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- Alveolar macrophages polarization switch via α2-adrenoceptor activation
ameliorates pulmonary inflammation following kidney ischemia reperfusion-
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Abstract: Purpose The present study aimed to explore the anti-inflammatory mechanism of dexmedetomidine (Dex), an α2-adrenoceptor (α2-AR) agonist, in renal ischemia-reperfusion (RIR)-induced acute lung injury (ALI). Methods RIR was induced in C57BL/6J mice by bilateral renal pedicles occlusion for 60 min followed by 24 h of reperfusion. Mice were pretreated with Dex alone or in combination with atipamezole (Atip), an α2-AR antagonist. Pulmonary histopathological assessment, arterial blood gas analysis, cell count and multiple cytokine examination in bronchoalveolar lavage fluid (BALF), evaluation of the global inflammation status in lung tissue, and investigation of alveolar macrophage phenotypes were carried out. In vitro, the polarization of mouse alveolar macrophages (MH-S) treated with serum from normal or RIR mice was indirectly detected by quantitative polymerase chain reaction (qPCR). Results The findings demonstrated that, in comparison to RIR animals, dexmedetomidine mitigated lung injury and remarkably promoted macrophage polarization towards an anti-inflammatory M2 phenotype in the pulmonary tissue. Concurrently, a reduction in inflammatory cell infiltration and levels of pro-inflammatory cytokines was observed. In vitro studies verified that dexmedetomidine directed MH-S towards the M2 phenotype after stimulation with RIR serum. However, these effects were mostly reversed following administration of atipamezole. Conclusion Dexmedetomidine alleviates renal ischemia-reperfusion-induced ALI by activating α2-adrenoceptor, thereby inducing macrophage polarization towards an anti-inflammatory phenotype and reducing pulmonary global inflammation.
PubDate: 2025-04-17
- SARS-CoV-2 nucleocapsid protein induces a Mincle-dependent macrophage
inflammatory response in acute kidney injury-
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Abstract: Background Although the COVID-19 pandemic has receded, the SARS-CoV-2 virus still poses a significant threat to individuals with pre-existing renal conditions, leading to severe acute kidney injury (AKI). However, the underlying mechanisms remain poorly understood. Methods In this study, we used ultrasound microbubble technology to transfect and overexpress the SARS-CoV-2 nucleocapsid (N) protein in the kidneys of IRI (ischemia-reperfusion injury) and Cis (cisplatin) induced AKI mice. Additionally, we generated macrophage-specific Mincle knockout mice to investigate the amplifying effects of the SARS-CoV-2 N protein on AKI renal injury and the critical regulatory role of macrophage inducible C-type lectin (Mincle). Finally, we employed Mincle-neutralizing antibodies to intervene in the SARS-CoV-2 N-induced exacerbation of kidney injury in AKI. Results We found that the specific overexpression of the SARS-CoV-2 N protein significantly aggravates kidney injury in the context of AKI. Mechanistically, we found that the exacerbation of acute kidney injury by the SARS-CoV-2 N protein is dependent on Mincle, as the SARS-CoV-2 N protein activates Mincle to enhance the Syk/NF-κB signaling pathway, leading to damage and inflammation of renal tubular epithelial cells. This was confirmed in Mincle knockout mice and cells, where Mincle knockout alleviated the renal tubular injury and inflammation caused by SARS-CoV-2 N transfection. Importantly, the use of anti-Mincle neutralizing antibodies could effectively mitigate the acute kidney injury exacerbated by the SARS-CoV-2 N protein. Conclusions In summary, we identified the SARS-CoV-2 N protein as a key mediator of kidney injury in AKI and demonstrated that it exacerbates the injury through a Mincle-dependent mechanism. Targeting Mincle may represent a novel therapeutic strategy for treating COVID-19-related acute kidney injury.
