Activation Of Inflammatory Cells Research Articles

Intra-bone marrow mesenchymal stem cell transplantation modulates myeloid bias tendency of hematopoietic stem and progenitor cells in severe MRL/lpr lupus mice

The hematopoietic homeostasis in the bone marrow is inextricably intertwined with the immune milieu in peripheral circulation. Researches investigating the pathogenesis of systemic lupus erythematosus (SLE) have defined considerable secretion of inflammatory mediators and activation of pro-inflammatory cells. However, the impacts of “extrinsic” factors on hematopoietic stem and progenitor cells (HSPCs) remain unclear, and it is uncertain whether treatments can help coordinate the biased differentiation. In this study, we showed differences in the proportions of common myeloid progenitors (CMP) and myeloid output in the bone marrow of premorbid and morbid MRL/lpr mice using flow cytometry. RNA-seq analysis of lineage-affiliated transcriptional factors and dysregulated genes within lin- HSPCs revealed inflammation potentiation during disease progression. Further, intra-bone marrow mesenchymal stem cells transplantation (IBM-MSCT) partially coordinated myeloid generation and counteracted lupus-associated inflammation gene alterations, compared to intravenous injection. Additionally, co-culturing with umbilical cord mesenchymal stem cells (UC-MSCs) intervened in myeloid lineage tendency, as detected by RT-qPCR of myeloid-related genes. Our research demonstrated enhanced tendency toward myeloid differentiation and highlighted the feasibility of IBM-MSCT for lineage-biased HSPCs in MRL/lpr lupus model, providing novel insight into hematopoiesis and MSC-related treatments for SLE.

Plasma exosomes from patients with active thyroid-associated orbitopathy induce inflammation and fibrosis in orbital fibroblasts

BackgroundThe pathogenesis of thyroid-associated orbitopathy (TAO) remains incompletely understand. The interaction between immunocytes and orbital fibroblasts (OFs) play a critical role in orbital inflammatory and fibrosis. Accumulating reports indicate that a significant portion of plasma exosomes (Pla-Exos) are derived from immune cells; however, their impact upon OFs function is unclear.MethodsOFs were primary cultured from inactive TAO patients. Exosomes isolated from plasma samples of patients with active TAO and healthy controls (HCs) were utilized for functional and RNA cargo analysis. Functional analysis in thymocyte differentiation antigen-1+ (Thy-1+) OFs measured expression of inflammatory and fibrotic markers (mRNAs and proteins) and cell activity in response to Pla-Exos. RNA cargo analysis was performed by RNA sequencing and RT-qPCR. Thy-1+ OFs were transfected with miR-144-3p mimics/inhibitors to evaluate its regulation of inflammation, fibrosis, and proliferation.ResultsPla-Exos derived from active TAO patients (Pla-ExosTAO−A) induced stronger production of inflammatory cytokines and hyaluronic acid (HA) in Thy-1+ OFs while inhibiting their proliferation. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis and single sample gene set enrichment analysis (ssGSEA) suggested that the difference in mRNA expression levels between Pla-ExosTAO−A and Pla-ExosHC was closely related to immune cells. Differential expression analysis revealed that 62 upregulated and 45 downregulated miRNAs in Pla-ExosTAO−A, with the elevation of miR-144-3p in both Pla-Exos and PBMCs in active TAO group. KEGG analysis revealed that the target genes of differentially expressed miRNA and miR-144-3p enriched in immune-related signaling pathways. Overexpression of the miR-144-3p mimic significantly upregulated the secretion of inflammatory cytokines and HA in Thy-1+ OFs while inhibiting their proliferation.ConclusionPla-Exos derived from patients with active TAO were immune-active, which may be a long-term stimulus casual for inflammatory and fibrotic progression of TAO. Our finding suggests that Pla-Exos could be used as biomarkers or treatment targets in TAO patients.

Poly (ADP-ribose) Polymerase-1 modulations in the genesis of thrombosis.

