Inflammation最新文献

Depression, recognized globally as a primary cause of disability, has its pathogenesis closely related to neuroinflammation and neuronal damage. Arctiin (ARC), the major bioactive component of Fructus arctii, has various pharmacological activities, such as anti-inflammatory and neuroprotective effects. Building on previous findings that highlighted ARC's capability to mitigate depression by dampening microglial hyperactivation and thereby reducing neuroinflammatory responses and cortical neuronal damage in mice, the current study delves deeper into ARC's therapeutic potential by examining its impact on hippocampal neuronal damage in depression. Utilizing both chronic unpredictable mild stress (CUMS)-induced depression model in mice and corticosterone (CORT)-stimulated PC12 cell model of neuronal damage, the techniques including Nissl staining, immunohistochemistry, western blotting, ELISA, lactate dehydrogenase assays, colony formation assays, immunofluorescence staining and molecular docking were employed to unravel the mechanisms behind ARC's neuroprotective effects. The findings revealed that ARC not only mitigates hippocampal neuropathological damage and reduces serum CORT levels in CUMS-exposed mice but also enhances cell activity while reducing lactate dehydrogenase release in CORT-stimulated PC12 cells. ARC attenuated neuroinflammatory responses and neuronal apoptosis by inhibiting the overactivation of the P2X7 receptor (P2X7R)/NOD-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome signaling pathway, similar to the effect of A438079 (P2X7R antagonist). Interestingly, pretreatment with A438079 blocked the neuroprotective effect of ARC. Computer modeling predicted that both ARC and A438079 have strong binding with P2X7R and they have the same binding site. These results suggested that ARC may exert a neuroprotective role by binding to P2X7R, thereby inhibiting the P2X7R/NLRP3 inflammasome signaling pathway.

UVB radiation induces inflammatory and oxidative stress responses, contributing to skin damage, yet the underlying mechanisms are not fully understood. N-Myc downstream-regulated gene 2 (NDRG2), an emerging stress-associated gene, remains unexplored in UVB-induced skin injury. In this study, we detected skin NDRG2 expression after UVB irradiation for the first time and further used Ndrg2 knockout mice to clarify the role of NDRG2 in UVB-induced skin injury. Three-month-old male Ndrg2^+/+ and Ndrg2^-/- mice (16-18g) were exposed to UVB to induce acute skin damage, and then dorsal skin samples were collected for subsequent analyses. UVB-induced skin damage was scored. Western Blot Analysis, immunofluorescence (IF) double labeling, and immunohistochemistry (IHC) were employed to assess NDRG2 expression and/or distribution. The concentrations of TNF-α, IL-6, IL-1β, MPO, MMP8, superoxide dismutase (SOD), catalase (CAT), and glutathione (GSH) were quantitatively assessed using enzyme-linked immunosorbent assay (ELISA). Hematoxylin and eosin (HE) staining were employed to determine pathological changes. RNA sequencing and analysis were performed to estimate transcript expression levels and analyze mRNA expression. DESeq2 software was employed to identify differentially expressed genes (DEGs). DEGs were visualized using volcanic and heat maps. Gene Ontology (GO) functions and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways were analyzed to identify primary biological functions, metabolic pathways, or signal transduction pathways associated with DEGs. UVB-challenged Ndrg2^-/- mice exhibited significantly exacerbated skin damage (erythema, edema, and erosion), neutrophil infiltration, and apoptosis compared to Ndrg2^+/+ mice. Furthermore, UVB-challenged Ndrg2^-/- mice displayed significantly elevated pro-inflammatory cytokines, myeloperoxidase (MPO), matrix metalloproteinase-8 (MMP8), and reduced antioxidant expression. RNA sequencing identified 1091 significantly differentially expressed genes enriched in inflammation, immune response, and oxidative stress pathways. In conclusion, the deficiency of Ndrg2 markedly exacerbated UVB-induced skin damage by promoting inflammatory responses and inhibiting antioxidant responses. This suggests that stabilizing NDRG2 expression holds promise as a therapeutic strategy for protecting against UVB-induced skin damage.