PubDate: 2025-04-17
- TIPE2 deficiency amplifies inflammation and immune dysregulation in MASH
through modulating hepatic lipid metabolism and immune cell function-
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Abstract: Background Metabolic Dysfunction-Associated Steatohepatitis (MASH) affects nearly 25% of the global population, yet there are no effective pharmacological treatments. Tumor necrosis factor α–induced protein 8–like 2 (TIPE2) is expressed in various immune cells and is crucial for regulating both innate and adaptive immune responses. However, its role in MASH development and the underlying mechanisms remain unclear. Method In this study, the role of TIPE2 in MASH was investigated using TIPE2 knockout (KO) mice and human hepatic LO2 cells. Immune cell infiltration, cytokine levels, and gene expression were analyzed. Techniques included flow cytometry for immune cell profiling, cytokine analysis, RNA sequencing, and quantitative PCR (qPCR) for validating gene expression changes. Results TIPE2 was identified as a key regulator in MASH, influencing immune modulation and metabolic processes. TIPE2 KO mice exhibited increased infiltration and activation of natural killer (NK) cells, M1 macrophages, and myeloid-derived suppressor cells (MDSCs), along with elevated pro-inflammatory cytokines such as IFN-gamma, TNF-alpha, IL- 1 beta, and IL- 6. MDSCs from TIPE2 KO mice demonstrated enhanced PD-L1 expression, contributing to chronic liver inflammation through T cell suppression. RNA sequencing revealed that TIPE2 overexpression in human hepatic LO2 cells upregulated genes associated with amino acid biosynthesis, carbon metabolism, lipid regulation, glycolysis, and gluconeogenesis. These findings were supported by qPCR analyses of liver samples from mice, confirming TIPE2’s role in maintaining lipid homeostasis and modulating immune responses. Conclusion The study highlights the pivotal role of TIPE2 in immune regulation and its influence on immune cell activation and inflammatory responses, which are critical in MASH progression. By exploring TIPE2-mediated immune regulation and its impact on the interplay between immune cell dynamics and liver metabolism, this research underscores TIPE2’s central role in linking immune dysfunction to metabolic disturbances in MASH.
PubDate: 2025-04-17
- RAGE deficiency ameliorates abdominal aortic aneurysm progression
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Abstract: Background Abdominal aortic aneurysm (AAA) is a vascular disease characterized by inflammation and arterial wall degradation. The receptor for advanced glycation end products (RAGE) plays a pivotal role in regulating inflammatory pathways, but its specific contribution to AAA pathogenesis remains unclear. Purpose This study aimed to investigate the role of RAGE in AAA development by examining its expression in human and mice AAA tissues and exploring the effects of RAGE deficiency on aneurysm progression, macrophage polarization, and inflammatory responses. Methods RAGE expression was analyzed in human AAA samples and porcine pancreatic elastase (PPE) induced AAA mouse models using Western blotting, immunohistochemistry, and immunofluorescence. In vivo RAGE-deficient (RAGE−/−) mice were generated to assess the impact of RAGE knockout on AAA progression. In vitro experiments utilized RAW264.7 transfected with RAGE-targeting siRNA to study macrophage polarization and NF-κB signaling. Results RAGE expression was elevated in AAA tissues, particularly in macrophages. RAGE−/− mice exhibited reduced AAA incidence, mortality, and aortic dilation compared to wild-type mice. Histological analysis showed preserved elastic fibers and smooth muscle layers, along with decreased inflammatory cell infiltration and MMP2/MMP9 expression. RAGE deficiency inhibited M1-like macrophage polarization and pro-inflammatory cytokine secretion, mediated through suppression of the NF-κB pathway. Conclusions RAGE deficiency mitigates AAA progression by modulating macrophage polarization and reducing inflammation via the NF-κB pathway. These findings highlight RAGE as a potential therapeutic target for AAA treatment.
