Sites Of Inflammation Research Articles

Cooperation Between Platelet β1 and β3 Integrins in the Arrest of Bleeding Under Inflammatory Conditions in Mice-Brief Report.

Platelets prevent bleeding in a variety of inflammatory settings, the adhesion receptors and activation pathways involved being highly context-dependent and functionally redundant. In some situations, platelets recruited to inflammatory sites act independently of aggregation. The mechanisms underlying stable platelet adhesion in inflamed microvessels remain incompletely understood, in particular, whether and if so, how β1 and β3 integrins are involved. The impact of isolated or combined platelet deficiency in β1 and β3 integrins on inflammation-associated hemostasis was investigated in 3 models of acute inflammation: immune complex-based cutaneous reverse passive Arthus reaction, intranasal lipopolysaccharide-induced lung inflammation, and cerebral ischemia-reperfusion following transient (2-hour) occlusion of the middle cerebral artery. Mice with platelet-directed inactivation of Itgb1 (PF4Cre-β1-/-) displayed no bleeding in any of the inflammation models, while mice defective in platelet Itgb3 (PF4Cre-β3-/-) exhibited bleeding in all 3 models. Remarkably, the bleeding phenotype of PF4Cre-β3-/- mice was exacerbated in the reverse passive Arthus model by the concomitant deletion of β1 integrins, PF4Cre-β1-/-/β3-/- animals presenting increased bleeding. Intravital microscopy in reverse passive Arthus experiments highlighted a major defect in the adhesion of PF4Cre-β1-/-/β3-/- platelets to inflamed microvessels. Unlike PF4Cre-β1-/- and PF4Cre-β3-/- mice, PF4Cre-β1-/-/β3-/- animals developed early hemorrhagic transformation 6 hours after transient middle cerebral artery occlusion. PF4Cre-β1-/-/β3-/- mice displayed no more bleeding in lipopolysaccharide-induced lung inflammation than PF4Cre-β3-/- animals. Altogether, these results show that the requirement for and degree of functional redundancy between platelet β1 and β3 integrins in inflammation-associated hemostasis vary with the inflammatory situation.

Gastrointestinal Self-Adaptive and Nutrient Self-Sufficient Akkermansia muciniphila-Gelatin Porous Microgels for Synergistic Therapy of Ulcerative Colitis.

To realize effective and long-term synergistic therapy of ulcerative colitis (UC) with probiotics, we developed gastrointestinal self-adaptive and nutrient self-sufficient Akkermansia muciniphila (AKK)-gelatin porous microgels (AKK@GPMGs). In AKK@GPMGs, AKK was covered with sequential layers of proanthocyanidins (PAs), mucin (MUC), and phosphatidylcholine (PC) to obtain AKK@PAs-MUC-PC (AKK@PMP), and then encapsulated within the methacrylate-modified gelatin porous microgels. AKK@GPMGs provide sufficient mucus as a nutrition source for AKK and boost resistance to stomach acid by 30.49-fold, and colonization in the intestines is enhanced by 83.46 times. The microgels can be dissociated by matrix metalloproteinase at the inflammatory sites of the intestine, and release AKK@PMP, which acts as "band-aid" that adheres to the inflamed colon for a long time and offers improved synergistic therapy for UC. Compared to uncoated AKK, AKK@GPMGs increase reactive oxygen species scavenging capacity by 26.47 times, improve the intestinal mucus layer thickness by 5.63 times, increase the goblet cells abundance by 3.93 times, reduce intestinal permeability by 5.60 times and significantly enhance beneficial gut microbiota while repressing harmful microbiota. These results indicate that AKK@GPMGs can restore mucus layer and tight junction integrity, reduce inflammation and oxidative stress, and regulate gut microbiota homeostasis to effectively treat intestinal inflammation.

The Role of Inducible Nitric Oxide Synthase in Assessing the Functional Level of Coronary Artery Lesions in Chronic Coronary Syndrome.