Thrombosis, a coagulation disorder, occurs due to altered levels of coagulation, fibrinolytic and immune factors, which are otherwise known to maintain hemostasis in normal physiological conditions. Here, we review the direct and indirect participation of a multifunctional nuclear enzyme poly (ADP-ribose) polymerase-1 (PARP1) in the expression of key genes and cellular processes involved in thrombotic pathogenesis. PARP1 biological activities range from maintenance of genomic integrity, chromatin remodeling, base excision DNA repair, stress responses to cell death, angiogenesis and cell cycle pathways. However, under homeostatic imbalances, PARP1 activities are linked with the pathogenesis of diseases, including cancer, aging, neurological disorders, and cardiovascular diseases. Disease-associated distressed cells employ a variety of PARP-1 functions such as oxidative damage exacerbations, cellular energetics and apoptosis pathways, regulation of inflammatory mediators, promotion of endothelial dysfunction, and ERK-mediated signaling in pathogenesis. Thrombosis is one such pathogenesis that comprises exacerbation of coagulation cascade due to biochemical alterations in endothelial cells, platelet activation, overexpression of adhesion molecules, cytokines release, and leukocyte adherence. Thus, the activation of endothelial and inflammatory cells in thrombosis implicates a potential role of PARP1 activation in thrombogenesis. This review article explores the direct impact of PARP1 activation in the etiology of thrombosis and discusses PARP1-mediated endothelial dysfunction, inflammation, and epigenetic regulations in the disease manifestation. Understanding PARP1 functions associated with thrombosis may elucidate novel pathogenetic mechanisms and help in better disease management through newer therapeutic interventions targeting PARP1 activity.

The Role of Chemokine-Like Receptor-1 in Recruitment and Activation of Myeloid Cells During WNV Encephalitis

Abstract Recent increases in West Nile Neuroinvasive Disease (WNND) outbreaks in the US underscore the urgent need to understand CNS viral clearance mechanisms. In response to WNV, neurons secrete chemokines (CCL2, CCL5, and CXCL10), facilitating leukocyte entry into the CNS. CNS-infiltrating macrophages amplify this signal, recruiting and activating neuroprotective leukocytes, limiting harmful accumulation, and aiding repair. CMKLR1 promotes CNS inflammatory responses during infectious and autoimmune diseases via inducing macrophage and DC migration following chemerin activation. However, the specific role of chemerin/CMKLR1 in WNND remains unclear. WT and CMKLR1-/- mice were infected with WNV to investigate this. WNV-infected CMKLR1-/- mice exhibited a slight increase in mortality but elevated clinical scores and reduced recovery compared to WT. We hypothesize that CMKLR1 limits WNV pathogenesis by regulating CNS recruitment and activation of inflammatory myeloid cells during WNV encephalitis. Assessing key inflammatory mediators and activation markers in CNS-resident and infiltrating cells in WT and CMKLR1-/- animals will elucidate how CMKLR1 influences the recruitment/activation of these cells, clarifying processes resulting in infection resolution and neural repair.

Effects of Chronic Inflammatory Activation of Murine and Human Arterial Endothelial Cells at Normal Lipoprotein and Cholesterol Levels In Vivo and In Vitro.

The activation of endothelial cells is crucial for immune defense mechanisms but also plays a role in the development of atherosclerosis. We have previously shown that inflammatory stimulation of endothelial cells on top of elevated lipoprotein/cholesterol levels accelerates atherogenesis. The aim of the current study was to investigate how chronic endothelial inflammation changes the aortic transcriptome of mice at normal lipoprotein levels and to compare this to the inflammatory response of isolated endothelial cells in vitro. We applied a mouse model expressing constitutive active IκB kinase 2 (caIKK2)-the key activator of the inflammatory NF-κB pathway-specifically in arterial endothelial cells and analyzed transcriptomic changes in whole aortas, followed by pathway and network analyses. We found an upregulation of cell death and mitochondrial beta-oxidation pathways with a predicted increase in endothelial apoptosis and necrosis and a simultaneous reduction in protein synthesis genes. The highest upregulated gene was ACE2, the SARS-CoV-2 receptor, which is also an important regulator of blood pressure. Analysis of isolated human arterial and venous endothelial cells supported these findings and also revealed a reduction in DNA replication, as well as repair mechanisms, in line with the notion that chronic inflammation contributes to endothelial dysfunction.

