Mediators of Inflammation最新文献

Introduction: Cognitive impairment is a vital complication of chronic kidney disease (CKD). The effect of irisin on CKD-induced cognitive impairment remains unclear. In the present study, we aimed to investigate the role of Irisin in mitigating cognitive impairment and explore the underlying mechanisms in CKD. Methods: A CKD mice model was established by adenine. Cognitive function was assessed via the novel object recognition (NOR). Interleukin-1β (IL-1β) levels were measured by enzyme-linked immunosorbent assay (ELISA), while pyroptosis-related protein expression was analyzed using western blotting. Results: Our data showed an upregulation of cell pyroptosis in hippocampus tissues of CKD mice, accompanied by significant cognitive impairment. Pyroptosis and cognitive impairment was both improved by Irisin treatment in vivo. Additionally, irisin markedly downregulated pyroptosis levels through aryl hydrocarbon receptor (AhR)/NF-κB p65 signaling in HT-22 cells pretreated with indoxyl sulfate (IS). In vitro experiments further confirmed that pyroptosis was inhibited by AhR and NF-κB p65 inhibitors. Conclusions: We first demonstrated that irisin alleviated cognitive impairment by inhibiting AhR/NF-κB-NLRP3-mediated pyroptosis of hippocampal neurons in CKD. Overall, irisin may have the potential to serve as a critical antipyroptotic agent for improving CKD-induced cognitive impairment.

Endothelial dysfunction and pathological alterations are pivotal in the pathogenesis of cardiovascular disease. To date, effective interventions for these endothelial changes are lacking. Tumor necrosis factor-alpha (TNF-α) is known to significantly contribute to these alterations. It has been reported the potential of luteolin to mitigate TNF-α-induced inflammation, yet its specific mechanisms and targets still remain to be elucidated. This study aims to investigate the effects and mechanisms of luteolin on TNF-α-induced inflammatory injury in human microvascular endothelial cells, thereby advancing the understanding of luteolin's medicinal properties. Our findings demonstrate that luteolin notably inhibits TNF-α-induced phosphorylation of Akt, mitogen activated protein kinase (MAPK), and the nuclear factor-kappaB (NF-κB) p65. It significantly reduces the transcriptional activity of NF-κB p65 and AP-1 and decreases the expression of mRNA and proteins related to adhesion molecules and inflammatory mediators. Additionally, luteolin inhibited the reduction in STAT3 phosphorylation. In conclusion, luteolin effectively suppresses TNF-α-induced inflammatory injury in endothelial cells via the Akt/MAPK/NF-κB pathway.

Bronchopulmonary dysplasia (BPD) is the most common chronic respiratory disease in preterm infants. Little is known about the regulatory effect of lung Lactobacillus and its mechanism in BPD. This study explored the effect of L. reuteri on hyperoxia-induced mice lung injuries and examined whether L. reuteri played a role via the IL-22/STAT3 pathway. We found that the intranasal administration of L. reuteri and its tryptophan metabolite indole-3-aldehyde (3-IAld) ameliorated hyperoxia-induced mice lung BPD-like changes, deceased proinflammatory cytokines (IL-1β, IL-6, and TNF-α), and increased the levels of surfactant-associated protein C (SPC), aquaporin 5 (AQP5), and vascular endothelial growth factor receptor 2 (VEGFR2, also known as FLK-1). Furthermore, L. reuteri and 3-IAld increased the expression of IL-22. IL-22 was also confirmed to ameliorate hyperoxia-induced mice lung pathological changes, and the protective effects of L. reuteri could be inhibited by anti-IL-22 neutralizing antibody. Finally, we confirmed STAT3 activation by IL-22 in MLE-12 cells. In summary, our study confirmed L. reuteri alleviated hyperoxia-induced lung BPD-like changes in mice by activating the IL-22/STAT3 signaling pathway via IL-22 production. Probiotics Lactobacillus is a potential treatment for hyperoxia-induced lung injury in newborns.