Chronic coronary syndrome (CCS) is a long-term manifestation of coronary artery disease, marked by stable but recurring chest pain and myocardial ischemia due to the gradual buildup of atherosclerotic plaques in the coronary arteries. It is a metabolic disorder of coronary arteries characterized by oxidative stress, endothelial dysfunction, inflammation, and hyperlipidemia. The imbalance in oxidative-antioxidative status contributes to stable ischemic heart disease. Oxidative stress involves reactive oxygen and nitrogen species, leading to low-density lipoprotein (LDL) oxidation. Endothelial dysfunction, marked by reduced nitric oxide (NO) bioavailability, is an early onset of CCS, affecting vasodilation, cell proliferation, and inflammatory responses. Enzyme myeloperoxidase (MPO), traditionally considered protective, plays a dual role in initiating and progressing inflammatory diseases. MPO interacts with NO, modulating its catalytic activity. Elevated NO levels inhibit MPO through a reversible complex formation, preventing NO-induced inhibition by inducible nitric oxide synthase (iNOS). MPO also inactivates endothelial nitric oxide synthase (eNOS) and reacts with L-arginine, hindering NO synthesis. The interplay between MPO and NO significantly influences inflammation sites, impacting peroxidation rates and oxidation reactions. Peroxynitrite, a reactive species, contributes to nitration of tyrosine residues and lipid peroxidation. Mechanistic pathways suggest MPO enhances iNOS catalytic activity, influencing CCS development. iNOS, implicated in inflammation and atherosclerosis, is connected to NO regulation. This review analyzes the complex interplay of MPO, iNOS, and NO that affects plaque morphology, oxidative stress, and inflammation, contributing to atherosclerosis progression. Therefore, it is possible that the phenotypes of atherosclerotic plaques, focal and diffuse coronary artery disease, could be defined by the relationship between MPO and iNOS.

Targeting the Sphingosine-1-Phosphate Pathway: New Opportunities in Inflammatory Bowel Disease Management.

Inflammatory bowel diseases (IBD), including Crohn's disease (CD) and ulcerative colitis (UC) are chronic immune-mediated diseases which primarily target the intestines. In recent years, the development and regulatory approval of various immunotherapies, both biological agents and small molecules, that target specific pathways of the IBD-associated inflammatory cascade have revolutionized the treatment of IBD. Small molecules offer the advantages of oral administration and short wash-out times. Sphingosine-1-phosphate (S1P) is a bioactive metabolite of ceramide, which exerts its functions after binding to five G-protein-coupled receptors (S1PR1-S1PR5). Concerning IBD, S1P participates in the egress of lymphocytes from the secondary lymphoid tissue and their re-circulation to sites of inflammation, mainly through S1PR1 binding. In addition, this system facilitates the differentiation of T-helper cells towards proinflammatory immunophenotypes. Recently, S1P modulators have offered a valuable addition to the IBD treatment armamentarium. They exert their anti-inflammatory function via sequestration of T cell subsets in the lymphoid tissues and prevention of gut homing. In this review, we revisit the role of the S1P/S1PR axis in the pathogenesis of IBD and discuss efficacy and safety data from clinical trials and real-world reports on the two S1PR modulators, ozanimod and etrasimod, that are currently approved for IBD treatment, and comment on their potential positioning in the IBD day-to-day management. We also present recent data on emerging S1P modulators. Finally, based on the successes and failures of S1PR modulators in IBD, we discuss future avenues of IBD treatments targeting the S1P/S1PR axis.

Can pin-site inflammation be detected with thermographic imaging? A cross-sectional study from the USA and Denmark of patients treated with external fixators.