PubDate: 2025-04-17
- Single-cell hdWGCNA reveals a novel diagnostic model and signature genes
of macrophages associated with chronic obstructive pulmonary disease-
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Abstract: Background Chronic obstructive pulmonary disease (COPD) is the leading cause of respiratory system-related mortality worldwide. Although COPD is associated with immune regulation, its underlying mechanisms remain unclear. Methods Cells from the single-cell RNA sequencing (scRNA-seq) datasets were subjected to clustering analysis and cell type identification to isolate immune cell subgroups specifically expressed in COPD. High-dimensional weighted gene co-expression network analysis (hdWGCNA) was used to identify hub genes related to the immune cell subpopulations. Machine learning algorithms were applied to identify diagnostic genes in the immune cell subpopulations and construct clinical diagnostic models for COPD. In bulk RNA sequencing data, AUC curves were used to assess the stability of the diagnostic models in predicting COPD. Results Through 2 rounds of clustering analysis, the macrophage subgroups 1, 2, 7, 11, and 13 which specifically expressed in COPD (COPD_Mφ) were identified. HdWGCNA analysis revealed a hub set of genes closely related to COPD_Mφ from black, blue, yellow, and brown modules. Nonnegative Matrix Factorization (NMF) analysis separated the COPD samples into 2 clusters, with significant increases in the infiltration of Monocytic_lineage, Myeloid_dendritic_cells, and Neutrophils in cluster 1 (P
PubDate: 2025-04-17
- APOE4 impairs autophagy and Aβ clearance by microglial cells
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Abstract: Alzheimer’s disease (AD) is a predominant form of dementia in elderly. In sporadic AD and in families with higher risk of AD, correlation with apolipoprotein E4 (APOE) allele expression has been found. How APOE4 induces its pathological effects is still unclear. Several studies indicate that autophagy, a major degradation pathway trough the lysosome, may be compromised in AD. Here we studied, the effects of APOE isoforms expression in microglia cells. By using an in-situ model, the clearance of Aβ plaques from brain sections of transgenic 5xFAD mice by the APOE expressing microglia was examined. The results show that APOE4 microglia has Impairment In clearance of insoluble Aβ plaques as compared to APOE3 and APOE2 microglia. Furthermore, APOE4 affect the uptake of soluble Aβ. We found that microglia expressing APOE4 exhibit reduced autophagic flux as compared to those expressing APOE3. The autophagy inhibitor chloroquine also blocked Aβ plaque uptake in APOE3 expressing cells. Furthermore, we found that APOE4 expressing microglia have altered mitochondrial dynamics protein expression, mitochondrial morphology and mitochondrial activity compared to those expressing APOE2, and APOE3. Rapamycin treatment corrected Mitochondrial Membrane Potential in APOE4-expressing cells. Taken together, these findings suggest that APOE4 impairs the activation of autophagy, mitophagy, and Aβ clearance and that autophagy-inducing treatments, such as rapamycin, can enhance autophagy and mitochondrial functions in APOE4 expressing microglia. Our results reveal a direct link between APOE4 to autophagy activity in microglia, suggesting that the pathological effects of APOE4 could be counteracted by pharmacological treatments inducing autophagy, such as rapamycin.
PubDate: 2025-04-01
- Identification of inflammatory protein biomarkers for predicting the
different subtype of adult with tuberculosis: an Olink proteomic study-
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Abstract: Objective This study aimed to identify the potential inflammatory molecular biomarkers that could be utilized for the early prediction of different subtypes of tuberculosis (TB) in adults. Methods Plasma samples were obtained from a cohort of adults diagnosed with 48 cases of active TB, including drug-susceptible TB (S-TB, n = 28), multidrug-resistant TB (R-TB, n = 20), latent TB infection (LTBI, n = 20), as well as a control group of healthy individuals without any infection (HC, n = 20). The expression level of 92 inflammatory-related proteins was detected by using the high-throughput Olink proteomics platform. Results There were 47 inflammatory proteins showing a significant difference (p
PubDate: 2025-04-01
- Inflammatory pain and electroacupuncture: how the P2X3 receptor can help
modulate inflammation—a review of current literature-
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Abstract: Aim Inflammatory pain arises from tissue stress or injury and is initiated by signaling molecules that stimulate the immune and nervous systems. Evidence suggests that purinergic signaling pathways can modulate pain and inflammation through the activation of P1 and P2 purinergic receptors, such as the P2X3 receptor, which are stimulated by extracellular molecules like adenosine triphosphate (ATP). Electroacupuncture (EA) exhibits precise mechanisms that modulate inflammatory pain through the activation of the P2X3 receptor. Objective This review analyzed evidence regarding the role of electroacupuncture and the purinergic system, particularly the P2X3 receptor, in modulating inflammation and pain. Materials and methods A search for the most relevant articles available in the SciVerse Scopus and MEDLINE/PubMed databases was conducted for publications from 1995 to 2024. Articles were initially selected by reading the title, abstract, and main text, respectively. Results It was found that the P2X3 receptor, as well as the molecules activating purinergic receptors, such as ATP and adenosine, have the potential to regulate pain and inflammation. Additionally, EA can modulate the purinergic system in an anti-inflammatory response. EA may stimulate analgesia mainly through the conversion of ATP to adenosine, a crucial molecule in pain control. Conclusion The purinergic system directly influences inflammatory pain and controls inflammation. In this context, EA has the potential to orchestrate this system to control pain and inflammation.
