Recent studies have suggested that alterations in natural killer (NK) cell function may contribute to the development of COVID-19. Additionally, dysregulated NK cells may increase susceptibility to COVID-19 and affect the severity of the infection. This study aimed to explore the causal relationship between NK cell-related immune traits and the risk of COVID-19 infection. A two-sample Mendelian randomization (MR) analysis was conducted to explore the causal relationship between NK cell-related immune traits and COVID-19. Exposure and outcome data were analyzed using the two-sample Mendelian Randomization (MR) method. The results of the study suggest that there is a causal relationship between the absolute number of NK cells in COVID-19 infection and the risk of severe illness. The results also demonstrated that the morphological parameters are not causally related to COVID-19 infection but were causally related to COVID-19 hospitalization and COVID-19 severity. This finding has important implications for our understanding of the pathophysiology of COVID-19 and the development of future therapies and interventions for this disease.

Acute respiratory distress syndrome (ARDS) is a clinical syndrome characterized by high morbidity and mortality rates. Sepsis-induced ARDS involves excessive inflammatory responses, which are modulated by macrophages. This study aimed to elucidate the effect of Recombinant Mouse IL-27 Protein on macrophage ferroptosis and polarization, as well as its impact on sepsis-induced ARDS. A cecal ligation and puncture (CLP)-induced sepsis model was established using wild-type (WT) or IL27R−/− mice. Then, the mice were randomly divided into 4 groups: a control group, a CLP group, an IL-27 + CLP combination group, and an IL-27, CLP, and Oltipraz combination group. RAW 264.7 cells and BMDMs were used to further determine the role and mechanism of IL-27 in vitro. In vitro, IL-27 alone did not alter the expression of proteins linked to the ferroptosis pathway or macrophage polarization. Contrastingly, the combination of IL-27 with LPS further amplified LPS-induced alterations in the ferroptosis pathway, thereby promoting macrophage M1 polarization and inhibiting M2 polarization. Additionally, IL-27 + LPS increased ROS levels in macrophages. A sepsis-induced ARDS mouse model was then established via CLP. In vivo, IL-27 exacerbated CLP-induced lung injury in WT mice. Additionally, it decreased the expression levels of ferroptosis-related proteins (Nrf2, HO-1, GPX4) and increased those of Ptgs2 in the lung tissue of septic mice. Besides, GSH and SOD levels in lung tissue were also reduced. Moreover, IL-27 also promoted M1 polarization and inhibited M2 polarization in macrophages. In IL27R−/− mice, the effects of IL-27 were abrogated. Oltipraz inhibited IL-27-induced changes by up-regulating Nrf2 expression. Overall, this present study demonstrated that the combination of IL-27 and LPS-induced macrophage ferroptosis, promoted macrophage M1 polarization, and inhibited M2 polarization by inhibiting the Nrf2/HO-1 pathway. Oltipraz may alleviate ARDS-related lung injury by up-regulating Nrf2 expression and concurrently inhibiting macrophage ferroptosis.

Group 2 innate lymphoid cells (ILC2) are the main group of tissue-resident ILCs in the lungs, which protect airway barrier integrity following infection. Macrophages are integral to the regulation of immune homeostasis in sepsis. However, the relationship between ILC2 and macrophages in the context of sepsis induced acute lung injury remains uncertain. The sepsis was conducted by cecal ligation and puncture (CLP) model in Wild Type (WT) mice and ILC2 depleted mice. Septic mice were injected intratracheally IL-9, and the frequency and markers expression of ILC2 and macrophage were measured by Flow cytometry and CyTOF. The lung injury was conducted with pathological analysis. In vitro studies, MH-S cells were exposed to LPS with/without interleukin-9 (IL-9), and mTOR level and MH-S cells death were measured with western bloting or Flow cytometry. Sepsis induced the accumulation of ILCs and pulmonary macrophages in lungs. Furtherly, we revealed that ILC2 and CD45+F4/80+CD11c+ macrophages expanded during sepsis induced acute lung injury. Meanwhile, ILC2 depletion significantly enhanced macrophages expansion. In vivo and in vitro studies determined that pulmonary macrophage death followed by sepsis were protedced by IL-9, which was main secreted by ILC2 in lung. Furthermore, IL-9 significantly declined the expression of mTOR, and the presence of ILC2 or IL-9 reduced the expression of M1 markers (CD86 or MHC II). IL-9 secreted by ILC2 has a protective role in sepsis induced lung injury by reducing macrophage apoptosis and M1 polarization via mTOR.