Patients with external fixators are at risk of pin-site infection. A tool for objective monitoring of pin sites for evolving signs of infection is warranted. We aimed to investigate the temperature (MaxTp) difference between clean and visually inflamed pin sites using thermography and to establish the optimal cut-off value of MaxTp using thermography as a screening tool for inflammation detection. This was a cross-sectional study performed in the USA and Denmark of patients with circular external fixators. Pin sites were visually judged by a surgeon or a nurse as clean or as showing signs of inflammation. The MaxTp was obtained at the pin site by thermographic imaging using an infrared camera (FLIR T540). We included 1,970 pin sites from 83 patients. The mean MaxTp for clean pin sites (n = 1,739) was 33.1°C (95% confidence interval [CI] 32.8-33.4) and the mean MaxTp for visual inflamed pin sites (n = 231) was 34.0°C (CI 33.6-34.3). The mean difference, when adjusted for repeated observations of patients and pin sites, was statistically significant with a difference of 0.9°C (CI 0.7-1.1) (P < 0.001). The area under the receiver operating characteristic curve for MaxTp as a screening tool to detect visual signs of inflammation was 0.71 (CI 0.65-0.76). The empirically optimal cut-off value was 34.1°C with a sensitivity of 65%, a specificity of 72%, a positive predictive value of 23%, and a negative predictive value of 94%. We found a statistically significant difference in mean temperature between pin sites with and without visual signs of inflammation. Thermography could be a promising tool for future point of care technology for monitoring inflammation around pin sites.

Neutrophil elastase-activated carbon dots for non-invasive early diagnosis of inflammatory bowel disease by near-infrared-II fluorescence imaging

Most near-infrared-II (NIR-II) fluorescent probes produce an “always-on” output with poor signal specificity for biomarkers. Neutrophil elastase (NE) is a critical factor in chronic inflammation or in the acute response to infection and injury, and NE activatable NIR-II fluorescent probes can aid in the early clinical diagnosis of inflammatory bowel disease (IBD). In this paper, we synthesized OPDG-PFA@PEI carbon dots (CDs) through a two-step reaction of solvothermal/surface covalent bond modification, which can “turn on” specific NIR-II fluorescence signals related to the level of NE produced by neutrophils and target sites of inflammation effectively, thus realizing the monitoring of in-situ NE in cells and in vivo. OPDG-PFA@PEI CDs fluorescent nanoprobe show high-performance real-time non-invasive NIR-II fluorescence imaging for early diagnostic evaluation of IBD in mouse models of DSS-induced IBD, providing a promising approach for the development of clinical non-invasive and more convenient early diagnosis of IBD.

Impaired tolerance of monocyte-macrophages to lipopolysaccharide in patients with coronary atherosclerosis

Atherosclerosis is a chronic disease in which lipids, cells and various proteins accumulate in the walls of the arteries, forming atherosclerotic plaques. The growth of plaques leads narrowing of the lumen of the blood vessels. Atherosclerosis is accompanied by local inflammation, while the number of hematogenous macrophages are derived from monocytes increases in the vascular wall. The reasons why the inflammatory reaction cannot be completed and becomes chronic are not clear. To resolve inflammation and protect tissues from high concentrations of cytokines that can cause apoptosis, there is a mechanism of immune tolerance of innate immunity. Lipopolysaccharide (LPS) tolerance of monocyte-macrophages is a phenomenon in which cells reduce their sensitivity to repeated exposure to LPS. This condition is characterized by a decrease in the ability of macrophages to produce proinflammatory cytokines and promotes resolution of inflammation. We hypothesized that in atherosclerosis, tolerance violations in monocyte-macrophages are possible. The study included patients who were admitted to the department of cardiac surgery, Moscow Regional Research and Clinical Institute (MONIKI). Patients were divided into patients with coronary atherosclerosis (CAD) with detected stenosis in 2 or more arteries and healthy controls without stenosis in the arteries according to the results of coronary angiography. In the present study, we examined the ability of macrophages from 13 patients with CAD and 11 patients without CAD to develop tolerance to LPS. To do this, we isolated CD14+ monocytes from the blood by positive selection using immunomagnetic separation and subjected them to two sequential LPS stimulations, immediately after cell isolation and after 6 days of culture. The secretion of cytokines TNFα, IL-1b, IL-6, IL-10, IL-8, and CCL2 was measured in cell culture supernatants using by ELISA. Our results showed impaired macrophage tolerance for CCL2 secretion and improved tolerance for IL-8 secretion in macrophages from patients with CAD compared with patients without. Since IL-8 and CCL2 are chemoattractants for other immune cells, it can be assumed that the observed impairment of macrophage tolerance to LPS in atherosclerosis increases the infiltration of other monocytes into the inflammatory site, contributing to the chronicity of inflammation.