PubDate: 2025-03-28
- Unique signatures of airway and systemic immunity in severe COVID-19
patients infected with alpha to Omicron SARS-CoV-2 variants of concern-
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Abstract: In this study, systemic and localized immunity induced by SARS-CoV-2 variants of concern or interest (VOC/VOI) was investigated. For that, serum and tracheal aspirate soluble chemokines, pro-inflammatory/regulatory cytokines, and growth factors were measured in severe COVID-19 patients under mechanical ventilation upon infection with different SARS-CoV-2 variants, namely Alpha, Gamma, Zeta, Delta and Omicron. Increased levels of soluble mediators were observed in serum from severe COVID-19 patients regardless of the variant. In tracheal aspirate samples, the patients infected with the Gamma, Zeta, Delta, and Omicron variants exhibited reduced levels of inflammatory cytokines when compared to those infected with the Alpha variant. The trend of lower cytokine levels was also observed in the serum of patients across these variants, except for the Delta variant. By using network analysis and cytokine storm signatures, the data confirmed that severe COVID-19 induced by different variants have a completely divergent pattern of connectivity in serum samples as well as tracheal aspirates. Patients infected with variants at later time points in the pandemic such as Omicron exhibited networks of weak central architecture in serum samples as compared to tracheal aspirates, with lower number of neighborhood connections and clusters of pro-inflammatory and regulatory cytokines. By and large, this study points out to important systemic and local divergences and to loss of airway localized immunity in severe COVID-19 patients infected with SARS-CoV-2 variants, which brings insight into understanding host responses and viral escape vis-à-vis the virus mutations and evolution.
PubDate: 2025-03-28
- Luteolin modulates liver macrophage subtype polarization and play
protective role in sepsis induced acute hepatic injury-
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Abstract: Background Luteolin has an anti-inflammatory effect, but the mechanism has not been elucidated in sepsis-induced acute hepatic injury (AHI). The purpose of this study was to investigate the effects and potential mechanisms of luteolin on sepsis-induced AHI. Methods In this study, we utilized both wild-type (WT) mice and Toll-like receptor 4 (TLR4)-deficient (TLR4−/−) mice alongside RAW264.7 cells. We constructed a CLP-induced AHI mouse model to study the effects of luteolin on liver inflammation, survival and liver macrophage subtypes in mice. In addition, we extracted mouse serum, mouse bone marrow-derived macrophages (BMDMs) and liver tissue and analysed the effects of luteolin on macrophage polarization subtypes and downstream inflammatory cytokines by flow cytometry, ELISA, Western blotting (WB) and qPCR. To further verify the effect of luteolin on macrophage polarization and explore the possible potential mechanism, we used a CLP-induced AHI mouse model and LPS-stimulated RAW 264.7 macrophages to assess the effect of luteolin on macrophage polarization; the expression of TNF-α and IL-10 in the cell culture supernatant; and the expression of iNOS, ARG-1, NF-κB (P65), p-P65 and MyD88 by flow cytometry, ELISA, immunohistochemistry and Western blotting. Results We found that luteolin reduced liver injury and inflammatory response and improved the survival rate of mice. Luteolin modulated the macrophage subtype proportion, promoted the change of macrophages from a proinflammatory M1 phenotype to an anti-inflammatory M2 phenotype, and reduced the inflammatory response both in vivo and in vitro. Moreover, luteolin reduced the expression of NF-κB (p-P65), TLR4 and MyD88. By integrating the predictions from network pharmacology with the in vitro and in vivo experimental results, it was determined that the mechanism by which luteolin alleviates sepsis-induced acute hepatic injury is closely related to the TLR4/MyD88/NF-κB pathway. Conclusions The results of this study suggest that luteolin helps alleviate liver injury, reduces the expression of proinflammatory cytokines and promotes the expression of anti-inflammatory factors in sepsis-induced acute hepatic injury. This effect may be related to the regulation of macrophage polarization by luteolin through the TLR4/MyD88/NF-κB signalling pathway.