High Mobility Group Box 1 (HMGB1), a multifunctional non-histone protein, and its involvement in various physiological and pathological contexts has garnered significant attention. Given HMGB1’s central function in modulating key biological activities, such as inflammatory responses and cellular death, its contribution to the pathogenesis of digestive system diseases has become a focus of growing interest. This review aims to comprehensively explore the mechanisms by which HMGB1 contributes to the progression of inflammatory bowel disease (IBD), liver disorders, and pancreatitis. Furthermore, we explore the prospective clinical applications and outline future research directions for HMGB1 in digestive diseases, providing fresh perspectives that highlight the necessity of ongoing studies to understand its role in these conditions.

One of the etiologic components of degenerative spinal illnesses is intervertebral disc degeneration (IVDD), and the accompanying lower back pain is progressively turning into a significant public health problem. Important pathologic characteristics of IVDD include inflammation and acidic microenvironment, albeit it is unclear how these factors contribute to the disease. To clarify the functions of inflammation and the acidic environment in IVDD, identify the critical connections facilitating glycolytic crosstalk and nucleus pulposus cells (NPCs) pyroptosis, and offer novel approaches to IVDD prevention and therapy. By developing keywords search strategy, literature was found and screened using databases such as PUBMED, Google Scholar, Web of Science, China National Knowledge Infrastructure, and others. Hub genes, protein interaction networks, clinical transcriptome data validation, and enrichment analysis were used to further validate relevant biological pathways. It is clear that disc degeneration is associated with apoptosis or pyroptosis, inflammation, and an acidic environment based on literature review. The process of IVDD is intimately associated with pyroptosis, inflammation, and an acidic environment. The precise mechanism may entail the regulation of key genes such NLRP3, ASIC1a, IL1β, TNF-a, and GSDMD. While the acidic environment exacerbated extracellular matrix degradation and promoted cellular senescence and inflammatory factor expression, it was found to be unfavorable for NPCs survival and proliferation. Moreover, NPCs pyroptosis in an acidic environment, the molecular mechanism behind this phenomenon may be connected to ASIC1a mediated Ca + influx. On the other hand, IVDD can be constantly promoted by the interaction between the degenerating disc’s acidic and inflammatory environments through “crosstalk” between anaerobic glycolysis and positive feedback. In summary, the inflammatory process in NPCs is made worse by the buildup of glucose brought on by metabolic problems, such as anaerobic glycolytic processes, and pyroptosis caused by excessive glucose may be mitigated by inhibiting endoplasmic reticulum stress. A new therapeutic approach for IVDD will involve using ASIC1a as a regulatory target to enhance the inflammatory environment and decrease the incidence of NPCs pyroptosis. Following this, anaerobic glycolysis will be regulated, lactic acid generation will be reduced, and the degenerative vicious loop will be blocked.

Sclerostin (SOST) is traditionally regarded as an osteocyte-derived secreted glycoprotein that regulates bone mineralization. Recent studies reported that SOST is also released from non-skeletal sources, especially during inflammation. However, the cellular source and regulatory mechanisms governing SOST generation in inflammation remain unclear. This study investigated whether macrophages produce SOST in response to inflammatory stimuli and determined associated regulatory pathways. The effect of lipopolysaccharide (LPS)-induced inflammation in SOST generation and its underlying regulatory mechanism was examined on mouse macrophage RAW 264.7 by western blot and immunofluorescent staining. Transfection with miR-92a-3p mimic and inhibitor were used to validate its role in SOST production. The role of NF-κB and TLR4 were studied using pharmacological inhibitors BAY 11-7085 and TAK242, respectively. The involvement of NF-κB and TLR4 in LPS-induced SOST production was further validated through nuclear NF-κB p65 immunoprecipitation and TLR4 small interfering RNA (siRNA) experiments, respectively.GW4869 and manumycin A (extracellular vesicles (EV) biogenesis inhibitors) were used to examine the associated of SOST and EV. Finally, SOST expression and characteristics of the isolated EV were assessed by Western blot and nanoparticle tracking analysis (NTA). LPS significantly induced SOST protein expression and secretion in RAW 264.7. MiR-92a-3p was upregulated by LPS stimulation in macrophages. Transfection of miR-92a-3p mimic increased SOST generation in RAW 264.7. Inhibition of TLR4 and NF-κB signalling pathways using pharmacological inhibitors significantly suppressed LPS-induced SOST in RAW 264.7. Similarly, TLR4 siRNA effectively suppressed LPS-induced SOST level. However, the LPS-induced upregulation of miR-92a-3p was only regulated by TLR4, but not by NF-κB. NF-κB was found to directly bind to the mouse sost promoter, thereby activating sost transcription. Additionally, SOST secretion was found predominantly associated with EV from LPS-stimulated cells, and inhibition of EV biogenesis suppressed SOST production in RAW 264.7 cells. In conclusion, our study showed, for the first time, that LPS induced SOST generation and secretion via TLR4/miR-92a-3p/PTEN/NF-κB singling pathway in murine macrophage RAW 264.7 cells. Moreover, we showed that SOST is secreted from the RAW 264.7 cells in the form of extracellular vesicle. This study identified macrophage as a novel source of SOST, highlighting its potential role in inflammatory diseases.