Reactive Oxygen Species Triggered Cleavage of Thioketal‐Containing Supramolecular Nanoparticles for Inflammation‐Targeted Oral Therapy in Ulcerative Colitis

AbstractCombating reactive oxygen species (ROS) and targeted drug delivery to inflammatory sites are considered effective therapeutic strategies for ulcerative colitis (UC), a refractory chronic inflammatory disease. Herein, a ROS‐responsive thioketal (TK) crosslinked cyclodextrin metal‐organic framework (TCOF) is fabricated, to which a non‐ROS‐sensitive vector, sulfur substituted by carbon chain‐crosslinked cyclodextrin metal‐organic framework (CCOF) is parallelly designed as ROS negative reference. Dexamethasone (DEX) loaded in TCOF (TCD) and CCOF (CCD) are investigated to demonstrate the advantages of precision medicine for UC. After the ROS‐induced collapse of nanoparticles, TCD selectively triggered the release of DEX. Moreover, TCD effectively protected cells from oxidative stress damage and reduced inflammation levels in vitro. Remarkably, the TK group of TCD is oxidatively broken by consuming ROS at the inflammatory site, exposing the thiol group to mucosal adhesion, which enhances the retention of TCD at colons. In vivo studies of UC treatment reveals that oral administration of TCD demonstrated excellent inflammation‐targeting properties, remarkably attenuated oxidative stress, and ameliorated both acute and chronic colitis compared to CCD. Furthermore, TCD exhibits an excellent safety profile in mice. These results instill confidence in advancing targeted drug delivery and precision therapy for UC.

Preschool-age children maintain a distinct memory CD4+ T cell and memory B cell response after SARS-CoV-2 infection.

The development of the human immune system lasts for several years after birth. The impact of this maturation phase on the quality of adaptive immunity and the acquisition of immunological memory after infection at a young age remains incompletely defined. Here, using an antigen-reactive T cell (ARTE) assay and multidimensional flow cytometry, we profiled circulating severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-reactive CD3+CD4+CD154+ T cells in children and adults before infection, during infection, and 11 months after infection, stratifying children into separate age groups and adults according to disease severity. During SARS-CoV-2 infection, children younger than 5 years old displayed a lower antiviral CD4+ T cell response, whereas children older than 5 years and adults with mild disease had, quantitatively and phenotypically, comparable virus-reactive CD4+ T cell responses. Adults with severe disease mounted a response characterized by higher frequencies of virus-reactive proinflammatory and cytotoxic T cells. After SARS-CoV-2 infection, preschool-age children not only maintained neutralizing SARS-CoV-2-reactive antibodies postinfection comparable to adults but also had phenotypically distinct memory T cells displaying high inflammatory features and properties associated with migration toward inflamed sites. Moreover, preschool-age children had markedly fewer circulating virus-reactive memory B cells compared with the other cohorts. Collectively, our results reveal unique facets of antiviral immunity in humans at a young age and indicate that the maturation of adaptive responses against SARS-CoV-2 toward an adult-like profile occurs in a progressive manner.

Enteric-coated cerium dioxide nanoparticles for effective inflammatory bowel disease treatment by regulating the redox balance and gut microbiome

Reactive oxygen species (ROS) play crucial roles in the pathogenesis of inflammatory bowel disease (IBD) by disrupting the mucosal barrier and subsequently leading to the dysregulation of the gut microbiome. Therefore, ROS scavengers present a promising and comprehensive strategy for the effective IBD treatment. In the current work, we explored the therapeutic potential of cerium dioxide (CeO2) nano-enzyme, which is well-known for their potent antioxidant properties and capability to mimic natural antioxidant enzymes in the regulation of oxidative stress. We developed a novel enteric-coated nanomedicine (CeO2@S100) aiming at improving the oral delivery efficacy of CeO2 in the complex gastrointestinal environment. CeO2@S100 is composed of a CeO2 nanoparticle core and a protective polyacrylic acid resin shell (Eudragit S100), ensuring targeted delivery of the core specifically at inflamed intestinal sites due to the negative surface charge. In vivo experiments revealed CeO2@S100 significantly alleviates the IBD by balancing oxidative stress and regulating gut microbiota in a dextran sulfate sodium-induced mouse colitis model. The uncomplicated synthesis of CeO2@S100 highlights its promise for clinical use, presenting an effective and safe approach to managing IBD.

