern. However, when a total of 100 ng IL-6 concentration is applied, A549 cells expand rapidly, potentially influencing Jurkat cell migration. Jurkat cell mobility is lower, possibly due to increased A549 cell presence and heightened cell-cell interactions. Different IL-6 concentration gradients can modulate the expression of some CD markers like CD69 and programed cell death protein 1 in CD4+ T cells, suggesting that IL-6 concentration gradients affect immune cell phenotypes. This suggests that IL-6 plays a crucial role in activating T helper cells and may be involved in the later phases of inflammation. Also, the increased levels of IFN-γ and TNF-α highlight IL-6's impact on T cell inflammatory response. This study emphasizes the intricate effects of IL-6 on T cell activation, phenotype, cytokine production, and phenotypic heterogeneity, providing valuable insights into immune response modulation in an experimental setting.

Macrophage membrane-functionalized manganese dioxide nanomedicine for synergistic treatment of atherosclerosis by mitigating inflammatory storms and promoting cholesterol efflux

Atherosclerosis (AS) poses a significant threat to human life and health. However, conventional antiatherogenic medications exhibit insufficient targeting precision and restricted therapeutic effectiveness. Moreover, during the progression of AS, macrophages undergo polarization toward the proinflammatory M1 phenotype and generate reactive oxygen species (ROS) to accelerate the occurrence of inflammatory storms, and ingest excess lipids to form foam cells by inhibiting cholesterol efflux. In our study, we developed a macrophage membrane-functionalized hollow mesoporous manganese dioxide nanomedicine (Col@HMnO2-MM). This nanomedicine has the ability to evade immune cell phagocytosis, enables prolonged circulation within the body, targets the inflammatory site of AS for effective drug release, and alleviates the inflammatory storm at the AS site by eliminating ROS. Furthermore, Col@HMnO2-MM has the ability to generate oxygen autonomously by breaking down surplus hydrogen peroxide generated at the inflammatory AS site, thereby reducing the hypoxic microenvironment of the plaque by downregulating hypoxia-inducible factor (HIF-1α), which in turn enhances cholesterol efflux to inhibit foam cell formation. In an APOE−/− mouse model, Col@HMnO2-MM significantly reduced inflammatory factor levels, lipid storage, and plaque formation without significant long-term toxicity. In summary, this synergistic treatment significantly improved the effectiveness of nanomedicine and may offer a novel strategy for precise AS therapy.

Ventricular parasystole as a new indicator suggesting ventricular arrhythmias in cardiac sarcoidosis

Abstract Background In cardiac sarcoidosis (CS), it is considered that inflammation occurs in localized areas such as the basal septum. Inflammation has been suggested to be associated with ventricular fibrillation (VF). Meanwhile, ventricular parasystole is strongly associated with VF in non-ischemic cardiomyopathy. However, the relationship between CS and ventricular parasystole remains unclear. Purpose The purpose is to examine the frequency of parasystole in cases of VF and ventricular tachycardia (VT) in CS, and whether there is a correlation between the inflammatory activity of sarcoidosis and the origin of ventricular parasystole. Methods We evaluated ventricular arrhythmias (VA) in a cohort of 213 consecutive cases diagnosed with CS from 1989 to 2021 (median age 69 years, 104 males, median LVEF 36%) in our center. We investigated parasystole in cases that developed VA, using 5,313 electrocardiograms, 94 Holter electrocardiograms, and 3,174 ICD interrogation records. Classic parasystole is defined as three ventricular ectopic beats with the same morphology at a fixed interval but different coupling intervals (CI) in a 10-second continuous ECG. A new definition of parasystole requires two ventricular ectopic beats with a CI difference of more than 120ms. We also investigated the correlation of the inflammation site with ECG morphology. Results VAs were observed in 95 individuals (33.7%), and 22 developed VF (23.2%). In the VF group, parasystole was observed in 12 of 22 individuals (classic: 5, new: 7), and in the VT group observed in 20 of 73 individuals (classic: 5, new: 15), with parasystole being significantly more frequent in the VF group (P=0.018) and classic parasystole (P=0.033). In VF patients with recorded 12-lead ECGs of parasystole, the inflammation site on PET within 3 months of the VA and PVC origin matched in all 4 out of 4 cases, but no VF starting from ventricular parasystole ectopic beats was recorded. Conclusion Ventricular parasystole was detected in 54.5% of CS patients with VF. There is a possibility that the presence of parasystole and the inflammatory activity in the CS can predict the occurrence of VF.