PubDate: 2025-03-28
- Roquin-1 interaction with Regnase-1 inhibits the progression of rheumatoid
arthritis via suppressing FGF2 expression and NF-κB pathway-
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Abstract: Objective This study aimed to explore the effect of Roquin-1 on rheumatoid arthritis (RA) and its potential mechanisms. Methods Firstly, we used TNF-α to stimulate fibroblast-like synoviocytes (FLSs) to establish an in vitro model of RA. Moreover, a rat model of RA was established with bovine type II collagen and complete Freund’s adjuvant. EdU and transwell assays were applied for evaluating the proliferation and migration of FLSs. The multiple mRNA and proteins expressions in FLSs and rats synovial tissues were measured using qRT-PCR, ELISA, western blot, immunohistochemistry staining and immunofluorescence staining. Double immunofluorescence staining and co-IP assay were used to validate the protein interaction between Roquin-1 and Regnase-1. Additionally, cycloheximide (CHX) chase assay was applied for assessing the degradation of fibroblast growth factor 2 (FGF2). Besides, the state of synovial hyperplasia and articular cartilage were also evaluated using HE and Safranin O/Fast Green staining. Results The mRNA and protein expressions of Roquin-1 were significantly reduced in TNF-α-stimulated FLSs and the synovial tissues of RA rats. Roquin-1 interacted with Regnase-1 to promote FGF2 degradation and further inhibit the proliferation, migration and inflammation response in TNF-α-stimulated FLSs. Moreover, we also demonstrated that Roquin-1 interacted with Regnase-1 to inhibit NF-κB pathway via suppressing FGF2 expression in TNF-α-stimulated FLSs. In addition, Roquin-1 suppressed inflammatory response in RA rats. Conclusion Our findings demonstrated that Roquin-1 could interact with Regnase-1 to inhibit the progression of RA via suppressing FGF2 expression and NF-κB pathway.
PubDate: 2025-03-18
- Mediation of macrophage M1 polarization dynamics change by
ubiquitin-autophagy-pathway regulated NLRP3 inflammasomes in PD-1
inhibitor-related myocardial inflammatory injury-
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Abstract: Objective and design Immune checkpoint inhibitors (ICIs)-induced cardiac injury is a life-threatening immune-related adverse events (irAEs). However, the current understanding of its pathogenesis and therapeutic options is relatively limited. We aimed to provide a comprehensive overview of the myocardial inflammatory injury process and underlying mechanisms associated with ICIs. Material or subjects We conducted a descriptive analysis of lung cancer patients with ICIs-induced myocarditis at our institution and validated our clinical findings using single-cell sequencing (scRNA-seq) data. Furthermore, we established animal and cellular models to investigate the underlying mechanisms. Results Our findings revealed that lung cancer patients with ICIs-induced myocarditis exhibit an early increase in peripheral blood monocytes, which migrate to the heart and differentiate into macrophages, ultimately leading to myocardial inflammation. Mechanistically, programmed death-1 (PD-1) inhibition triggers myocardial inflammation through the activation of the signal transducer and activator of transcription 1 (STAT1)/nuclear factor kappa-B (NF-κB)/oligomerization domain (NOD)-like receptor thermal protein domain-associated protein 3 (NLRP3) signaling pathway and drives the polarization of macrophages towards the M1 phenotype. However, the ubiquitin (Ub)-autophagy pathway degrades NLRP3 inflammasomes, resulting in the gradual resolution of inflammation and the transition of M1 macrophages to the M2 phenotype. Finally, mouse experiments confirmed that NLRP3 inhibition using MCC950 effectively alleviates myocardial inflammatory injury. Conclusions We recommend monitoring fluctuations in peripheral blood monocyte counts in lung cancer patients undergoing ICIs treatment. Additionally, MCC950 holds potential as a therapeutic agent for ICIs-induced cardiac inflammation injury.
PubDate: 2025-03-18
- The RNA-binding protein KSRP reduces asthma-like characteristics in a
murine model-
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Abstract: Background and objective Asthma is a chronic inflammatory disease characterized by dysregulated cytokine expression. The RNA-binding protein KSRP reduces the expression of several pro-inflammatory mediators. Therefore, we investigated whether KSRP modulates Th2-associated immune responses in vivo in an ovalbumin-induced (OVA) allergic asthma model in C57BL/6 KSRP-deficient mice (KSRP−/−). Methods Asthma severity in OVA-immunized wild type or KSRP−/− mice was determined by airway hyperresponsiveness (AHR), structural changes of lung tissue, and OVA-specific antibody production. Cytokine expression in bronchoalveolar lavage fluid (BALF) was measured by Cytometric Bead Array (CBA) analysis. Cellular signaling pathways involved in KSRP-mediated effects in asthma pathogenesis were analyzed in vitro in cell culture models using specific inhibitors. Results KSRP deficiency exacerbates OVA-induced allergic asthma compared to wild type mice, as indicated by increased AHR, more severe lung damage, goblet cell hyperplasia and increased OVA-specific antibody production. CBA analyses confirmed, that KSRP deficiency enhances IL-4, IL-5 and IL-13 production in BALF. The effect of KSRP on Th2-associated cytokine expression appears to be mediated by modulation of the STAT6 and NFAT signaling pathway rather than by inhibiting the stability of cytokine-encoding mRNA species. Conclusion Our data demonstrate that KSRP dampens Th2 immune cell activity and therefore seems to be important for the pathogenesis of Th2-mediated diseases.