Role of Reactive Oxygen Species in the Pathogenesis of Bronchial Asthma and Obstructive Pulmonary Diseases: Systematic Review

The article discusses the role of reactive oxygen species (ROS) in the pathogenesis of bronchial asthma and obstructive pulmonary diseases. The review follows a structured approach beginning with a comprehensive search of electronic databases, then findings from the included studies were summarized and used to draw comprehensive conclusions. The authors state that increased activity of oxidative processes and insufficient activity of the antioxidant system lead to the accumulation of ROS in the respiratory tract. This leads to direct damage to epithelial cells, activation of inflammatory cells, and stimulation of inflammatory mediators. ROS also activate transcription factors that increase inflammation and airway obstruction. Thus, maintaining the balance of the oxidant-antioxidant system is an important strategy for the treatment of these diseases.Keywords: Reactive oxygen species; Bronchial asthma; Chronic obstructive pulmonary disease; Oxidative stress; Antioxidant system

Cellular response of keratinocytes to the entry and accumulation of nanoplastic particles

Plastic accumulation in the environment is rapidly increasing, and nanoplastics (NP), byproducts of environmental weathering of bulk plastic waste, pose a significant public health risk. Particles may enter the human body through many possible routes such as ingestion, inhalation, and skin absorption. However, studies on NP penetration and accumulation in human skin are limited. Loss or reduction of the keratinized skin barrier may enhance the skin penetration of NPs. The present study investigated the entry of NPs into a human skin system modeling skin with compromised barrier functions and cellular responses to the intracellular accumulations of NPs. Two in vitro models were employed to simulate human skin lacking keratinized barriers. The first model was an ex vivo human skin culture with the keratinized dermal layer (stratum corneum) removed. The second model was a 3D keratinocyte/dermal fibroblast cell co-culture model with stratified keratinocytes on the top and a monolayer of skin fibroblast cells co-cultured at the bottom. The penetration and accumulation of the NPs in different cell types were observed using fluorescent microscopy, confocal microscopy, and cryogenic electron microscopy (cryo-EM). The cellular responses of keratinocytes and dermal fibroblast cells to stress induced by NPs stress were measured. The genetic regulatory pathway of keratinocytes to the intracellular NPs was identified using transcript analyses and KEGG pathway analysis. The cellular uptake of NPs by skin cells was confirmed by imaging analyses. Transepidermal transport and penetration of NPs through the skin epidermis were observed. According to the gene expression and pathway analyses, an IL-17 signaling pathway was identified as the trigger for cellular responses to internal NP accumulation in the keratinocytes. The transepidermal NPs were also found in co-cultured dermal fibroblast cells and resulted in a large-scale transition from fibroblast cells to myofibroblast cells with enhanced production of α-smooth muscle actin and pro-Collagen Ia. The upregulation of inflammatory factors and cell activation may result in skin inflammation and ultimately trigger immune responses.

The Heart Does Not Itch, But it Feels Pain: Three Cases of Kounis Syndrome

Background: Kounis syndrome is defined as the occurrence of acute coronary artery syndrome as a result of activation of inflammatory cells after conditions such as allergy, hypersensitivity, anaphylaxis or anaphylactic reactions. This case reports were presented to provide the latest knowledge on Kounis syndrome, increase awareness of this disease among healthcare providers and researchers, and promote early and appropriate diagnosis and management of this syndrome. Summary of Cases: In the first case, a 45-year-old female patient with no history of coronary artery disease developed anaphylaxis due to a locally applied anesthetic drug. This led to transient coronary artery vasospasm and acute coronary syndrome. In the second case, a 70-year-old male patient with a history of coronary artery disease developed anaphylaxis due to a bee sting. This caused rupture of the coronary artery plaque, resulting in inferior myocardial infarction. In the third case, a 73-year-old male patient with a stent in his coronary artery developed an allergic reaction/anaphylaxis to midazolam, which was administered for sedation before the biopsy procedure. This reaction resulted in restenosis of the old stent and caused an anterior myocardial infarction. Conclusion: Kounis syndrome is a life-threatening condition that requires attention. Ensuring coronary artery patency in the treatment of ischaemia is important to protect cardiomyocyte health and prevent arrhythmias. Ischaemia caused by allergens can be resolved with a combination of antiallergenic treatments. Therefore, for effective management of suspected cases of Kounis syndrome, collaboration between cardiology and allergy-immunology clinics is essential.