Background: BG is a novel bioactive peptide derived from bitter gourd (Momordica charantia), known for its anti-inflammatory and immunomodulatory properties. In the present study, our objective is to investigate the functional roles and mechanisms of BG in the context of rheumatoid arthritis (RA). Methods: A rat model of adjuvant-induced arthritis (AIA) was established by administering complete Freund's adjuvant (CFA). The viability of BG-mediated AIA was evaluated by assessing changes in rat body weight, joint swelling, ankle joint pathology, inflammation, necroptosis, the formation of neutrophil extracellular traps (NETs), and gut microbiota. Results: The results of the study showed that peptide BG was effective in improving weight loss, joint swelling, serum IgM-rheumatoid factor (IgM-RF) level, and pathological injury of ankle joint in rats with AIA. BG administration resulted in a decrease in erythrocyte sedimentation rate, serum C-reactive protein (CRP), and inflammatory factor (interferon-γ (IFN-γ), interleukin-1β (IL-1β), and tumor necrosis factor-α (TNF-α)) in AIA rats. Additionally, the administration of CFA resulted in an increase in the protein levels of myeloperoxidase (MPO), neutrophil elastase (NE), citrullinated histone H3 (CitH3), peptidyl arginine deiminase 4 (PAD4), p-mixed lineage kinase domain-like (p-MLKL), and cleaved caspase 8. However, this increase was found to be inhibited by BG treatment. Furthermore, it has been found that peptide BG possesses the capacity to regulate the species composition structure of the intestinal microbiota, thereby, facilitating the reestablishment of microbial diversity and equilibrium. Conclusion: Peptide BG has demonstrated efficacy in ameliorating AIA through its regulation of the necroptosis/NETs/inflammation axis and the gut microbiota. This finding underscores the potential of BG as a promising therapeutic intervention for RA.

Background: Hepatic macrophages play an indispensable role in liver pathophysiology, serving as key orchestrators of both liver injury and repair processes. ATG16L1 (autophagy-related 16 like 1) has emerged as a novel and critical autophagy marker. In macrophages, ATG16L1 assumes a particularly crucial role. The current understanding of how macrophage ATG16L1 regulates liver inflammation in the context of liver fibrosis is unclear. Methods: This study included clinical patient samples of liver fibrosis and established a murine model with myeloid-specific Atg16l1 knockout, creating a mouse model of liver fibrosis. Employing RNA sequencing, we sought to elucidate the mechanisms of macrophage ATG16L1 in liver fibrosis by identifying critical signaling pathways. To assess the influence of macrophage ATG16L1 on hepatocyte apoptosis and hepatic stellate cell (HSC) activation, we constructed a dedicated culture system. Ultimately, the introduction of mice with myeloid-specific Atg16l1 knock-in substantiated the protective role of myeloid-specific Atg16l1 against inflammatory signaling, hepatocyte apoptosis, and activation of HSCs. Results: An upregulation of the ATG16L1 signal was observed in the liver tissues of patients with liver fibrosis and in fibrotic mice, predominantly localized to hepatic macrophages. In Atg16l1 ^ΔMφ mice afflicted with liver fibrosis, we detected exacerbated liver damage, evidenced by heightened inflammatory signal expression, increased hepatocyte apoptosis, and enhanced activation of HSCs. The absence of macrophage Atg16l1 was found to result in elevated TNF receptor-associated factor 1 (TRAF1) signaling, triggering inflammatory activation, intensifying hepatocyte apoptosis, and facilitating HSC activation through the transforming growth factor beta 1 (TGF-β1) signaling. The detrimental effects of macrophage Atg16l1 depletion were demonstrated to be mitigated upon Atg16l1 reintroduction. Conclusions: This research delved into the mechanisms by which the macrophage ATG16L1 signal influences inflammatory signaling, hepatocyte apoptosis, and activation of HSCs in liver fibrosis. Consequently, it offers theoretical substantiation and an experimental groundwork for the identification of biological targets for therapeutic intervention in liver fibrosis.