PubDate: 2025-03-17
- CUR-PDT induces ferroptosis of RA-FLS via the Nrf2/xCT/GPX4 pathway to
inhibit proliferation in rheumatoid arthritis-
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Abstract: Objective Ferroptosis is a non-apoptotic cell death mechanism driven by reactive oxygen species (ROS) and iron. Its significance in inflammatory arthritis is well-established, but its role in rheumatoid arthritis (RA) remains uncertain. This study aimed to clarify the mechanisms through which curcumin-mediated photodynamic therapy (CUR-PDT) triggers ferroptosis in RA fibroblast-like synoviocytes (FLSs). Methods In vivo studies using a collagen-induced arthritis (CIA) rat model evaluated CUR-PDT effects on joint edema, synovial inflammation, and fibrosis through paw volume measurements and H&E and Masson’s trichrome staining. The expression of Nrf2, xCT, and GPX4 in FLSs was assessed via ELISA and immunohistochemistry. In vitro, MH7A cells treated with TNF-α were analyzed for viability, proliferation, invasion, and migration through various assays. Mitochondrial potential and morphology were examined using JC-1 staining and transmission electron microscopy (TEM). Ferroptosis biomarkers, including ROS, malondialdehyde (MDA), glutathione (GSH), superoxide dismutase (SOD), and Fe2+ levels, were measured. Nrf2, xCT, and GPX4 levels were quantified with RT-qPCR, Western blot, and immunofluorescence. Small interfering RNA (siRNA) was employed to knock down Nrf2 to validate the effect of CUR-PDT on ferroptosis in RA-FLS. Results The CUR-PDT therapy markedly reduced joint inflammation and collagen deposition in the synovial tissue of CIA rats. It effectively alleviated both inflammation and hyperplasia. Moreover, this therapy facilitated ferroptosis within the synovial tissue. In vitro analyses indicated that CUR-PDT diminished the proliferation and viability of FLSs, resulting in increased ROS levels in the cells. This cascade initiated ferroptosis, as evidenced by decreased glutathione, heightened iron concentrations, mitochondrial shrinkage, and reduced mitochondrial membrane potential. Crucially, the expression of xCT and GPX4 was significantly lowered. Interestingly, knocking down the Nrf2 gene amplified this effect, leading to an even greater reduction in xCT and GPX4 expression. In this context, RA-FLSs exhibited more pronounced ferroptotic traits, including diminished proliferation, invasion, and migration. Conclusions This study elucidated a mechanism by which CUR-PDT triggers ferroptosis in FLSs through the downregulation of the Nrf2-xCT-GPX4 signaling cascade, thereby effectively hindering the progression of RA and emphasizing the importance of targeting Nrf2 in disease advancement.
PubDate: 2025-03-14
- Vitamin D3 suppresses NLRP3 inflammasome pathway and enhances steroid
sensitivity in a neutrophilic steroid hyporesponsive asthma mouse model-
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Abstract: Objective Severe steroid hyporesponsive asthma is a heterogeneous group of chronic inflammatory diseases characterized by irreversible airflow limitation, hyperresponsiveness, inflammation, and remodelling of the airways. Severe asthmatics account for more than 60% of asthma-related healthcare cost worldwide given they are hyporesponsive to corticosteroids and due to the absence of targeted treatment specifically for the T helper-17 (Th-17) high endotype. Hence, there is a clear unmet need to investigate other treatment options to control patients’ symptoms. The role of the NLRP3 inflammasome pathway has been highlighted in the literature to contribute to disease pathogenesis and severity. Interestingly, vitamin D3 is an important regulator of the NLRP3 inflammasome pathway. Methods Using house dust mite (HDM) and lipopolysaccharide (LPS), we induced a neutrophilic steroid hyporesponsive asthma mouse model to investigate the effect of vitamin D3 on downregulating the NLRP3 inflammasome pathway and enhancing steroid sensitivity. Results We showed that calcitriol, the active form of vitamin D3, could downregulate the NLRP3 inflammasome pathway. This was associated with a significant reduction in airway hyperresponsiveness, IL-17 release, neutrophil infiltration, and mucus secretion. Further, calcitriol enhanced steroid sensitivity by inhibiting the expression of GR-β. Mechanistically, calcitriol targeted the NLRP3 inflammasome to ubiquitination. Conclusions Our research highlights the potential use of calcitriol as a low cost and accessible supplement to ameliorate airway inflammation during severe steroid hyporesponsive asthma.