Hypertrophic scar (HS) is a severe skin fibrosis. Transplanting stem cells carrying anti-fibrotic cytokine genes, like interferon-gamma (IFN-γ), is a novel therapeutic strategy. Human amniotic epithelial cells (hAECs) are ideal seed cells and gene vectors. Microencapsulation creates a favorable environment for transplanted cells. This study investigates the effect of alginate-polylysine-alginate (APA)-microencapsulated hAECs modified with IFN-γ on HS fibrosis. hAECs were isolated from human placentas and characterized. The full-length IFN-γ gene was cloned into the pcDNA3.1 vector to create the recombinant plasmid IFN-γ-pcDNA3.1. This plasmid was then transfected into hAECs, resulting in the generation of IFN-γ-modified hAECs (IFN-γ-hAECs). Subsequently, these IFN-γ-hAECs were microencapsulated with APA to produce APA-IFN-γ-hAECs. In vitro, the release of IFN-γ, as well as the cellular and metabolic activities, growth, proliferation, migration, apoptosis, and trans-differentiation were assessed using HS-derived fibroblasts. In vivo, the weight loss of HS xenografts, collagen fiber arrangement, tissue oxidative stress, and inflammatory response were evaluated using a nude mouse model that had been transplanted with human HS tissues. In vitro, APA-IFN-γ-hAECs exhibited significantly sustained and enhanced IFN-γ release, increased cellular vitality, and inhibited fibroblast growth, proliferation, migration, and trans-differentiation into myofibroblasts. APA-IFN-γ-hAECs also remarkably downregulated extracellular matrix (ECM) components and promoted apoptosis. In vivo, they significantly accelerated the weight reduction of HS xenografts, improved collagen fiber arrangement, and mitigated oxidative stress and inflammation. This study suggests that APA-microencapsulated IFN-γ-hAECs may have potential in alleviating HS fibrosis, offering a new direction for exploring effective clinical HS management strategies.

Celastrol is one of the main active ingredients extracted from the plant Tripterygium wilfordii Hook F. A growing number of studies have shown that celastrol has various pharmacological effects, including anti-inflammation, anti-rheumatism, treatment of neurodegenerative diseases, and anti-tumor. This article systematically summarized the mechanism and role of celastrol in lipid metabolism and obesity, rheumatoid arthritis (RA), osteoarthritis (OA), gouty arthritis, inflammatory bowel disease, neurodegenerative diseases, and cancer and other diseases (such as diabetes, respiratory-related diseases, atherosclerosis, psoriasis, hearing loss, etc.). The celastrol played roles in inflammation response, cell apoptosis, autophagy, ferroptosis, and lipid metabolism mainly by acting on chondrocytes, macrophages, mitochondria, and endoplasmic reticulum (ER) through NF-κB, STAT, MAPK, TLR, PI3K-AKT-mTOR, and other signal pathways. This review could provide a reference for the clinical application and further development and utilization of celastrol.

Hyperoxia-induced brain injury is a severe neurological complication that is often accompanied by adverse long-term prognosis. The pathogenesis of hyperoxia-induced brain injury is highly complex, with neuroinflammation playing a crucial role. The activation of the nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3) inflammasome, which plays a pivotal role in regulating and amplifying the inflammatory response, is the pathological core of hyperoxia-induced brain injury. Additionally, astrocytes actively participate in neuroinflammatory responses. However, there is currently no comprehensive overview summarizing the role of astrocytes in hyperoxia-induced brain injury and the NLRP3 signaling pathways in astrocytes. This article aims to provide an overview of studies reported in the literature investigating the pathological role of astrocyte involvement during the inflammatory response in hyperoxia-induced brain injury, the mechanisms of hyperoxia activateing the NLRP3 inflammasome to mediate pyroptosis in astrocytes, and the potential therapeutic effects of drugs targeting the NLRP3 inflammasome to alleviate hyperoxia-induced brain injury. We searched major databases (including PubMed, Web of Science, and Google Scholar, etc.) for literature encompassing astrocytes, NLRP3 inflammasome, and pyroptosis during hyperoxia-induced brain injury up to Oct 2024. We combined with studies found in the reference lists of the included studies. In this study, we elucidated the transition of function in astrocytes and activation mechanisms under hyperoxic conditions, and we summarized the potential upstream of the trigger involved in NLRP3 inflammasome activation during hyperoxia-induced brain injury, such as ROS and potassium efflux. Furthermore, we described the signaling pathways of the NLRP3 inflammasome and pyroptosis executed by GSDMD and GSDME in astrocytes under hyperoxic conditions. Finally, we summarized the inhibitors targeting the NLRP3 inflammasome in astrocytes to provide new insights for treating hyperoxia-induced brain injury.