Rhein kills Actinobacillus pleuropneumoniae, reduces biofilm formation, and effectively treats bacterial lung infections in mice.

Background. Actinobacillus pleuropneumoniae, a member of the Pasteurellaceae family, is known for its highly infectious nature and is the primary causative agent of infectious pleuropneumonia in pigs. This disease poses a considerable threat to the global pig industry and leads to substantial economic losses due to reduced productivity, increased mortality rates, and the need for extensive veterinary care and treatment. Due to the emergence of multi-drug-resistant strains, Chinese herbal medicine is considered one of the best alternatives to antibiotics due to its unique mechanism of action and other properties. As a type of Chinese herbal medicine, Rhein has the advantages of a wide antibacterial spectrum and is less likely to develop drug resistance, which can perfectly solve the limitations of current antibacterial treatments.Methods. The killing effect of Rhein on A. pleuropneumoniae was detected by fluorescence quantification of differential expression changes of key genes, and scanning electron microscopy was used to observe the changes in A. pleuropneumoniae status after Rhein treatment. Establishing a mouse model to observe the treatment of Rhein after A. pleuropneumoniae infection.Results. Here, in this study, we found that Rhein had a good killing effect on A. pleuropneumoniae and that the MIC was 25 µg ml-1. After 3 h of action, Rhein (4×MIC) completely kills A. pleuropneumoniae and Rhein has good stability. In addition, the treatment with Rhein (1×MIC) significantly reduced the formation of bacterial biofilms. Therapeutic evaluation in a murine model showed that Rhein protects mice from A. pleuropneumoniae and relieves lung inflammation. Quantitative RT-PCR (Quantitative reverse transcription polymerase chain reaction is a molecular biology technique that combines both reverse transcription and polymerase chain reaction methods to quantitatively detect the amount of a specific RNA molecule) results showed that Rhein treatment significantly downregulated the expression of the IL-18 (Interleukin refers to a class of cytokines produced by white blood cells), TNF-α, p65 and p38 genes. Along with the downregulation of genes such as IL-18, it means that Rhein has an inhibitory effect on the expression of these genes, thereby reducing the activation of inflammatory cells and the production of inflammatory mediators. This helps reduce inflammation and protects tissue from further damage.Conclusions. This study reports the activity of Rhein against A. pleuropneumoniae and its mechanism, and reveals the ability of Rhein to treat A. pleuropneumoniae infection in mice, laying the foundation for the development of new drugs for bacterial infections.

Transcriptional Changes in Radiation-Induced Lung Injury: A Comparative Analysis of Two Radiation Doses for Preclinical Research.

In a recent stereotactic body radiation therapy animal model, radiation pneumonitis and radiation pulmonary fibrosis were observed at around 2 and 6 weeks, respectively. However, the molecular signature of this model remains unclear. This study aimed to examine the molecular characteristics at these two stages using RNA-seq analysis. Transcriptomic profiling revealed distinct transcriptional patterns for each stage. Inflammatory response and immune cell activation were involved in both stages. Cell cycle processes and response to type II interferons were observed during the inflammation stage. Extracellular matrix organization and immunoglobulin production were noted during the fibrosis stage. To investigate the impact of a 10 Gy difference on fibrosis progression, doses of 45, 55, and 65 Gy were tested. A dose of 65 Gy was selected and compared with 75 Gy. The 65 Gy dose induced inflammation and fibrosis as well as the 75 Gy dose, but with reduced lung damage, fewer inflammatory cells, and decreased collagen deposition, particularly during the inflammation stage. Transcriptomic analysis revealed significant overlap, but differences were observed and clarified in Gene Ontology and KEGG pathway analysis, potentially influenced by changes in interferon-gamma-mediated lipid metabolism. This suggests the suitability of 65 Gy for future preclinical basic and pharmaceutical research connected with radiation-induced lung injury.