Macrophage-T cell hybrid membrane-camouflaged biomimetic nanoparticles ameliorate autoimmune myocarditis via suppressing macrophage pyroptosis by target gene silencing

Abstract Background Current management of myocarditis mainly relies on conventional approaches and immunosuppressive therapies. However, these strategies often yield limited efficacy. Our previous research revealed the pivotal role of macrophage pyroptosis in myocarditis pathogenesis. Therefore, targeted intervention to inhibit macrophage pyroptosis may provide new insights into myocarditis treatment. Purpose We previously identified interferon regulatory factor 1 (IRF1) as the key modulator of macrophage pyroptosis in myocarditis. In this study, we synthesized a nano-delivery platform consisting of a macrophage-T cell hybrid membrane-coated zeolitic imidazolate framework-8 (ZIF-8) encapsulating IRF1-small interfering RNA (siRNA@ZIF@HM). We aimed to evaluate its targeting capability and therapeutic efficacy for macrophage pyroptosis in myocarditis. Methods The fabrication of siRNA@ZIF@HM was validated using transmission electron microscopy (TEM) and dynamic light scattering (DLS). Cellular uptake, cytotoxicity, endolysosome escape, IRF1 silencing, and anti-pyroptotic effect were assessed using mouse bone marrow-derived macrophages and the mouse macrophage cell line J774A.1 and RAW264.7. An experimental autoimmune myocarditis (EAM) mouse model was induced in Balb/c mice for in vivo investigations. Pharmacokinetics and targeting capability were determined with ex vivo fluorescence imaging and immunofluorescence staining. Subsequently, mice were randomly allocated into control, EAM + siRNA, EAM + siRNA@ZIF, and EAM + siRNA@ZIF@HM groups to assess the therapeutic efficacy. Additionally, the biodistribution and biosafety of siRNA@ZIF@HM were also evaluated. Results TEM, DLS, and element mapping confirmed the successful fabrication of siRNA@ZIF@HM, with a diameter of approximately 130 nm. The nanoparticle exhibited pH responsiveness and membrane markers of macrophage and T lymphocytes (Figure 1). It demonstrated high targeting specificity for pro-inflammatory macrophages and myocarditis. Immunofluorescence microscopy revealed successful endolysosome escape of IRF1-siRNA in macrophages. Consequently, the nanoparticle significantly silenced IRF1 protein expression and suppressed macrophage pyroptosis both in vivo and in vitro, resulting in the amelioration of autoimmune myocarditis (Figure 2). Furthermore, the nanoparticle showed good biocompatibility with no significant changes observed in other organs. Conclusions The pH-responsive, macrophage-T cell hybrid membrane-coated biomimetic nanoparticle demonstrates promising capability for targeted siRNA delivery to myocardial inflammation sites, particularly pro-inflammatory macrophages. Additionally, targeting IRF1-mediated macrophage pyroptosis represents a potential therapeutic strategy for myocarditis treatment.Figure 1Figure 2

Progranulin derivative attenuates lung neutrophilic infiltration from diesel exhaust particle exposure.

Air pollutants, such as diesel exhaust particles (DEPs), induce respiratory disease exacerbation with neutrophilic infiltration. Progranulin (PGRN), an epithelial cell and macrophage-derived secretory protein, is associated with neutrophilic inflammation. PGRN is digested into various derivatives at inflammatory sites and is involved in several inflammatory processes. PGRN and its derivatives likely regulate responses to DEP exposure in allergic airway inflammation. To investigate the role of PGRN and its derivatives in the regulation of responses to DEP exposure in allergic airway inflammation. A murine model of allergic airway inflammation was generated in PGRN-deficient mice, and they were simultaneously exposed to DEP followed by intranasal administration of full-length recombinant PGRN (PGRN-FL) and a PGRN-derived fragment (FBAC). Inflammatory status was evaluated by bronchoalveolar lavage fluid and histopathologic analyses. Human bronchial epithelial cells were stimulated with DEPs and house dust mites (HDMs), and the effect of FBAC treatment was evaluated by assessing various intracellular signaling molecules, autophagy markers, inflammatory cytokines, and intracellular oxidative stress. DEP exposure exaggerated neutrophilic inflammation, enhanced IL-6 and CXCL15 secretions, and increased oxidative stress in the murine model; this effect was greater in PGRN-deficient mice than in wild-type mice. The DEP-exposed mice with PGRN-FL treatment revealed no change in neutrophil infiltration and higher oxidative stress status in the lungs. On the contrary, FBAC administration inhibited neutrophilic infiltration and reduced oxidative stress. In human bronchial epithelial cells, DEP and HDM exposure increased intracellular oxidative stress and IL-6 and IL-8 secretion. Decreased nuclear factor erythroid 2-related factor 2 (Nrf2) expression and increased phosphor-p62 and LC3B expression were also observed. FBAC treatment attenuated oxidative stress from DEP and HDM exposure. FBAC reduced neutrophilic inflammation exaggerated by DEP exposure in a mouse model of allergic airway inflammation by reducing oxidative stress. PGRN and PGRN-derived proteins may be novel therapeutic agents in attenuating asthma exacerbation induced by air pollutant exposure.