Parkinson's disease (PD) is a complex neurodegenerative disorder marked by the gradual deterioration of dopaminergic neurons, especially in the substantia nigra pars compacta (SNc). Dysregulation of the transcription factor FoxO1 is associated with various neurodegenerative conditions, including Alzheimer's disease and PD, though the specific mechanisms involved are not fully understood. This study explores the effects of α-Synuclein preformed fibrils (PFF) on BV-2 microglial cells, focusing on changes in molecular characteristics and their impact on neuronal degeneration. Our results demonstrate that PFF treatment significantly increases FoxO1 mRNA (p = 0.0443) and protein (p = 0.0216) levels, leading to its nuclear translocation (p = 0.0142) and enhanced expression of genes involved in the detoxification of reactive oxygen species (ROS), such as Catalase (Cat, p = 0.0249) and superoxide dismutase 2 (Sod2, p = 0.0313). Furthermore, we observed that PFF treatment elevates mitochondrial ROS levels. However, cells lacking FoxO1 or treated with FoxO1 inhibitors showed increased vulnerability to PFF-induced ROS, attributed to reduced expression of ROS detoxifying enzymes Cat and Sod2 (p < 0.0001). Besides enhancing ROS production, inhibiting FoxO1 also heightens neurotoxicity induced by PFF treatment in microglia-conditioned medium (p < 0.0001). Conversely, treatment with N-acetylcysteine or bacterial superoxide dismutase A mitigated the ROS increase induced by PFF (p < 0.0001). These findings suggest the essential role of FoxO1 in regulating ROS levels, which helps alleviate pathology in PFF-induced PD models. Our study provides insights into the genetic mechanisms of PD and suggests potential pathways for developing novel therapeutic strategies.

Periodontitis is a multifactorial chronic inflammatory disease that destroy periodontium. Apart from microbial infection and host immune responses, emerging evidence shows aging and endoplasmic reticulum stress (ER stress) play a key role in periodontitis pathogenesis. The aim of this study is to identify aging-related genes (ARGs) and endoplasmic reticulum stress-related genes (ERGs) in periodontitis. Data were obtained from the Gene Expression Omnibus (GEO), Human Ageing Genomic Resources (HAGR) and GeneCards databases to identify differentially expressed mRNAs/miRNAs/lncRNAs (DEmRNAs/DEmiRNAs/DElncRNAs), ARGs and ERGs, respectively. We used the MultiMiR database for the reverse prediction of miRNAs and predicted miRNA-lncRNA interactions using the STARBase database. Afterwards, we constructed a mRNA-miRNA-lncRNA ceRNA network. A total of 10 hub genes, namely LCK, LYN, CXCL8, IL6, HCK, IL1B, BTK, CXCL12, GNAI1 and FCER1G, and 5 DEmRNAs-ARGs-ERGs were then discovered. Further, weighted gene co-expression network analysis (WGCNA) and single sample gene set enrichment analysis (ssGSEA) were performed to explore co-expression modules and immune infiltration respectively. Finally, we used transmission electron microscope (TEM), inverted fluorescence microscopy, quantitative real-time polymerase chain reaction (qRT-PCR) and Western Blot to verify the bioinformatic results in periodontal ligament stem cells (PDLSCs) infected with Porphyromonas gingivalis (P. gingivalis). The experimental results broadly confirmed the accuracy of bioinformatic analysis. The present study established an aging- and ER stress-related ceRNA network in periodontitis, contributing to a deeper understanding of the pathogenesis of periodontitis.

Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by systemic polyarticular pain, and its main pathological features include inflammatory cell infiltration, synovial fibroblast proliferation, and cartilage erosion. Immune cells, synovial cells and neuroendocrine factors play pivotal roles in the pathophysiological mechanism underlying rheumatoid arthritis. Biological clock genes regulate immune cell functions, which is linked to rhythmic changes in arthritis pathology. Additionally, the interaction between biological clock genes and neuroendocrine factors is also involved in rhythmic changes in rheumatoid arthritis. This review provides an overview of the contributions of circadian rhythm genes to RA pathology, including their interaction with the immune system and their involvement in regulating the secretion and function of neuroendocrine factors. A molecular understanding of the role of the circadian rhythm in RA may offer insights for effective disease management.