A New Modulator of Neuroinflammation in Diabetic Retinopathy: USP25

Diabetic retinopathy (DR) is a diabetes-associated complication that poses a threat to vision, distinguished by persistent and mild inflammation of the retinal microvasculature. The activation of microglia plays a crucial role in driving this pathological progression. Previous investigations have demonstrated that ubiquitin-specific peptidase 25 (USP25), a deubiquitinating enzyme, is involved in the regulation of immune cell activity. Nevertheless, the precise mechanisms through which USP25 contributes to the development of DR remain incompletely elucidated. Firstly, we have demonstrated the potential mechanism by which ROCKs can facilitate microglial activation and augment the synthesis of inflammatory mediators through the modulation of NF-κB signaling pathways in a high-glucose milieu. Furthermore, our study has provided novel insights by demonstrating that the regulatory role of USP25 in the secretion of proinflammatory factors is mediated through the involvement of ROCK in modulating the expression of NF-κB and facilitating the nuclear translocation of the phosphatase NF-κB. This regulatory mechanism plays a crucial role in modulating the activation of microglial cells within a high-glycemic environment. Hence, USP25 emerges as a pivotal determinant for the inflammatory activation of microglial cells, and its inhibition exhibits a dual effect of promoting retinal neuron survival while suppressing the inflammatory response in the retina. In conclusion, the promotion of diabetic retinopathy (DR) progression by USP25 is attributed to its facilitation of microglial activation induced by high glucose levels, a process mediated by the ROCK pathway. These findings highlight the importance of considering USP25 as a potential therapeutic target for the management of diabetic neuroinflammation.

Defective Mitophagy Impairs Response to Inflammatory Activation of Macrophage-Like Cells.

The role of mitophagy in atherosclerosis has been extensively studied during the last few years. It was shown that mitophagy is involved in the regulation of macrophages, which are important players as immune cells in atherosclerosis development. In this study, we investigated the relationship between mitophagy and response to inflammatory stimulation of macrophage-like cells. Six cybrid cell lines with normal mitophagy, that is, increasing in response to stimulation, and 7 lines with defective mitophagy not responding to stimulation were obtained. The objective of the study was to compare the nature of the inflammatory response in normal and defective mitophagy in order to elucidate the role of mitophagy defects in inflammation. We used cytoplasmic hybrids (cybrids) as cellular models, created using mitochondrial DNA from different atherosclerosis patients. Mitophagy was stimulated by carbonyl cyanide m-chlorophenyl hydrazone (CCCP) and assessed as the degree of colocalization of mitochondria with lysosomes using confocal microscopy. Western blotting methods were used for the determination of proteins involved in the exact mechanism of mitophagy. Experiments with stimulation of mitophagy show a high correlation between these two approaches (microscopy and blotting). The pro-inflammatory response of cybrids was stimulated with bacterial lipopolysaccharide (LPS). The extent of the inflammatory response was assessed by the secretion of cytokines CCL2, IL8, IL6, IL1β, and TNF measured by ELISA. Basal level of secretion of cytokines CCL2, IL8 and TNF was 1.5-2 times higher in cultures of cybrids with defective mitophagy compared to cells with normal mitophagy. This suggests a persistently elevated inflammatory response in cells with defective mitophagy, even in the absence of an inflammatory stimulus. Such cells in the tissue will constantly recruit other immune cells, which is characteristic of macrophages derived from monocytes circulating in the blood of patients with atherosclerosis. We observed significant differences in the degree and type of response to inflammatory activation in cybrids with defective mitophagy. These differences were not so much quantitative as they were dramatically qualitative. Compared with cells with normal mitophagy, in cells with defective mitophagy, the relative (to basal) secretion of IL8, IL6 and IL1b increased after the second LPS activation. This indicates a possible lack of tolerance to inflammatory activation in cells with defective mitophagy, since typically, re-activation reveals a smaller pro-inflammatory cytokine response, allowing the inflammatory process to resolve. In cells with normal mitophagy, exactly this normal (tolerant) inflammatory reaction was observed. Data on the involvement of mitophagy, including defective mitophagy, in disturbances of the inflammatory response in sepsis, viral infections, autoimmune diseases and other pathologies have previously been reported. In this work, we studied the role of defective mitophagy in non-infectious chronic inflammatory diseases using the example of atherosclerosis. We showed a dramatic disruption of the inflammatory response associated with defective mitophagy. Compared with cybrids with normal mitophagy, in cybrids with defective mitophagy, the secretion of all studied cytokines changed significantly both quantitatively and qualitatively. In particular, the secretion of 3 of 5 cytokines demonstrated an intolerant inflammatory response manifested by increased secretion after repeated inflammatory stimulation. Such an intolerant reaction likely indicates a significant disruption of the pro-inflammatory response of macrophages, which can contribute to the chronification of inflammation. Elucidating the mechanisms of chronification of inflammation is extremely important for the search for fundamentally new pharmacological targets and the development of drugs for the prevention and treatment of chronic inflammatory diseases, including atherosclerosis and diseases characteristic of inflammation. Such diseases account for up to 80% of morbidity and mortality.