PubDate: 2025-03-14
- Dog allergen-induced asthma in mice: a relevant model of T2low severe
asthma with airway remodelling-
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Abstract: Objective and design Airway remodelling (AR) is a disabling phenomenon in patients with severe asthma, yet suitable models are lacking. We previously developed a dog allergen-induced murine asthma model characterized by T2low Th17-driven neutrophilic airway inflammation and AR. To assess its relevance to human AR associated with T2low severe asthma, a condition characterised by poor response to inhaled steroids, we tested the steroid sensitivity of the key features of this model. Material Asthma was induced in C57BL/6 J mice by intranasal sensitization, followed by a three-week challenge with dog allergen. Treatment: Daily intraperitoneal 1 mg kg−1 dexamethasone was administrated during the last week of challenge. Methods: We measured airway resistances in response to methacholine, cellular inflammation in bronchoalveolar lavage, lung cytokines, and quantified AR features, in response to dexamethasone. Results Dexamethasone-treated mice showed persistent airway hyperresponsiveness, neutrophilic inflammation, and Il17a overexpression, whereas Il22 expression was abrogated. Pathological AR features, including mucus hyperproduction, subepithelial fibrosis and smooth muscle hypertrophy were not eliminated by dexamethasone. Conclusions Our dog allergen-induced murine model of asthma mirrors the steroid-insensitive traits of human severe T2low asthma with AR, making it a relevant tool for identifying novel therapeutic targets in this orphan asthma subset.
PubDate: 2025-03-14
- Interlukin-23 inhibitors as an induction and maintenance therapy for
moderate to severe ulcerative colitis: a systematic review and
meta‑analysis of randomized controlled trials-
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Abstract: Background and objective Targeting the interleukin (IL)-23 axis is an emerging treatment target for ulcerative colitis (UC), with several positive randomized controlled trials (RCTs). We aim to investigate the safety and efficacy of IL-23 inhibitors for the induction and maintenance treatment of moderate to severe UC. Methods A systematic review and meta-analysis synthesizing evidence from RCTs obtained from PubMed, Cochrane, Scopus, and Web of Science from inception to August 2024. We used the fixed-effects model to report dichotomous outcomes using the risk ratio (RR) with a 95% confidence interval (CI). PROSPERO ID: CRD42024589935. Results Four records, reporting four induction trials and three maintenance trials, with 2,699 patients in the induction phase and 1,015 in the maintenance phase, were included. IL-23 inhibitors significantly increased the rate of clinical remission in the induction phase (RR: 2.19, 95%CI [1.72, 2.78]) and maintenance phase (RR: 1.55, 95%CI [1.26, 1.90]); endoscopic remission in induction phase (RR: 1.76, 95%CI [1.41, 2.18]) and maintenance phase (RR: 1.63, 95%CI [1.21, 1.85]); histo-endoscopic mucosal healing in induction phase (RR: 2.06, 95%CI [1.60, 2.64]) and maintenance phase (RR: 1.48, 95%CI [1.14, 1.90]). Also, IL-23 inhibitors significantly decreased the incidence of serious adverse events in the induction phase (RR: 0.37, 95%CI [0.26, 0.55]) and maintenance phase (RR: 0.53, 95%CI [0.33, 0.83]). Conclusion IL-23 inhibitors are effective as an induction and maintenance therapy for moderate to severe UC based on the significantly increased rates of clinical, endoscopic, and histological remission. Also, the safety profile of IL-23 inhibitors is favorable, with a significantly decreased incidence of serious adverse events compared to placebo.