Oral lichen planus (OLP) and oral lichenoid lesion (OLL) are chronic inflammatory diseases involving the oral mucosa. B cells infiltration in OLP and OLL, however, little is known about these cells in OLP and OLL. To analyze the function and infiltrating features of B lymphocytes in OLP and OLL, and to preliminarily evaluate their correlation with clinical outcomes. Tissue samples were collected from OLP, OLL, and healthy mucosa. The phenotypes and amounts of B cells in tissues were analyzed by single-cell sequencing. Their proportion and infiltrating features in tissues were examined by immunohistochemistry and immunofluorescence. With the systemic medication of corticoids, the correlation between B cells infiltrating characteristics and the clinical outcomes were evaluated. A quantified proportion increase of B cells was shown in both OLP and OLL. B cells in OLP demonstrated heightened activation and enhanced regulation in immune response. A cohort of 100 patients with OLP/OLL and 13 healthy controls were examined to investigate the B cells infiltration pattern. B cells were distributed in the superficial layer of lamina propria in 92.9% and 41.9% of OLP and OLL, respectively(P < 0.01); focally distributed in 25.0% and 62.9% of OLP and OLL, respectively(P < 0.01). With the systemic medication of corticoids, the cases with B cell infiltration (B⁺) in OLP and OLL groups showed a statistically significant reduction in REU scores before and after treatment (P < 0.01). B cells are widely present in OLP and OLL, and B cell infiltration in OLP and OLL are related to the better therapeutic effect of oral corticoids.

Following ischemic stroke, aquaporin 4 (AQP4) expression modifications have been associated with increased inflammation. However, the underlying mechanisms are not fully understood. This study aims to elucidate the mechanistic basis of post-cerebral ischemia-reperfusion (I/R) inflammation by employing the AQP4-specific inhibitor, AER-271. The middle cerebral artery occlusion (MCAO) model was used to induce ischemic stroke in mice. C57BL/6 mice were randomly allocated into four groups: sham operation, I/R, AER-271, and 2-(nicotinamide)-1,3,4-thiadiazole (TGN-020) treatment, with observations recorded at 1 day, 3 days, and 7 days post-tMCAO. Each group consisted of 15 mice. Procedures included histological examination through HE staining, neurological scoring, Western blot analysis, and immunofluorescence staining. AER-271 treatment yielded significant improvements in post-stroke weight recovery and neurological scores, accompanied by a reduction in cerebral infarction volume. Moreover, AER-271 exhibited a noticeable influence on autophagic and apoptotic pathways, affecting the activation of both pro-inflammatory and anti-inflammatory cytokines. Alterations in the levels of inflammatory biomarkers MCP-1, NLRP3, and caspase 1 were also detected. Finally, a comparative assessment of the effects of AER-271 and TGN-020 in mitigating apoptosis and microglial polarization in ischemic mice revealed neuroprotective effects with no significant difference in efficacy. This study provides essential insights into the neuroprotective mechanisms of AER-271 in cerebral ischemia-reperfusion injury, offering potential clinical applications in the treatment of ischemic cerebrovascular disorders.

Diabetic kidney disease (DKD) is the most significant complication in diabetic patients, ultimately leading to renal fibrosis. The most important manifestation of DKD is the epithelial-mesenchymal transition (EMT) of renal tubular cells, which can lead to renal fibrosis and inflammatory injury in special situations. Sphingosine 1-phosphate (S1P) is involved in various signal transduction pathways and plays a role through G protein-coupled receptors. Research has demonstrated that blocking the S1P / S1PR2 pathway inhibits inflammation and fibrosis. However, the interaction between S1P/S1PR1 and the pathophysiology of EMT remains ambiguous. The purpose of this study was to investigate the mechanism of S1P/S1PR1 on high glucose (HG)-induced renal EMT. We found that HG markedly increased the S1P and EMT marker levels in renal tubular epithelial cells. At the same time, HG could stimulate NF-κB/ROS/NLRP3 expression, but these phenomena were reversed after blocking S1PR1. In mice models of DKD, FTY720 (S1P antagonist) could significantly improve renal function and reduce the infiltration of inflammatory cells. ROS, as well as NLPR3 inflammasome, were markedly decreased in the treatment group. FTY720 inhibits extracellular matrix synthesis and improves renal fibrosis. In brief, the HG stimulates S1P/S1PR1 synthesis and activates the S1P/S1PR1 pathway. Through the S1P/S1PR1 pathway, activates NF-κB, promotes ROS generation and NLRP3 inflammasome activation, and ultimately causes EMT.

