Inflammation最新文献

This study aimed to investigate whether and how lipopolysaccharide (LPS) activated hepatic stellate cells (HSCs) regulate macrophage activity and to explore the impact of microRNAs (miRNAs) in exosomes from HSCs on this process. Mice subjected to LPS or cecal ligation and puncture (CLP) were used to explore sepsis-induced liver injury. Liver injury was evaluated using HE staining, and alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels were measured. LPS-Exo or N-LPS-Exo from HSCs were added to hepatic macrophages, and iNOS, IL-1β, and TNF-α expression was detected via Western blotting. miRNA microarray analysis and PCR were used to evaluate differentially expressed miRNAs between LPS-Exo and N-LPS-Exo. Target genes were screened using the TargetScan database and verified with luciferase assays and WB. Inflammation and macrophage activity were observed in vivo using HE and CD86 staining in mice injected with PKH67-labeled LPS-Exo or N-LPS-Exo. Sepsis-related liver injury activates hepatic stellate cells, which regulate macrophage activity through exosomes. Specifically, exosomal miR-146a-5p secreted by hepatic stellate cells targets KLF-4, regulating the macrophage inflammatory response through the JNK signaling pathway. Exosomes containing miRNA-146a-5p released from HSCs following LPS treatment may increase macrophage sensitivity to LPS and trigger an inflammatory response. Exosomal miR-146a-5p derived from HSCs accelerates sepsis-induced liver injury by suppressing KLF-4 expression.

Andrographolide (AGP), a bioactive diterpene lactone, is an active constituent extracted from Andrographis paniculata. It has many biological activities, such as antioxidant, antitumor, antivirus, anti-inflammation, hepatoprotection, and cardioprotection. The aim of the present study is to investigate the cardioprotective effects of AGP in a mouse model of myocardial ischemia-reperfusion injury (MIRI). Adult male C57BL/6 J mice were pre-treated orally with AGP (25 mg/kg) for six days. After 30 min of the left anterior descending coronary artery occlusion followed by 24 h of reperfusion, mice received an additional dose of AGP. The results showed that: (i) AGP pretreatment significantly reduced myocardial infarct size and cardiac injury biomarkers in MIRI mice and improved left ventricular ejection fraction (EF) and fractional shortening (FS); (ii) AGP pretreatment attenuated MIRI-induced oxidative stress imbalance in MIRI mice by increasing total antioxidant capacity (T-AOC) and reducing the levels of hydrogen peroxide (H₂O₂), nitric oxide (NO), malondialdehyde (MDA), and dihydroethidium (DHE); (iii) AGP pretreatment increased Bcl-2 expression and decreased caspase-3 and Bax expression in ischemic myocardial tissue, along with a reduction in TUNEL-positive cells. Further analysis showed that stimulation by I/R decreased peroxisome proliferator-activated receptor-α (PPAR-α) expression in ischemic cardiac tissue, which was prevented by AGP administration. Moreover, administration of the PPAR-α antagonist GW6471 (1 mg/kg) abolished the protective effect of AGP on oxidative stress and apoptosis in the ischemic heart tissue of mice stimulated by ischemia-reperfusion. Taken together, these results suggest that AGP attenuates MIRI-induced cardiac injury by up-regulating PPAR-α expression, thereby preventing oxidative stress and cellular apoptosis.

Chronic inflammation has been associated with the progression of age-related macular degeneration (AMD) and diabetic retinopathy (DR), and the levels of various inflammatory factors are significantly increased in intraocular fluids of patients with AMD and DR. Therefore, elucidating the roles of inflammatory factors in the oxidative damage of RPE cells will help uncover the pathogenesis of AMD and DR. We have previously demonstrated that E2F1 plays an important role in the antioxidant capacity of RPE cells. Here, our transcriptome analysis shows that E2F1 affected the expressions of DNA repair genes in RPE cells. In addition, we found that E2F1 transactivated the splicing factor SRSF1. SRSF1 knockdown promoted DNA oxidative damage and apoptosis and decreased the mRNA stability of DNA repair genes XRCC2, POLK and LIG4 in RPE cells. Moreover, we found that SRSF1 could bind to the RNA stabilizing factor MATR3, and knockdown of the latter affected the mRNA stability of these DNA repair genes. Notably, interleukin-6 (IL-6), an inflammatory factor upregulated in intraocular fluids of patients with AMD and DR, decreased SRSF1 expression by inducing acetylation of E2F1 at the K125 position. Consistently, SRSF1 overexpression relieved IL-6-induced DNA oxidative damage and apoptosis in RPE cells. In vivo experiment results also confirmed that IL-6 could aggravate retinal oxidative damage. In conclusion, high levels of IL-6 in the eyes of patients with AMD and DR destabilize the mRNAs of DNA repair genes by disrupting the expression of SRSF1, leading to abnormal repair of DNA oxidative damage in RPE cells.