Objective: This study aims to investigate the predictive value of interleukin-6 (IL-6) and lymphocyte subsets for death in children with influenza-associated encephalopathy (IAE). Patients: This study included 76 children with IAE who were divided into a death group and a survival group. The differences in the levels of IL-6 and lymphocyte subsets between the two groups were analyzed, and the predictive value of these two parameters was compared by receiver operating characteristic (ROC) curve analysis. Results: The level of IL-6 and the percentage of natural killer (NK) cells in the death group were higher than those in the survival group (p  < 0.05). The percentage of CD4⁺ T cells and CD4⁺/CD8⁺ levels in the death group were lower than those in the survival group. ROC curves were used for analysis, and the area under the curves (AUCs) of IL-6, the percentage of CD4⁺ T cells, the percentage of CD4⁺/CD8⁺, and the percentage of NK cells were 0.812, 0.810, 0.740, and 0.706, respectively. The AUC of the combination of these four metrics was 0.870. There was a little difference in the efficacy of the four clinical indicators, and the predictive efficacy of the combined test was higher than that of the single test. Conclusion: The IL-6 concentration, percentage of CD4⁺ T cells, percentage of NK cells, and CD4⁺/CD8⁺ have predictive value for death in children with IAE, and the combination of these four metrics has improved the predictive value.

Mixed lineage kinases (MLKs), comprising seven members: MLK1-4, dual leucine zipper kinase (DLK), leucine zipper kinase (LZK), and sterile alpha motif and leucine zipper containing kinase (ZAK), belong to the mitogen-activated protein kinase kinase kinase (MAP3K) family. These kinases are implicated in the progression of numerous cancers by activating mitogen-activated protein kinase (MAPK) cascades or functioning as ser/thr and tyr kinases. However, their specific roles in glioma remain elusive. In the present study, we utilized bioinformatics approaches to investigate the expression patterns of MLKs in low-grade gliomas (LGG) and glioblastoma multiforme (GBM). Additionally, we analyzed their clinical significance and delved into the potential mechanisms underlying MLK activity as well as their association with tumor-immune infiltrating cells (TIICs) in glioma. Furthermore, we conducted in vitro studies to elucidate the functional roles of MLK1-2 in glioma. Our findings revealed that the expressions of MLK1-2 were conspicuously downregulated in GBM and positively correlated with patients' overall survival. Conversely, ZAK exhibited an opposing trend. Notably, our newly devised risk score model exhibited superior performance in predicting patient prognoses. Moreover, we analyzed the potential mechanisms of MLK activity and its interplay with tumor immune infiltration. Last, we validated the antitumor effect of MLK1-2 at the in vitro level. In summary, our study sheds new insights into the roles of MLKs in glioma, particularly MLK1-2, and their potential as therapeutic targets.

Background: Repetitive transcranial magnetic stimulation (rTMS) of the prefrontal cortex (PFC) and transcutaneous electrical nerve stimulation (TENS) have both been demonstrated as effective at alleviating neuropathic pain (NP). However, the comparative efficacy of these two neuromodulation techniques and the specific neural mechanisms underlying their effects remain unclear. Objective: This study aims to compare the efficacy of rTMS in the PFC and TENS in mitigating peripheral NP and to investigate the impact of rTMS on neuroinflammation. Methods: Eighteen adult male Sprague-Dawley rats were randomly divided into three groups: NP (chronic constriction injury [CCI] group, n = 6), rTMS (n = 6), and TENS (n = 6). rTMS was applied to the PFC, while TENS was applied to the right hind limb of the rats 1 week postoperatively. This treatment regimen was administered once daily, 5 days a week, for 4 consecutive weeks. The paw withdrawal mechanical threshold (PWMT) was measured to assess the pain-alleviating effects of rTMS and TENS. We further conducted enzyme-linked immunosorbent assays (ELISAs) to measure the levels of interleukin (IL)-1β, IL-6, and tumor necrosis factor alpha (TNF-α) in the PFC and L4-L6 spinal cord to evaluate their impact on neuroinflammation. Additionally, we examined transient receptor potential vanilloid type 1 (TRPV1) expression in the PFC and the L4‒L6 spinal cord using western blotting and real-time quantitative reverse transcriptase polymerase chain reaction (qRT-PCR) to explore the potential mechanisms involved. Hematoxylin and eosin (H&E) staining of the sciatic nerve was further performed to observe pathological changes. Results: Compared to the CCI group, both the rTMS and TENS groups exhibited a significant increase in PWMT, with the rTMS group demonstrating a notably greater PWMT than the TENS group. Furthermore, rTMS treatment triggered a significant decrease in IL-1β, IL-6, and TNF-α levels in the PFC and spinal cord, while TENS only decreased IL-1β expression in these regions. In both treatment groups, TRPV1 expression was significantly lower in the spinal cord, while H&E staining indicated improved pathological manifestations in the sciatic nerve. Conclusion: Both rTMS and TENS effectively ameliorated CCI-induced NP, with rTMS of the PFC showing superior performance. Both treatments reduced TRPV1 expression and suppressed neuroinflammation in the spinal cord, indicating that this may be one of the mechanisms through which they exert their therapeutic effects.