Allergic rhinitis (AR) represents a persistent inflammatory condition affecting the upper respiratory tract, characterized by abnormal initiation of the immunoglobulin E (IgE)-mediated cascade. Follicular helper T (Tfh) cells and regulatory T (Tfr) cells are pivotal in orchestrating the development of IgE production in AR patients. IL-35, an anti-inflammatory cytokine, secreted by various cellular subpopulations. To investigate the interplay and underlying mechanisms between interleukin-35 (IL-35) and Tfr/Tfh2 cells in the context of AR. Experimental animal models employing BALB/c mice and IL-35-deficient mice underwent sensitization and challenge procedures utilizing ovalbumin (OVA) as the antigen in vivo. IL-35 was administered intranasally prior to OVA challenges. Nasal histopathological examination, PBMC isolation, Tfr/Tfh2 cell staining, Tfr/Tfh2 sorting and culture, and qPCR analysis as well as enzyme-linked immunosorbent assay (ELISA) were conducted for exploring the effect of IL-35 on Tfr/Tfh2 cells. Administration of IL-35 suppressed OVA-elicited allergic inflammation in murine models. IL-35 treatment led to an elevation in the proportion of peripheral blood Tfr cells and a decrease in Tfh2 cells. IL-35 also downregulated IL-4 and IL-21 protein expression by Tfh2 cells and upregulated IL-10 and transforming growth factor-β (TGF-β) production by Tfr cells. The anti-ICOS treatment abrogated the effect of IL-35 on Tfh2 and Tfr cells. Our study provided novel insights into the mechanisms of IL-35 action and its promoting effects on Tfh2 and inhibiting effects on Tfr cells by targeting key transcription factors, contributing to the understanding of the pathogenesis and treatment of AR.

This study seeks to elucidate the role and molecular mechanisms of IL-8 in nasal epithelial cell pyroptosis and its impact on glucocorticoid (GC) resistance. We assessed the expression of pyroptosis-related biomarkers and IL-8 in tissues and human nasal epithelial cells (hNECs) from both control and nasal polyp patients using western blot. Their localization was determined through immunohistochemistry and immunofluorescence. Cell death and cytotoxicity assay, electron microscopy, ELISA, and immunofluorescence were utilized to investigate IL-8-induced pyroptosis and GC resistance in hNECs, alongside the examination of the involved signaling pathways via western blot and immunofluorescence. In a murine model, hematoxylin-eosin staining and immunohistochemistry clarified relationship between pyroptosis and GC resistance. IL-8 and pyroptotic biomarker expression were significantly higher in nasal polyp-derived tissues and hNECs compared to controls. IL-8 showed a positive correlation and co-localized with the pyroptotic biomarkers. IL-8 triggered pyroptosis in hNECs by activating the ERK signaling pathway, leading to increased IL-1β and IL-18 secretion. Moreover, IL-8-induced pyroptosis was found to contribute to GC resistance by affecting phosphorylation of GC receptor Ser211. Inhibition of pyroptotic proteins mitigated IL-8-induced GC resistance both in vitro and in vivo. Elevated IL-8 facilitates pyroptosis via the ERK signaling pathway and plays a significant role in GC resistance in nasal polyps.

Cardiovascular diseases (CVDs) continue to be a substantial global healthcare burden despite considerable progress in therapies. The inflammatory response during the progression of CVD has attracted considerable attention. Mitochondria serve as the principal energy source for the heart. In cardiovascular illnesses, mitochondrial homeostasis is disrupted, accompanied by structural and functional impairments. During mitochondrial stress or injury, mitochondrial damage-associated molecular patterns (mtDAMPs), such as mitochondrial DNA, cardiolipin, N-formyl peptide, and adenosine triphosphate, are released to activate pattern recognition receptors and trigger immunological responses. Inflammatory responses mediated by mtDAMPs substantially contribute to the pathophysiology of cardiovascular illnesses. In this review, we discuss the molecular mechanisms by which different mtDAMPs control the inflammatory response, address the pathological consequences of mtDAMPs in inducing or exacerbating the inflammatory response in CVDs, and summarize potential therapeutic targets in relevant experimental studies. Preventing or reducing mtDAMP release may play a role in CVD progression by alleviating the inflammatory response.