PubDate: 2025-03-08
- Peroxisome proliferator-activated receptor gamma prevents activation of
RBL-2H3 cells by inhibiting FcεRI-mediated signal transduction-
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Abstract: Background Mast cells are essential contributors to the pathophysiology of allergic diseases. Peroxisome proliferator-activated receptor gamma (PPAR-γ) has recently been identified as being involved in the anti-inflammatory response by inhibiting mast cell activation. Method In this study, the PPAR-γ agonist pioglitazone (PIO) was employed to evaluate the effects of PPAR-γ on the degranulation and production of pro-inflammatory mediators in RBL-2H3 cells. Meanwhile, differentially expressed genes (DEGs) were characterised in mast cells exposed to PIO, and pathway enrichment analysis were conducted. Furthermore, we conducted validation to confirm the involvement of PPAR-γ signaling pathways in the FcεRI-mediated signal transduction in mast cells. Results Administration of PIO significantly reduced the release of β-hexosaminidase and the mRNA expression levels of pro-inflammatory cytokines induced by the cross-linking of FcεRIs expressed on the surface of RBL-2H3 cells. A total of 24 DEGs were identified between RBL-2H3 cells treated with and without PIO, and there were 15 up-regulated and 9 down-regulated. GO and KEGG analyses revealed that the immune system, signal transduction, infectious disease, and signaling molecules and interactions were the most enriched annotations. According to PPI network analysis, most DEGs interacted with PPAR-γ. PPAR-γ agonist could activate PPAR-γ and NRF2 signaling pathways in resting RBL-2H3 cells. The protein expression levels of PPAR-γ, Cpt1a, and Acsl4 were greatly upregulated in activated RBL-2H3 cells mediated by FcεRI aggregation. Moreover, the suppressive effects of PPAR-γ agonist on degranulation and phosphorylation levels of FcεRI-mediated signaling molecules in RBL-2H3 cells were PPAR-γ-dependent. Conclusion These data demonstrate that PPAR-γ inhibits FcεRI-mediated mast cell activation by modulating intracellular-specific signal transduction in a PPAR-γ-dependent manner.
PubDate: 2025-03-08
- Decoy oligonucleotides targeting NF-κB: a promising therapeutic approach
for inflammatory diseases-
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Abstract: Nuclear factor-kappa B (NF-κB) transcription factor plays a crucial function in controlling several cellular processes, including the production of inflammatory mediators. The aberrant activation of this transcription factor and its signaling pathway is associated with the pathophysiology of many diseases. Therefore, discovering drugs that target NF-κB is crucial for treating various diseases. Decoy oligonucleotides (decoy ONs) are a pharmacological approach that specifically inhibits NF-κB activation and are used to treat several inflammatory diseases. Decoys that target NF-κB have been shown to enhance radiosensitivity and drug sensitivity in vitro and strongly block IL-6 and IL-8 gene expression induced by TNF-α in experimental cell systems. In vivo, NF-κB decoy reduced atherosclerotic plaque, prevented atopic dermatitis and extended cardiac transplant survival. Decoys have the potential to be used in clinical applications, but they face several challenges. To overcome these limitations, researchers have conducted studies on chemical modifications and delivery techniques. Innovative compounds that target NF-κB, such as NF-κB-decoy-based sensor-containing models, phosphorothioate hairpin-modified oligonucleotides, and peptide nucleic acid (PNA)-based transcription factor decoys, are very attractive. This research aims to explore the use of decoys to combat NF-κB in various disorders.
PubDate: 2025-03-06
- Cxcl9-deficiency attenuates the progression of post-traumatic
osteoarthritis in mice-
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Abstract: Objective Osteoarthritis (OA) is one of the leading causes of disability in the aging population. While about 10% of the adult population is affected by OA, there is to date no curative treatment and joint replacement surgery remains the only option for treating end-stage OA. Previous studies found elevated levels of the chemokine C-X-C motif ligand 9 (CXCL9) in the synovial fluid of OA knees. However, the exact role of CXCL9 in OA progression is still unknown. Methods Female wild-type and Cxcl9-deficient mice were challenged with a unilateral anterior cruciate ligament transection (ACLT). Joint destruction in early and late stages of experimental OA was assessed using micro-CT scanning, histological scoring, histomorphometry, and gene expression analysis. Results Inactivation of Cxcl9 protected from cartilage destruction and osteophyte formation in post-traumatic OA in mice. Similarly, indices of joint inflammation including synovitis and expression of pro-inflammatory interleukin-1beta were reduced in OA knees of Cxcl9-deficient mice. However, bone erosion and pathophysiological changes in the subchondral bone compartment remained unaffected in Cxcl9-deficient mice with experimental OA. Conclusion Our results point towards a pro-inflammatory role of CXCL9 in OA and identify a potential new target for the pharmacological treatment of OA.
PubDate: 2025-03-06
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