Background: Acute myocardial infarction (AMI) is a life-threatening event that is associated with RNA modification and programmed cell death (PCD). This study attempted to investigate the impacts of zinc finger CCCH domain-containing protein 13 (ZC3H13)-mediated N6-methyladenosine (m6A) on ferroptosis in AMI.

Methods: The infarcted areas and cardiac function were evaluated, and the expression level of ZC3H13 was measured in AMI rats that were induced by isoproterenol. Meanwhile, oxygen glucose deprivation (OGD) in vitro model was induced to investigate the alterations on inflammation, oxidative stress and ferroptosis. The m6A modification site of lncRNA93358 modified by ZC3H13 was predicted using bioinformatics, and the interaction between ZC3H13 and lncRNA93358 was verified using the dual-luciferase reporter assays. ZC3H13 was overexpressed and lncRNA93358 was silenced to study their regulatory role in cell death, inflammation, oxidative stress and ferroptosis in AMI.

Results: Significant decreased expression of ZC3H13 was observed in AMI rats, with impaired cardiac function, enhanced inflammation and oxidative stress. ZC3H13 targeted the modification site GGACC of lncRNA93358 and downregulated lncRNA93358. Silencing lncRNA93358 inhibited cell death, reduced the levels of inflammatory cytokines tumor necrosis factor (TNF)-α, interleukin (IL)-6 and IL-1β, suppressed oxidative stress-related indicators (lactate dehydrogenase (LDH), reactive oxygen species (ROS), glutathione (GSH) and malondialdehyde (MDA), as well as downregulated ferroptosis-related acyl-CoA synthetase long chain family member 4 (ACSL4), prostaglandin-endoperoxide synthase 2 (PTGS2) and glutathione peroxidase 4 (GPX4). The effect of silencing lncRNA93358 was further enhanced by overexpression of ZC3H13.

Conclusion: This study reveals the ZC3H13-mediated epigenetic RNA modification targeting lncRNA93358 and suggests that ZC3H13 overexpression may be a promising approach for AMI treatment.

MicroRNA-146a (miR-146a) has been involved in the pathophysiology of inflammatory bowel disease (IBD). However, the precise processes are still not entirely understood. Contradictory studies suggest that miR-146a expression could be influenced by the miR-146a rs2910164 C > G polymorphism. This case-control study aimed to investigate the association of miR-146a rs2910164 C > G gene polymorphism and its impact on circulating miR-146a expression levels in Egyptian IBD patients. We included 40 IBD patients and 30 matched healthy controls. Genotyping of miR-146a rs2910164 polymorphism and assessment of miR-146a expression level were done using quantitative real-time PCR in all participants. MiR-146a rs2910164 GG genotype and the G allele were reported in 47% and 70% of the IBD patient group, respectively. And they were associated with increased IBD risk. All the IBD patients with the CC genotype (100%) and most of those with the CG genotype (66.67%) had an inactive disease, while most IBD patients with the GG genotype (73.68%) had an active disease. The miR-146a expression level was the highest with the CC genotype and the lowest with the GG genotype. Also, miR-146a expression level decreased significantly in IBD patients than controls and with disease activity. Combined detection of fecal calprotectin with miR-146a expression level improved the diagnostic sensitivity and the negative predictive value in differentiating IBD patients with active disease from those inactive. Our study identified a strong association of miR-146a rs2910164 GG genotype and G allele with IBD-increased susceptibility and activity in the Egyptian population. The miR-146a rs2910164 polymorphism can reduce miR-146a expression levels in these patients as well. Further research on a larger sample size and different ethnic populations can be the key to progress in establishing this genetic association.