Progesterone induces neuroprotection associated with immune/inflammatory modulation in experimental traumatic brain injury.

An imbalance of immune/inflammatory reactions aggravates secondary brain injury after traumatic brain injury (TBI) and can deteriorate clinical prognosis. So far, not enough therapeutic avenues have been found to prevent such an imbalance in the clinical setting. Progesterone has been shown to regulate immune/inflammatory reactions in many diseases and conveys a potential protective role in TBI. This study was designed to investigate the neuroprotective effects of progesterone associated with immune/inflammatory modulation in experimental TBI. A TBI model in adult male C57BL/6J mice was created using a controlled contusion instrument. After injury, the mice received consecutive progesterone therapy (8 mg/kg per day, i.p.) until euthanized. Neurological deficits were assessed via Morris water maze test. Brain edema was measured via the dry-wet weight method. Immunohistochemical staining and flow cytometry were used to examine the numbers of immune/inflammatory cells, including IBA-1 + microglia, myeloperoxidase + neutrophils, and regulatory T cells (Tregs). ELISA was used to detect the concentrations of IL-1β, TNF-α, IL-10, and TGF-β. Our data showed that progesterone therapy significantly improved neurological deficits and brain edema in experimental TBI, remarkably increased regulatory T cell numbers in the spleen, and dramatically reduced the activation and infiltration of inflammatory cells (microglia and neutrophils) in injured brain tissue. In addition, progesterone therapy decreased the expression of the pro-inflammatory cytokines IL-1β and TNF-α but increased the expression of the anti-inflammatory cytokine IL-10 after TBI. These findings suggest that progesterone administration could be used to regulate immune/inflammatory reactions and improve outcomes in TBI.

Heparin-loaded hierarchical fiber/microsphere scaffolds for anti-inflammatory and promoting wound healing

Chronic non-healing wounds induced by oxidative stress and inflammation can activate inflammatory cells and produce large amounts of inflammatory mediators, which fail to maintain homeostasis in the skin and delay the wound-healing process. To tackle this issue, heparin-loaded hierarchical composite scaffolds comprised of electrospun fibers and electrosprayed microspheres were prepared to act as an effective anti-inflammatory wound dressing. Microspheres with different electrosprayed densities were deposited into the surface of the electrospun fibers for the improvement of surface topographical cues and cellular activities. The results indicated that the electrospun fibers followed by electrosprayed for 3 ​min to fabricate the composite fiber/microsphere scaffolds contributed to the best performance in terms of promoting cellular activities, with no obvious cytotoxicity, good adhesion morphology, and the fastest cell migration rate. In addition, a suitable amount of heparin was added to the composite scaffolds to alleviate inflammation. The significant adsorption efficiency of heparin-loaded composite scaffolds on inflammatory mediator MCP-1 indicates a favorable anti-inflammation effect in vitro. Furthermore, the heparin-loaded hierarchical scaffolds accelerated the pace of inflammatory wound healing in vivo when compared to commercial 3 ​M Tegaderm and non-heparin-loaded scaffolds. Our work provided a facile strategy for fabricating heparin-loaded hierarchical fiber/microsphere scaffolds to modulate cellular activities via topographical cues and accelerating the inflammatory wound healing process by electrostatic interactions between heparin and MCP-1. These findings suggested that the heparin-loaded hierarchical scaffold was expected to be a promising dressing for inflammatory wound healing.