Keratinocytes can be activated by Cutibacterium acnes, leading to the production of proinflammatory cytokines via toll-like receptors (TLRs) 2 and 4. Although several studies have investigated keratinocytes, the mechanism of calcium-mediated activation remains unclear. Herein, we investigated whether calcium influx via TLR2 and TLR4 stimulation was involved in cytokine secretion by keratinocytes in HaCaT cells. Although TLR2 stimulation by peptidoglycan (PGN) increased intracellular calcium influx, TLR4 stimulation by lipopolysaccharide (LPS) did not increase it, as analyzed using flow cytometry with the calcium indicator Fluo-3. However, activation by either TLR2 or TLR4 ligands upregulated the intracellular calcium influx in THP-1 monocytes. Additionally, the expression of major proinflammatory cytokines and chemokines, such as interleukin (IL)-6, IL-8, IL-1α, granulocyte-macrophage colony-stimulating factor (GM-CSF), and monocyte chemoattractant protein-1 (MCP-1), was significantly increased by TLR2 in HaCaT cells. Moreover, treatment with the intracellular calcium chelator, BAPTA-AM, disrupted PGN-mediated induction of IL-6, IL-8, and MCP-1 production. Real-time quantitative polymerase chain reaction (PCR) and western blotting revealed that TLR2 stimulation induced expression of the epidermal differentiation marker keratin 1. In conclusion, TLR2-induced intracellular calcium influx plays a pivotal role in the secretion of proinflammatory cytokines, such as IL-6 and MCP-1, in keratinocytes. Moreover, the continuous influx of calcium via TLR2 activation leads to keratinization. In vitro studies using HaCaT cells provide basic research on the effect of TLR2-induced calcium on C. acnes-mediated inflammation in keratinocytes. These studies are limited in their ability to clinically predict what happens in human keratinocytes. Clinical studies on patients with acne, including three-dimensional (3D) cultures of primary keratinocytes, are required to develop new diagnostic markers for determining the severity of acne vulgaris.

Background: Allergy immunotherapy (AIT), a treatment approach for allergic rhinitis (AR), is recognized for its potential to modify the disease course beyond mere symptom relief. Interleukin-36γ (IL-36γ), a key player in immune responses, has been implicated in promoting eosinophilic inflammation in AR by activating eosinophils. We aimed to investigate the effect of IL-36γ on group II lymphoid cell (ILC2) in AR patients who underwent sublingual immunotherapy (SLIT). Methods: Twenty-four AR patients were enrolled and administered with SLIT. Serum proteins of IL-36γ, interleukin-5 (IL-5), and interleukin-13 (IL-13) during SLIT were quantitatively assessed using enzyme-linked immunosorbent assay (ELISA). The proportion of ILC2 was determined by flow cytometry. Sorted ILC2s were stimulated by IL-36γ and ILC2 cell differentiation, and type II cytokines expression were examined. Results: SLIT treatment decreased the serum protein levels of IL-36γ, IL-5, IL-13, and the proportion of ILC2 significantly. IL-36γ suppressed the proliferation of ILC2 by inhibiting the levels of ILC2 transcription factor. IL-36γ also inhibited IL-5 and IL-13 expression from ILC2. Conclusion: The changes of IL-36γ during SLIT were related to the inhibited function of ILC2, implying that IL-36γ may be used as a new biomarker for monitoring the efficacy of SLIT in AR.