Closed-loop theranostic microgels for immune microenvironment modulation and microbiota remodeling in ulcerative colitis

Inflammatory bowel disease (IBD) is characterized by the upregulation of reactive oxygen species (ROS) and dysfunction of gut immune system, and microbiota. The conventional treatments mainly focus on symptom control with medication by overuse of drugs. There is an urgent need to develop a closed-loop strategy that combines in situ monitoring and precise treatment. Herein, we innovatively designed the ‘cluster munition structure’ theranostic microgels to realize the monitoring and therapy for ulcerative colitis (a subtype of IBD). The superoxide anion specific probe (tetraphenylethylene-coelenterazine, TPC) and ROS-responsive nanogels consisting of postbiotics urolithin A (UA) were loaded into alginate and ion-crosslinked to obtain the theranostic microgels. The theranostic microgels could be delivered to the inflammatory site, where the environment-triggered breakup of the microgels and release of the nanogels were achieved in sequence. The TPC-UA group had optimal results in reducing inflammation, repairing colonic epithelial tissue, and remodeling microbiota, leading to inflammation amelioration and recovery of tight junction between the colonic epithelium, and maintenance of gut microbiota. During the recovery process, the local chemiluminescence intensity, which is proportional to the degree of inflammation, was gradually inhibited. The cluster munition of theranostic microgels displayed promising outcomes in monitoring inflammation and precise therapy, and demonstrated the potential for inflammatory disease management.

Leukocyte-based delivery systems for enhanced nanotheranostics of inflammation and cancer

As a part of the immune system, leukocytes (LEs) have the features of circumvention of immunogenicity as well as recruitment to sites of inflammation during infection and tumorigenesis. Utilizing LEs as vehicles to carry theranostic agents is a promising strategy for highly efficient targeted delivery and treatment for inflammation and cancer. Specifically, the LEs, similar to 'Trojan horses', can bypass the immune system and thus enhance the therapeutic effects on inflammation and cancer. In this context, the latest progress of LEs-based delivery systems for improving theranostics of inflammations and cancers is summarized, includingin vitroincubation andin vivointernalization strategy. Although the therapeutic efficacy of LEs-based delivery systems has been achieved, the system construction is complex and the effect is not fulfilling demand completely. Encouragingly, a most recent work reported that the supramolecular arrangement of proteins on the nanocarriers would drive them to be selectively uptaken by neutrophils, opening a new avenue for diagnosis and treatment of inflammation. Moreover, enucleated cells are considered as the biomimetic drug delivery vehicle to retain the organelles for a range of diseases in a safe, controllable and effective manner. These novel findings provide more opportunities for researchers to rethink and redesign the LEs-based delivery systems to overcome existing limitations and broaden their usage, especially in clinical medicine.

Reprogramming monocytes into M2 macrophages as living drug depots to enhance treatment of myocardial ischemia-reperfusion injury

Delivering therapeutic agents efficiently to inflamed regions remains an intractable challenge following myocardial ischemia-reperfusion injury (MI/RI) due to the transient nature of the enhanced permeability and retention effect, which disappears after 24 h. Leveraging the inflammation-homing and plasticity properties of circulating monocytes (MN) as hitchhiking carriers and further inducing their polarization into anti-inflammatory phenotype macrophages upon reaching the inflamed sites is beneficial for MI/RI therapy. Herein, DSS/PB@BSP nanoparticles capable of clearing reactive oxygen species and inhibiting inflammation were developed by employing hollow Prussian blue nanoparticles (PB) as carriers to encapsulate betamethasone sodium phosphate (BSP) and further modified with dextran sulfate sodium (DSS), a targeting ligand for the scavenger receptor on MN. This formulation was internalized into MN as living cell drug depots, reprogramming them into anti-inflammation type macrophages to inhibit inflammation. In vitro assessments revealed the successful construction of the nanoparticle. In a murine MI/RI model, circulating MN laden with these nanoparticles significantly enhanced drug delivery and accumulation at the cardiac injury site, exhibiting favorable therapeutic ability and promoting M2-biased differentiation. Our study provides an effective approach with minimally invasion and biosecurity that makes this nanoplatform as a promising candidate for immunotherapy and clinical translation in the treatment of MI/RI.