Photothermal Microneedle Hydrogel Patch for Refractory Soft Tissue Injuries through Thermosensitized Anti‐Inflammaging Modulation

Soft tissue injuries (STIs) are the most common cause of extremity pain and motion dysfunction. Persistent inflammatory activation of immune cells characterized by senescence‐associated secretory phenotype (SASP) and mitochondrial stress are considered the primary causes of STIs, a pathological process also termed inflammaging. Meanwhile, scavenging excessive “cellular waste” in the inflammaging microenvironment and further activating tissue repair processes remain elusive. Herein, an anti‐inflammaging photothermal hydrogel microneedle patch for treating STIs is developed. Taurine‐loaded Prussian blue nanoparticles (Taurine@PB) are encapsulated in a methacrylate‐based hyaluronic acid hydrogel (HAMA) and further fabricated into taurine@PB@HAMA@microneedles (TPH@MN) patches. The acidic microenvironment of chronic inflammation and mild photothermal effects promote taurine release and anti‐inflammaging immunomodulation, inhibiting mitochondrial stress via the SIRT3‐NF‐κB axis to promote glycolytic metabolic microenvironment of neutrophils reprogramming toward oxidative phosphorylation metabolism. Furthermore, TPH@MN activates macrophage efferocytosis and initiates the process of tissue repair. In mouse models of chronic diabetic wounds and tibialis anterior (TA) muscle injury, TPH@MN inhibits SASP expression and promotes STIs healing through thermosensitized anti‐inflammaging immunomodulation. In summary, TPH@MN circumvents the side effects of systemic administration, providing new translatable options in the treatment modalities for patients suffering from STIs worldwide.

Nebulized pH-Responsive Nanospray Combined with Pentoxifylline and Edaravone to Lungs for Efficient Treatments of Acute Respiratory Distress Syndrome.

The COVID-19 pandemic has become an unprecedented global medical emergency, resulting in more than 5 million deaths. Acute respiratory distress syndrome (ARDS) caused by COVID-19, characterized by the release of a large number of pro-inflammatory cytokines and the production of excessive toxic ROS, is the most common serious complication leading to death. To develop new strategies for treating ARDS caused by COVID-19, a mouse model of ARDS was established by using lipopolysaccharide (LPS). Subsequently, we have constructed a novel nanospray with anti-inflammatory and antioxidant capacity by loading pentoxifylline (PTX) and edaravone (Eda) on zeolite imidazolate frameworks-8 (ZIF-8). This nanospray was endowed with synergetic therapy, which could kill two birds with one stone: (1) the loaded PTX played a powerful anti-inflammatory role by inhibiting the activation of inflammatory cells and the synthesis of pro-inflammatory cytokines; (2) Eda served as a free radical scavenger in ARDS. Furthermore, compared with the traditional intravenous administration, nanosprays can be administered directly and inhaled efficiently and reduce the risk of systemic adverse reactions greatly. This nanospray could not only coload two drugs efficiently but also realize acid-responsive release on local lung tissue. Importantly, ZIF8-EP nanospray showed an excellent therapeutic effect on ARDS in vitro and in vivo, which provided a new direction for the treatment of ARDS.