Chronic inflammation is well recognized as a key factor related to renal function deterioration in patients with diabetic kidney disease (DKD). Neutrophil extracellular traps (NETs) play an important role in amplifying inflammation. With respect to NET-related genes, the aim of this study was to explore the mechanism of DKD progression and therefore identify potential intervention targets. Hub NET-related DEGs were screened via differential expression analysis and three machine learning methods, namely, LASSO, SVM-RFE and random forest. Consensus clustering was performed to analyze NET-related subtypes in DKD patients. KEGG enrichment analysis, GSEA, GSVA, ssGSEA and ESTIMATE were conducted to explore the molecular features of DKD patient subtypes. Leveraging single-nucleus RNA-seq datasets, the “scissor” and “bisqueRNA” algorithms were applied to identify the composition of renal cell types in DKD patient subtypes. Soft clustering analysis was performed to obtain gene groups with similar expression patterns during the development and progression of DKD. The correlations between hub NET-related DEGs and clinical parameters were mined from the Nephroseq V5 database. The core gene among the hub NET-related DEGs was selected by calculating semantic similarity. “Cellchat” algorithm, immunostaining, ELISA and flow cytometry were performed to explore the expression and function of the core gene. The Drug–Gene Interaction Database (DGIdb) was searched to identify candidate drugs. Six hub NET-related DEGs, namely, ACTN1, ITGB2, IL33, HRG, NFIL3 and CLEC4E, were identified. On the basis of these 6 genes, DKD patients were classified into 2 clusters. Cluster 1 patients, with higher NET scores, were evidently more immune-activating than those of cluster 2. Markedly increased numbers of immune cells, fibroblasts and proinflammatory proximal tubular cells were observed in cluster 1 but not in cluster 2. Cluster 1 also represented a more clinically advanced disease state. Among the 6 hub NET-related DEGs, the mRNA expression of ACTN1, ITGB2, IL33 and HRG was correlated with the eGFR. By semantic similarity analysis, IL33 was considered a central gene among the 6 genes. Cell-cell communication analysis further indicated that intercellular interactions via IL-33 were enhanced in DKD. Serum IL-33 concentration was negatively correlated with eGFR. IHC staining revealed that IL-33 expression was upregulated in the tubular epithelium in DKD patients. Supernatants from inflammatory tubular epithelial cells can increase MPO in neutrophils, whereas addition of anti-IL-33 antibody attenuated this phenotype. We identified 2 distinct NET-related subtypes in DKD patients, in which one subgroup was apparently more inflammatory and associated with a more severe clinical state. A significantly increased level of IL-33 in this inflammatory patient subgroup may play a role in aggravating inflammation via the IL-33-ST2 axis.

Dysbiosis of the nasal microbiome is considered to be related to the acute exacerbation of chronic rhinosinusitis (AECRS). The microbiota in the nasal cavity of AECRS patients and its association with disease severity has rarely been studied. This study aimed to characterize nasal dysbiosis in a prospective cohort of patients with AECRS. We performed a cross-sectional study of 28 patients with AECRS, 20 patients with chronic rhinosinusitis (CRS) without acute exacerbation (AE), and 29 healthy controls using 16S rRNA gene sequencing. Subjective and objective assessments of CRS disease severity during AE were also collected. Compared to healthy controls and patients with CRS without AE, AECRS presented with a substantial decrease of the Corynebacterium_1 and a significant increase of Ralstonia and Acinetobacter at the genus level (LDA score > 2.0 [P < 0.05]). Furthermore, genera with a mean relative abundance (MRA) of less than 1% were defined as rare components based on published studies, then 29 genera with a substantial alteration in AECRS were rare constituents of the microbiome, of which 18 rare genera were highly associated with subjective and objective disease severity. Moreover, a combination of 15 genera could differentiate patients with AECRS with an area under the curve of 0.870 (95% CI = 0.784–0.955). Prediction of microbial functional pathways involved significantly enhanced lipopolysaccharide biosynthesis pathways and significantly decreased folate biosynthesis, sulfur relay system, and cysteine and methionine metabolism pathways in patients with AECRS. The rare nasal microbiota (MRA < 1%) correlated with disease status and disease severity in patients with AECRS. The knowledge about the pattern of the nasal microbiome and its metabolomic pathway may contribute to the fundamental understanding of AECRS pathophysiology.

Acute pancreatitis (AP) represents a severe inflammatory condition of the exocrine pancreas, precipitating systemic organ dysfunction and potential failure. The global prevalence of acute pancreatitis is on an ascending trajectory. The condition carries a significant mortality rate during acute episodes. This underscores the imperative to elucidate the etiopathogenic pathways of acute pancreatitis, enhance comprehension of the disease’s intricacies, and identify precise molecular targets coupled with efficacious therapeutic interventions. The pathobiology of acute pancreatitis encompasses not only the ectopic activation of trypsinogen but also extends to disturbances in calcium homeostasis, mitochondrial impairment, autophagic disruption, and endoplasmic reticulum stress responses. Notably, the realm of epigenetic regulation has garnered extensive attention and rigorous investigation in acute pancreatitis research over recent years. One of these modifications, lysine acetylation, is a reversible post-translational modification of proteins that affects enzyme activity, DNA binding, and protein stability by changing the charge on lysine residues and altering protein structure. Numerous studies have revealed the importance of acetylation modification in acute pancreatitis, and that it is a favorable target for the design of new drugs for this disease. This review centers on lysine acetylation, examining the strides made in acute pancreatitis research with a focus on the contributory role of acetylomic alterations in the pathophysiological landscape of acute pancreatitis, thereby aiming to delineate novel therapeutic targets and advance the development of more efficacious treatment modalities.