Comparison of foci of active inflammation and fatty degeneration according to MRI and CT data of syndesmophytes in patients with ankylosing spondylitis

Introduction. Syndesmophyte, which is the hallmark of ankylosing spondylitis (AS), is a vertically oriented ossification located outside the fibrous ring of the intervertebral disc. In recent decades, the most widespread theory is that after inflammation in the area of attachment of the fibrous ring to the vertebral body, fatty degeneration occurs with reparative processes, as a result of which the growth of new bone – syndesmophyte – begins. It is believed that the likelihood of developing syndesmophyte is two to three times higher in the angles of those vertebrae in which active inflammation or fatty changes were detected on magnetic resonance tomography (MRI) in the previous 2 years, the latter having a stronger association with subsequent pathological bone formation. However, this relationship is ambiguous according to different studies.The aim – comparison of the exact localization of magnetic resonance tomography and computed tomography (CT) signs of lesions on the vertebral endplates, characteristic of axial spondyloarthritis, in patients with ankylosing spondylitis.Material and methods. The cross-sectional study included 10 patients with AS who met the inclusion criteria.All patients underwent a standard examination for AS, as well as MRI and CT examination of the lumbar spine.A special technique for joint assessment of changes detected during MRI and CT examination has been developed.For the primary analysis, changes found on the upper endplates of 5 lumbar vertebrae were taken.Results. On the upper endplates of 5 lumbar vertebrae, a CT examination revealed 35 syndesmophytes (from 1 to 7 syndesmophytes in 1 patient), and MRI revealed 9 foci of acute inflammation and 24 of chronic inflammation (fatty degeneration). When jointly analyzing the MRI foci of detectable inflammation and syndesmophytes transferred to the vertebral diagram, it turned out that in the majority of cases (68%), the latter were not associated with sites of active and/or chronic inflammation. Correlation analysis showed a certain direct relationship only between the number of syndesmophytes and foci of chronic inflammation (r=0.68).Discussion. Preliminary data show that the proposed method for comparing MRI and CT lesions in AS allows us to jointly study the localization of MRI and CT spinal injuries in patients with AS using multidirectional sections. The first results of our one-time study showed that in most cases the localization of developing syndesmophytes does not coincide with the foci of inflammation detected by MRI (both acute and chronic).

Thermo-Responsive Hydrogel Containing Microfluidic Chitosan Nanoparticles Loaded with Opuntia ficus-indica Extract for Periodontitis Treatment.

Periodontitis is a chronic inflammatory disease resulting from the dysbiosis of periodontal bacteria and the host's immune response, leading to tissue degradation and sustained inflammation. Traditional treatments, such as mechanical debridement and antimicrobial agents, often fail to fully eradicate pathogenic bacteria, especially in deep periodontal pockets. Consequently, the need for novel therapeutic approaches has increased the interest in bioactive natural extracts, such as that of Opuntia ficus-indica, known for its anti-inflammatory, antioxidant, and antimicrobial properties. This study investigates the encapsulation of Opuntia ficus-indica extract in OFI-loaded chitosan nanoparticles (OFI-NPs) via ionotropic gelation using a microfluidic system, allowing precise control over nanoparticle characteristics and enhancing protection against enzymatic degradation. To achieve localized and sustained release in periodontal pockets, a thermo-responsive hydrogel comprising hyaluronic acid and Pluronic F127 (OFI@tgels) was developed. The transition of OFI@tgels from a solution at low temperatures to a solid at body temperature enables prolonged drug release at inflammation sites. The in vitro application of the optimized formulation eradicated biofilms of S. mutans, P. aeruginosa (PAO1), and P. gingivalis over 36 h and disrupted extracellular polymeric substance formation. Additionally, OFI@tgel modulated immune responses by inhibiting M1 macrophage polarization and promoting a shift to the M2 phenotype. These findings suggest that OFI@tgel is a promising alternative treatment for periodontitis, effectively reducing biofilm formation and modulating the immune response.