MiRNome targeting NF-κB signaling orchestrates macrophage-triggered cancer metastasis and recurrence

Whether and how tumor intrinsic signature determines macrophage-elicited metastasis remain elusive. Here, we show, in detailed studies of data regarding 7,477 patients of 20 types of human cancers, that only 13.8%± 2.6%/27.9%± 3.03% of patients with high macrophage infiltration index exhibit early recurrence/vascular invasion. In parallel, although macrophages enhance the motility of various hepatoma cells, their enhancement intensity is significantly heterogeneous. We identify that the expression of malignant Dicer, a ribonuclease that cleaves miRNA precursors into mature miRNAs, determines macrophage-elicited metastasis. Mechanistically, the downregulation of Dicer in cancer cells leads to defects in miRNome targeting NF-κB signaling, which in turn enhances the ability of cancer cells to respond to macrophage-related inflammatory signals and ultimately promotes metastasis. Importantly, transporting miR-26b-5p, the most potential miRNA targeting NF-κB signaling in hepatocellular carcinoma, can effectively reverse macrophage-elicited metastasis of hepatoma invivo. Our results provide insights into the crosstalk between Dicer-elicited miRNome and cancer immune microenvironments and suggest that strategies to remodel malignant cell miRNome may overcome pro-tumorigenic activities of inflammatory cells.

Inflammation and Atherosclerosis

There are many biochemical elements implicated with the inflammation mediators and markers and this review show their identities and their atherosclerotic effects. Cytokines identified as participants in the mechanisms of atherogenesis were first discovered as involved in the process of natural (or innate) and specific (or acquired) immunity, responsible for defending against foreign organisms such as viral or bacterial agents. They are protein hormones produced mainly by mononuclear phagocytes (monocins) in direct response to microbes, or originated from T lymphocytes (lymphocins) when stimulated by antigen, as part of specific immunity. T lymphocytes produce several cytokines that primarily serve to regulate the activation, growth and differentiation of the various lymphocyte populations. Other cytokines derived from the T lymphocyte work primarily in the activation and regulation of inflammatory cells, such as mononuclear phagocytes, neutrophils and eosinophils. Thus, cytokines derived from T lymphocyte are effector molecules of cell-mediated immunity, and are also responsible for communications between the cells of the immune and inflammatory systems.

Various Clinical Phenotypes and Approach to Patients with NSAID Hypersensitivity

Nonsteroidal anti-inflammatory drugs (NSAIDs) can induce hypersensitivity reactions with various clinical manifestations including acute/delayed reactions and three common phenotypes, NSAID/aspirin-exacerbated respiratory disease (NERD or AERD) with/without chronic rhinosinusitis (CRS) and nasal polyps, NSAID-exacerbated cutaneous disease (NECD). NSAID-induced urticaria/angioedema (NIUA). NIAU is commonly combined with anaphylaxis and named as NIUAA. The major pathogenic mechanism is the inhibition of cyclooxygenase-1 with a reduction in prostaglandin E2 levels, leading to the overproduction of cysteinyl leukotrienes and activation of inflammatory cells, including eosinophils and mast cells. To confirm the diagnosis, provocation testing via the oral route or inhalation remains the gold standard; in vitro diagnostic methods are still not available. Essential managements are: (1) avoidance of cross-reacting NSAIDs along with the use of alternative analgesics; (2) pharmacologic treatment should follow standard guidelines in patients with underlying asthma/rhinitis (NERD, CRS), and urticaria (NECD). Aspirin desensitization and biologic treatment can be done when indicated. Delayed reactions, including fixed drug eruptions, maculopapular eruptions, and severe cutaneous adverse reactions, are rare and mediated by T-cell responses. Symptomatic treatment with avoidance is essential. NSAID is a cofactor of food-dependent exercise-induced anaphylaxis. In this talk, we will update various clinical phenotypes and discuss practical issues faced in real clinical practice.

Anti-Inflammatory Herbal Extracts and Their Drug Discovery Perspective in Atopic Dermatitis.

Atopic dermatitis (AD) is an allergic disorder characterized by skin inflammation. It is well known that the activation of various inflammatory cells and the generation of inflammatory molecules are closely linked to the development of AD. There is accumulating evidence demonstrating the beneficial effects of herbal extracts (HEs) on the regulation of inflammatory response in both in vitro and in vivo studies of AD. This review summarizes the anti-atopic effects of HEs and its associated underlying mechanisms, with a brief introduction of in vitro and in vivo experiment models of AD based on previous and recent studies. Thus, this review confirms the utility of HEs for AD therapy.