Fibroblast-like synoviocytes (FLS) are key players in rheumatoid arthritis (RA) by resisting apoptosis via increased autophagy. Elevated synovial aquaporin 1 (AQP1) affects RA FLS behaviors, but its relationship with FLS autophagy is unclear. We aim to clarify that silencing AQP1 inhibits autophagy to exert its anti-RA effects. We studied the effects and mechanisms of AQP1 silencing on autophagy in TNF-α-induced RA FLS and examined the crucial role of autophagy inhibition in its impacts on RA FLS pathogenic behaviors. We explored whether silencing synovial AQP1 relieved rat adjuvant-induced arthritis (AIA) by reducing synovial autophagy. TNF-α stimulation increased AQP1 expression and autophagy levels in RA FLS, with a positive correlation between them. AQP1 silencing inhibited autophagy in TNF-α-stimulated RA FLS, along with suppressing proliferation, promoting apoptosis, and mitigating inflammation. Notably, the inhibitory effects of AQP1 silencing on RA FLS pathogenic behaviors were cancelled by autophagy activation with rapamycin (Rapa) but enhanced by autophagy inhibition using 3-Methyladenine. Mechanistically, silencing AQP1 enhanced the binding of Bcl-2 to Beclin1 by decreasing Beclin1-K63 ubiquitination, thus inhibiting RA FLS autophagy. In vivo, silencing synovial AQP1 relieved the severity and development of rat AIA, alongside reducing Ki67 expression, promoting apoptosis, and decreasing autophagy within AIA rat synovium. Expectedly, the Rapa co-administration nullified the anti-AIA effects of silencing synovial AQP1. These findings reveal that silencing AQP1 inhibits RA FLS pathogenic behaviors and attenuates rat AIA through autophagy inhibition. This study may help clarify the pathogenic role of AQP1 in enhancing autophagy during RA development.

Traditional Chinese medicine (TCM) is a valuable resource for drug discovery and has demonstrated excellent efficacy in treating inflammatory diseases. This study aimed to develop a universal gene signature-based strategy for high-throughput discovery of anti-inflammatory drugs, especially Traditional Chinese medicine (TCM). The disease gene signature of liposaccharide-stimulated THP-1 cells and drug gene signatures of 655 drug candidates were established via sequencing. Anti-inflammatory drugs were screened based on similarities between drug gene signatures and the reversed disease gene signature. Through screening, 83 potential anti-inflammatory drugs were identified. The efficacy of the TCM formula Biyun Powder, along with individual TCMs, Centipedea Herba, Kaempferiae Rhizoma, and Schizonepetae Spica Carbonisata, was verified in vitro or in vivo. Mechanistically, they exerted anti-inflammatory effects by inhibiting the nuclear factor-kappa B pathway. Kaempferol and luteolin were identified as bioactive IκB kinase-β inhibitors in Kaempferiae Rhizoma and Schizonepetae Spica Carbonisata, respectively. We developed a universal gene signature-based approach for the high-throughput discovery of anti-inflammatory drugs that is applicable to compounds and to TCM herbs/formulae and established a workflow (screening, validation of efficacy, and identification of the mechanism of action and bioactive compounds) that can serve as a research template for high-throughput drug research.

Mitochondrial dysfunction and damage can result in the release of mitochondrial DNA (mtDNA) into the cytoplasm, which subsequently activates the cGAS-STING pathway, promoting the onset of inflammatory diseases. Various factors, such as oxidative stress, viral infection, and drug toxicity, have been identified as inducers of mitochondrial damage. This study aims to investigate the role of mtDNA as a critical inflammatory mediator in the pathogenesis of ketamine (KET)-induced cystitis (KC) through the cGAS-STING pathway. To investigate the role of the cGAS-STING pathway in KET-induced cystitis, we assessed the expression of cGAS and STING in rats with KET cystitis. Additionally, we evaluated STING expression in conditionally deficient Simian Virus-transformed Human Uroepithelial Cell Line 1 (SV-HUC-1) cells in vitro. Morphological changes in mitochondria were examined using transmission electron microscopy. We measured intracellular reactive oxygen species (ROS) production through flow cytometry and immunofluorescence techniques. Furthermore, alterations in associated inflammatory factors and cytokines were quantified using real-time quantitative PCR with fluorescence detection. We observed up-regulation of cGAS and STING expressions in the bladder tissue of rats in the KET group, stimulation with KET also led to increased cGAS and STING levels in SV-HUC-1 cells. Notably, the knockdown of STING inhibited the nuclear translocation of NF-κB p65 and IRF3, resulting in a decrease in the expression of inflammatory cytokines, including IL-6, IL-8, and CXCL10. Additionally, KET induced damage to the mitochondria of SV-HUC-1 cells, facilitating the release of mtDNA into the cytoplasm. This significant depletion of mtDNA inhibited the activation of cGAS-STING pathway, subsequently affecting the expression of NF-κB p65 and IRF3. Importantly, the reintroduction of mtDNA after STING knockdown partially restored the inflammatory response. Our findings confirmed the activation of the cGAS-STING pathway in KC rats and revealed mitochondrial damage in vitro. These results highlight the involvement of the cGAS-STING pathway in the pathogenesis of KC, suggesting its potential as a therapeutic target for intervention.