Non-infectious hypertrophic pachymeningitis associated with orbital inflammatory disease: a pooled analysis.

To describe four cases of non-infectious hypertrophic pachymeningitis (HP)-associated with orbital inflammatory disease (OID). This study summarises the clinico-radiological features, outcomes, and management of HP-associated OID. Retrospective case-series of patients with radiological evidence of HP and OID. Comprehensive literature review of all published English-language non-infectious causes of HP-associated OID. Reference lists were screened for inclusion of relevant articles. Thirty-seven cases of HP-associated OID (Mean age: 49.2 ± 17.4 years old; Male: 15) were identified, including four cases from our institution. Aetiologies included ANCA-associated vasculitis (12/37), non-specific/idiopathic (11/37), IgG4/multifocal fibrosclerosis (11/37), neurosarcoidosis (1/37), inflammatory myofibroblastic tumour (1/37), and giant cell arteritis (1/37). Orbital pain, headache, visual deterioration, and cranial nerve palsies were common clinical presentations. Both "focal" and "diffuse" HP were observed, with the most common sign of orbital involvement being an inflammatory orbital mass, typically with orbital apex involvement. Orbital myositis and dacryoadenitis were less common. The cavernous sinus was the most common site of extra-orbital inflammation. There was no single differentiating specific radiological feature between non-specific and specific forms of HP-associated OID. The clinico-radiological manifestations of HP-associated OID differ from those described in isolated HP or OID. There is no single specific radiological marker differentiating non-specific/idiopathic disease from secondary causes; however, the co-existence of HP in OID should prompt suspicion of an underlying cause. The disease may be refractory or resistant to initial treatment, although guidelines surrounding its management and the long-term prognosis remain to be determined.

Bioresponsive and transformable coacervate actuated by intestinal peristalsis for targeted treatment of intestinal bleeding and inflammation

Developing an oral in situ-forming hydrogel that targets the inflamed intestine to suppress bleeding ulcers and alleviate intestinal inflammation is crucial for effectively treating ulcerative colitis (UC). Here, inspired by sandcastle worm adhesives, we proposed a water-immiscible coacervate (EMNs-gel) with a programmed coacervate-to-hydrogel transition at inflammatory sites composed of dopa-rich silk fibroin matrix containing embedded inflammation-responsive core-shell nanoparticles. Driven by intestinal peristalsis, the EMNs-gel can be actuated forward and immediately transform into a hydrogel once contacting with the inflamed intestine to yield strong tissue adhesion, resulting from matrix metalloproteinases (MMPs)-triggered release of Fe3+ from embedded nanoparticles and rearrangement of polymer network of EMNs-gel on inflamed intestine surfaces. Extensive in vitro experiments and in vivo UC models confirmed the preferential hydrogelation behavior of EMNs-gel to inflamed intestine surfaces, achieving highly effective hemostasis, and displaying an extended residence time (> 48 h). This innovative EMNs-gel provides a non-invasive solution that accurately suppresses severe bleeding and improves intestinal homeostasis in UC, showcasing great potential for clinical applications.

Monitoring of Nanodrug Accumulation in Murine Breast Cancer Metastases.