2D speckle tracking echocardiography and comparison with cardiac magnetic resonance in children with acute myocarditis

BackgroundCardiac magnetic resonance (CMR) plays a major diagnostic role in acute myocarditis (AM) in children as biopsy is rarely performed in this age group. Contribution of standard echocardiography (ECHO) is limited in AM, but speckle tracking echocardiography (STE) quantitatively characterizes myocardial function, with good sensitivity for detecting subclinical left ventricular (LV) dysfunction and regional kinetics disorders beyond the site of inflammation. This work aimed to evaluate the diagnostic potential of STE as compared with CMR findings in pediatric patients with AM.MethodsThe study was conducted during 2022–2023. Troponin, electrocardiography, ECHO with STE, and CMR with early and late enhancement were performed on each patient. Affected heart segments were analyzed by both STE and CMR, and the correlation of the two methods was assessed.ResultsDuring the study period, 20 children were diagnosed with AM [14 boys, 6 girls; mean age 12 years (median 14)]. On ECHO, three patients had a deviation in LV biometry, and four patients had a mild systolic function disorder. STE showed at least one affected cardiac segment in all patients, most often the inferolateral segment (16/20; 80%). Of the 20 patients, STE showed a reduction in LV global longitudinal strain in 13 (65%) patients. In all patients, CMR identified an inflammatory focus, most frequently inferolateral (15/20; 75%). The strongest accordance between STE and CMR was observed for the involvement of anterolateral segments (k = 0.88) and the weakest for inferoseptal damage (k = 0.4).ConclusionsSTE can provide important diagnostic information in pediatric patients with AM. This modality supports the detection of early regional edema and subclinical myocardial dysfunction and can determine the impairment severity. STE is non-invasive and repeatable without the need for special patient preparation or for general anesthesia.

Causal relationship between circulating inflammatory proteins and risk of different types of encephalitis: A two-sample Mendelian randomization study

BackgroundCytokines are potent molecules of the immune response. They act at the site of inflammation and circulate in the bloodstream. However, there are few studies on encephalitis and circulating inflammatory proteins. MethodsIn this study, Mendelian randomization (MR) was used to explore the potential causal effect of 91 circulating inflammatory proteins on 3 different types of encephalitis. Causal effects were examined using Steiger, MR-Egger, weighted median, and inverse variance weighting (IVW) methods. IVW methods were primarily used for results interpretation. In addition, sensitivity analyses were performed, including assessment of heterogeneity, horizontal pleiotropy, and Leave-one-out techniques. ResultsWe subjected 91 circulating inflammatory proteins to MR analysis of causality with each of the three types of encephalitis. The results suggested that the inflammatory factors with a potential causal relationship with viral encephalitis were caspase 8, C-X-C motif chemokine 6, interleukin-10, interleukin-15 receptor subunit alpha, interleukin-7, and TNF-beta. Inflammatory factors potentially causally associated with acute disseminated encephalomyelitis are beta-nerve growth factor, cystatin D, interleukin-7,Latency-associated peptide transforming growth factor beta 1,and neurotrophin-3.Inflammatory factors potentially causally associated with autoimmune encephalitis are C–C motif chemokine 25, hepatocyte growth factor, latency-associated peptide transforming growth factor beta 1, programmed cell death 1 ligand 1, sulfotransferase 1A1, and tumor necrosis factor. ConclusionThis finding identifies potential causal effects of certain circulating inflammatory factors on susceptibility to three types of encephalitis. It also suggests the therapeutic potential of modulating the levels of these cytokines. A basis for further research is provided.

Inflammation-Targeted Biomimetic Nano-Decoys via Inhibiting the Infiltration of Immune Cells and Effectively Delivering Glucocorticoids for Enhanced Multiple Sclerosis Treatment.

Excessive infiltration of neutrophil and inflammatory cytokines accumulation as well as the inadequate delivery of drugs to the targeted site are key pathological cascades in multiple sclerosis (MS). Herein, inflammation-targeting biomimetic nano-decoys (TFMN) is developed that inhibit the infiltration of immune cells and effectively deliver glucocorticoids to lesions for enhanced MS treatment. Nano-decoys encapsulated with the glucocorticoid methylprednisolone (MPS) are prepared by coating neutrophil membrane (NM) on nanoparticles formed by the self-assembly of tannic acid and poloxamer188/pluronic68. Benefiting from the natural inflammation-targeting ability of activated neutrophil membranes, TFMN can target the lesion site and prevent neutrophils infiltration by adsorbing and neutralizing elevated neutrophil-related cytokines, subsequently modulating the inflammatory microenvironment in experimental autoimmune encephalomyelitis mice. TFMN exhibits a strong antioxidant capacity and scavenged excessive reactive oxygen species to enhance neuronal protection. Furthermore, at the inflammation site, perforin, discharged by cytotoxic T-lymphocytes, triggered the controlled release of MPS within the TFMN through perforin-formed pores in the NM. Simultaneously, this mechanism protected neurons from perforin-induced toxicity. The MPS liberated at the targeted site achieves optimal drug accumulation, thereby enhancing therapeutic efficacy. In conclusion, the innovative system shows potential for integrating various therapeutic agents, offering a novel strategy for CNS disorders.