Allergic asthma is a chronic complex airway disease characterized by airway hyperresponsiveness, eosinophilic inflammation, excessive mucus secretion, and airway remodeling, with increasing mortality and incidence globally. The pathogenesis of allergic asthma is influenced by various factors including genetics, environment, and immune responses, making it complex and diverse. Recent studies have found that various cellular functions of mitochondria such as calcium regulation, adenosine triphosphate production, changes in redox potential, and free radical scavenging, are involved in regulating the pathogenesis of asthma. This review explores the involvement of mitochondrial functional changes in the pathogenesis of asthma, and investigate the potential of targeting cellular mitochondria as a therapeutic approach for asthma. Those insights can provide a novel theoretical foundations and treatment strategies for understanding and preventing asthma.

Arthritis is a class of diseases, characterized by joint and surrounding inflammation, accompanied by joint swelling, pain, dysfunction. According to different factors, arthritis can be divided into osteoarthritis, rheumatoid arthritis, ankylosing spondylitis and so on. N6-methyladenosine (m6A) is the most common internal modification of eukaryotic mRNA and is involved in splicing, stabilization, output and degradation of RNA metabolism. This review systematically summarized current insights into the mechanism of m6A in arthritis. The studies related to the involvement of m6A in the pathogenesis of arthritis reported in PubMed, Google scholar, and other open source literatures were investigated to evaluate the important roles of m6A in arhtritis, and the clinical relevances. M6A methylation regulators play the roles of writers, erasers, and readers, are crucial for regulating gene expression, and play important roles in many biological processes such as virus replication and cell differentiation. In addition, more and more studies have shown that m6A is closely related to the development of arthritis. As a new therapeutic target for arthritis, m6A has a wide influence on the pathological mechanism of arthritis. However, further research is needed to determine how m6A affects arthritis pathology and its use in target therapy and diagnosis.

The pathogenesis of acute kidney injury (AKI) is not fully understood. Tax1-binding protein 1 (TAX1BP1) modulates inflammation and apoptosis through the NF-kB signaling pathway, however, its specific role in ischemic AKI remains unclear. We injected a TAX1BP1 overexpression plasmid into the tail vein of male C57BL/6 mice, followed by clamping the bilateral renal arteries to induce AKI. Additionally, TAX1BP1 overexpression and silencing vectors were transfected into NRK52E cells to establish an in vitro hypoxia-reoxygenation model. Renal tubular necrosis was assessed using PAS and H&E staining. Expression levels of TAX1BP1, caspase-3, Bcl2, phosphorylated p65, and total p65 were measured through Western blot in both models. RT-PCR was used to evaluate KIM-1, NGAL, IL-6, and TNFα expression, while TUNEL staining detected apoptosis in renal tubular epithelial cells. RNA sequencing identified potential TAX1BP1 targets, which were validated via Western blot and RT-PCR. Our results indicate that TAX1BP1 significantly influences ischemic AKI by modulating apoptosis and inflammation in kidney tissues. In vitro studies confirmed its critical role in renal tubular epithelial cell apoptosis and inflammation through NF-kB activation, potentially via PMAIP1. TAX1BP1 may protect renal tubular epithelial cells by targeting PMAIP1 through the NF-kB signaling pathway in ischemic AKI.