Metastatic breast cancer is a devastating disease with very limited therapeutic options, calling for new therapeutic strategies. Oncogenic miRNAs have been shown to be associated with the metastatic potential of breast cancer and are implicated in tumor cell migration, invasion, and viability. However, it can be difficult to deliver an inhibitory RNA molecule to the tissue of interest. To overcome this challenge and deliver active antisense oligonucleotides to tumors, we utilized magnetic iron oxide nanoparticles as a delivery platform. These nanoparticles target tissues with increased vascular permeability, such as sites of inflammation or cancer. Delivery of these nanoparticles can be monitored in vivo by magnetic resonance imaging (MRI) due to their magnetic properties. Translation of this therapeutic approach into the clinic will be more accessible because of its compatibility with this relevant imaging modality. They can also be labeled with other imaging reporters such as a Cy5.5 near-infrared optical dye for correlative optical imaging and fluorescence microscopy. Here, we demonstrate that nanoparticles labeled with Cy5.5 and conjugated to therapeutic oligomers targeting oncogenic miRNA-10b (termed MN-anti-miR10b, or "nanodrug") administered intravenously accumulate in metastatic sites, opening a possibility for therapeutic intervention of metastatic breast cancer.

Adipose-derived stem cell-based anti-inflammatory paracrine factor regulation for the treatment of inflammatory bowel disease

Stem cell-based therapies offer promising avenues for treating inflammatory diseases owing to their immunomodulatory properties. However, challenges persist regarding their survival and efficacy in inflamed tissues. Our study introduces a novel approach by engineering adipose-derived stem cells (ADSCs) to enhance their viability in inflammatory environments and boost the secretion of paracrine factors for treating inflammatory bowel disease (IBD). An arginine-glycine-aspartate peptide-poly (ethylene glycol)-chlorin e6 conjugate (RPC) was synthesized and coupled with ADSCs, resulting in RPC-labeled ADSCs (ARPC). This conjugation strategy employed RGD-integrin interaction to shield stem cells and allowed visualization and tracking using chlorin e6. The engineered ARPC demonstrated enhanced viability and secretion of paracrine factors upon light irradiation, regulating the inflammatory microenvironment. RNA-sequencing analysis unveiled pathways favoring angiogenesis, DNA repair, and exosome secretion in ARPC(+) while downregulating inflammatory pathways. In in vivo models of acute and chronic IBD, ARPC(+) treatment led to reduced inflammation, preserved colon structure, and increased populations of regulatory T cells, highlighting its therapeutic potential. ARPC(+) selectively homed to inflammatory sites, demonstrating its targeted effect. Overall, ARPC(+) exhibits promise as an effective and safe therapeutic strategy for managing inflammatory diseases like IBD by modulating immune responses and creating an anti-inflammatory microenvironment.

Optimal development of apoptotic cells-mimicking liposomes targeting macrophages

Macrophages are multifunctional innate immune cells that play indispensable roles in homeostasis, tissue repair, and immune regulation. However, dysregulated activation of macrophages is implicated in the pathogenesis of various human disorders, making them a potential target for treatment. Through the expression of pattern recognition and scavenger receptors, macrophages exhibit selective uptake of pathogens and apoptotic cells. Consequently, the utilization of drug carriers that mimic pathogenic or apoptotic signals shows potential for targeted delivery to macrophages. In this study, a series of mannosylated or/and phosphatidylserine (PS) -presenting liposomes were developed to target macrophages via the design of experiment (DoE) strategy and the trial-and-error (TaE) approach. The optimal molar ratio for the liposome formulation was DOPC: DSPS: Chol: PEG-PE = 20:60:20:2 based on the results of cellular uptake and cytotoxicity evaluation on RAW 264.7 and THP-1 in vitro. Results from in vivo distribution showed that, in the DSS-induced colitis model and collagen II-induced rheumatoid arthritis model, PS-presenting liposomes (PS-Lipo) showed the highest accumulation in intestine and paws respectively, which holds promising potential for macrophage target therapy since macrophages are abundant at inflammatory sites and contribute to the progression of corresponding diseases. Organs such as the heart, liver, spleen, lung, and kidney did not exhibit histological alterations such as inflammation or necrosis when exposed to PC-presenting liposomes (PC-Lipo) or PS-Lipo. In addition, liposomes demonstrated hemobiocompatibility and no toxicity to liver or kidney for circulation and did not induce metabolic injury in the animals. Thus, the well-designed PS-Lipo demonstrated the most potential for macrophage target therapy.