Vascularization after rib fracture is a crucial physiological process that is essential for the repair and healing of the rib. Studies have shown that CD90 plays a critical role in regulating rib fracture healing, but the underlying mechanism of its role has not been fully elucidated. CD90 adenovirus knockout mice were used to construct a rib injury model. The bone healing was observed by micro-CT. CD31/EMCN immunofluorescence staining was performed on bone tissue to observe the density of H-shaped and L-shaped blood vessels at the site of bone injury. CD31 and EMCN dual-stained single cells from the rib fracture sites were detected by flow cytometry. The periosteal stem cells transfected with CD90 or Notch1 overexpression and silencing vector were co-cultured with osteoblast MC3T3-E1 in osteogenic induction medium. Moreover, bone microvascular endothelial cells were extracted from the rib injury and co-cultured with the periosteal stem cells transfected with CD90. CCK-8 was used to detect cell viability, RT-qPCR and Western blot were used to detect Notch1, Notch2, Notch3, Notch4, CD31, HIF-1α, CD90, RUNX2, OCN and OPN expression. Alkaline phosphatase (ALP) staining and alizarin red staining were used to observe mineralized nodules. Immunofluorescence staining was used to detect the expression of Dll4, Notch, and CD90 in each group of cells. The angiogenesis experiment was conducted to observe cellular vascular formation. Compared with the Adsh-NC group, the bone healing in the Adsh-CD90 group was significantly impaired, with a marked reduction in the number and volume of blood vessels at the rib fracture site, as evidenced by CD31/EMCN immunofluorescence staining, which showed a reduction in the number of H type vessels at the site of bone injury. It was found that CD90 depletion can inhibit the signaling of Dll4/Notch in the rib fracture site. Furthermore, we found that overexpression of Notch1 reverses the impairment of tubule formation in bone microvascular endothelial cells caused by CD90 suppression.r.Dll4 protein reverses the inhibitory effect of CD90 deletion on periosteal stem cells and MC3T3-E1 cell viability and osteogenesis. In the end, we found that overexpression of Notch1 and CD90 can promote angiogenesis of bone microvascular endothelial cells and Notch pathway activation. CD90 can affect vascular formation in mouse rib fractures, and CD90 may be regulated by Dll4/Notch.

G proteins are a class of important signal transducers in mammalians. G proteins can corpoarated with G proteincoupled receptors (GPCRs) and transmit signals from extracellular stimuli into intracellular response, which will regulate a series of biological functions. G-proteins are heterotrimeric proteins composed of Gα, Gβ, and Gγ subunits. Based on structural and functional similarity of their α-subunits, G proteins are typically grouped into four classes (Gi, Gs, Gq/11, and G12/13). The Gq/11 subfamily consists of Gq, G11, G14, and G15/16 proteins. Gαq is the α-subunit of Gq protein and encoded by GNAQ. Our previous studies revealed that Gαq play an important role in regulating T cell survival and T cell differentiation. Inflammasomes are multiprotein complexes that play a critical role in modulating innate inflammatory response. NLRP3 inflammasome is currently the most extensively studied inflammasome. We found that Gαq suppressed NLRP3 inflammasome activation in macrophage, Gαq also suppressed NLRP3 inflammasome activation in a LPS-induced sepsis mouse model. Gαq can locate to mitochondria and Gαq was required for the maintenance of mitochondrial homeostasis. Gαq regulated NLRP3 inflammasome activation by modulating mitochondrial reactive oxygen species (mtROS). We found that Gαq suppressed NLRP3 inflammasome activation in macrophage, Gαq also suppressed NLRP3 inflammasome activation in a LPS-induced sepsis mouse model. Gαq can locate to mitochondria and Gαq was required for the maintenance of mitochondrial homeostasis. Gαq regulated NLRP3 inflammasome activation by modulating mitochondrial reactive oxygen species (mtROS). Our results indicate that Gαq regulates NLRP3 inflammasome activation by modulating mitochondrial ROS production. Our research provides new mechanistic insight into the activation of NLRP3 inflammasome. As it has been proved that NLRP3 inflammasome plays an important role in the pathogenesis many diseases such as Alzheimer’s disease, cancer, and inflammatory bowel disease, Gαq might become a novel drug target for these diseases in future.

Sepsis represents a significant global health and hygiene challenge. Excessive activation of macrophages in sepsis can result in certain patients displaying characteristics akin to those observed in Macrophage Activation Syndrome (MAS). MAS represents a grave immune system disorder characterized by persistent and severe inflammation within the body. In the context of sepsis, MAS presents atypically, leading some researchers to refer to it as Macrophage Activation-Like Syndrome (MALS). However, there are currently no effective treatment measures for this situation. The purpose of this article is to explore potential treatment methods for sepsis-associated MALS. The objective of this review is to synthesize the specific pathophysiological mechanisms and treatment strategies of MAS to investigate potential therapeutic approaches for sepsis-associated MALS. We searched major databases (including PubMed, Web of Science, and Google Scholar etc.) for literature encompassing macrophage activation syndrome and sepsis up to Mar 2024 and combined with studies found in the reference lists of the included studies. We have synthesized the underlying pathophysiological mechanism of MALS in sepsis, and then summarized the diagnostic criteria and the effects of various treatment modalities utilized in patients with MAS or MALS. In both scenarios, heterogeneous treatment responses resulting from identical treatment approaches were observed. The determination of whether the patient is genuinely experiencing MALS significantly impacts the ultimate outcomes of therapeutic efficacy. In order to tackle this concern, additional clinical trials and research endeavors are imperative.