OPTN (E50K) mutation is one of the significant pathogenic mutations in normal tension glaucoma (NTG). The molecular mechanism of NTG optic nerve injury is complex and diverse; its key mechanism is still unclear. The NLR family pyrin domain containing (NLRP3) inflammasome plays an essential role in the occurrence and development of inflammation. There is no report on whether NLRP3 inflammasome activation plays a crucial role in NTG optic nerve injury. Here, we explored the role of retinal inflammatory cascade reaction triggered by NLRP3 inflammasome activation in OPTN (E50K) mutated NTG optic nerve injury. This research may provide innovative strategies for effectively treating NTG optic nerve injury caused by OPTN (E50K) mutation. The R28 cell was constructed by AAV2 transfection, named GFP-R28, WT-R28, and E50K-R28 groups. Western blot, qPCR, and immunofluorescence were performed to measure the expression levels of the neurotrophic factors, the senescence indicators, the NLRP3-related indicators, the expression of the glial cell markers, and the inflammatory cytokines. Further, observe the changes in the above indicators in the WT-R28 and E50K-R28 groups after treatment with MCC950. Next, we compared the expression of neurotrophic factors and senescence indicators, NLRP3-related indicators, glial cell markers, and inflammatory factors between young and old WT and OPTN (E50K) mice. We examined the visual function of mice on days 1, 4 and 7. Furthermore, we observed the retinal morphology and the expression of neurotrophic factors and senescence indicators, NLRP3-related indicators, glial cell markers, and inflammatory factors between all groups were measured. We found that OPTN (E50K) mutations lead to NLRP3 inflammasome activation. The OPTN (E50K) mutant groups showed an inflammatory cascade, including glial cell activation and release of proinflammatory factors, leading to retinal structural and functional impairment in mice.MCC950 effectively inhibited the activation of the NLRP3 inflammasome and alleviated the retinal inflammatory cascade caused by the OPTN (E50K) mutation, ultimately improving visual function and retinal damage in mice. OPTN (E50K) mutation induces the activation of the NLRP3 inflammasome, which leads to a retinal inflammatory cascade. MCC950 can inhibit the activation of the NLRP3 inflammasome and retinal inflammatory cascade, improving visual function in OPTN (E50K) mutation mice.

Psoriasis is a common chronic inflammatory skin disease, that always seriously decreases the patient's quality of life. To date, the drugs used to treat psoriasis have severe side effects and poor efficacy, making the development of new drugs urgent. Scopoletin (SCP), a coumarin component extracted from plants such as Artemisia indica and Arabidopsis thaliana, was reported to have anti-inflammatory and immunomodulatory effects. In this study, network pharmacology and molecular docking techniques were utilized to predict the potential possibilities and mechanism of SCP's therapeutic effects on psoriasis. It was shown that SCP may mainly affect interleukin-17 (IL-17), tumor necrosis factor (TNF) and phosphoinositide-3 kinase/protein kinase-B/mammalian target of rapamycin (PI3K/Akt/mTOR) signaling pathway, especially the key targets including TNF, Akt1, IL-6, epidermal growth factor receptor (EGFR) and heat shock protein 90 alpha family class A member 1 (HSP90AA1). Imiquimod (IMQ)-induced psoriasis-like mice were used to verify the therapeutic effects of SCP. We observed SCP could significantly alleviate psoriasis-like skin symptoms, improve the pathological changes, inhibit spleen enlargement and decrease the expression of inflammation factors in IMQ-induced mice. Besides, SCP could also inhibit the phosphorylation of PI3K, Akt, and mTOR, and the good docking activity of SCP with the three pathway proteins further proved SCP can treat psoriasis via PI3K/Akt/mTOR signaling pathway. In conclusion, SCP may be a potential drug for treating psoriasis and is worth further research.

The purpose of our study was to investigate the expression of SH3 domain-binding protein 2 (SH3BP2) in spinal cord injury (SCI) rats and lipopolysaccharide (LPS)-induced microglia, and explored its impact as well as potential mechanism. We examined the level of SH3BP2 in SCI rats using GEO data, immunofluorescence co-staining, qRT-PCR and western blotting. Next, we constructed a rat model with SH3BP2 silencing by injecting LV-shSH3BP2 into the injury site of SCI rats, and then evaluated its neurological outcome, functional recovery, M1 polarization and neuroinflammation by Basso-Beattie-Bresnahan (BBB) score, inclined plane test, Nissl staining and hematoxylin-eosin (H&E). The SH3BP2-related signaling pathway was predicted by KEGG analysis in GSE45006 dataset. BV2 microglial cells and primary microglia were incubated with LPS, and then measured its activation and inflammation by qRT-PCR, western blotting and immunofluorescence. Further complement experiments were performed to explore the molecular mechanisms of SH3BP2. The expression of SH3BP2 was increased in the spinal dorsal horn tissues of SCI rats and LPS-induced microglia. Silencing of SH3BP2 improved neurological outcomes and functional recovery, attenuated neuroinflammation and microglia polarization in SCI rats. Additionally, the JAK/STAT pathway was regulated by SH3BP2. Silencing of SH3BP2 inhibited LPS-induced microglia inflammation and activation, decreased the phosphorylation levels of JAK and STAT. Silencing of SH3BP2 attenuated SCI by regulating the JAK/STAT pathway to inhibit the activation of microglia.

Airway inflammation plays a key role in the pathogenesis and development of asthma. Stanniocalcin-1 (STC-1) has powerful antioxidant, anti-inflammatory and anti-apoptotic functions but its impact on the airway inflammation in asthma lacks evidence. Here, we investigated the effect and potential mechanism of STC-1 on airway inflammation through asthmatic mice model and lipopolysaccharide (LPS)-treated BEAS-2B cells. The data showed that STC-1 treatment before the challenge exerted protective effect on ovalbumin (OVA)-induced asthmatic mice, i.e., decreased the inflammatory cell infiltration, mucus secretion, cytokine levels, apoptosis levels, and p38 MAPK signaling. Additionally, STC-1 reduced 5-LO expression. Meanwhile, STC-1 decreased p38 MAPK signaling, cytokine production, mucin MUC5AC production, 5-LO expression and nuclear translocation, and LTB4 production in vitro. Ultimately, transforming growth factor $\beta$ (TGF- $\beta$ ), as a 5-LO inducer, reversed the anti-inflammatory and anti-apoptotic effects of STC-1 in BEAS-2B cells by up-regulating 5-LO expression. It reveals the potential of STC-1 to act as an additional therapy to mitigate airway inflammation in asthma and inhibit 5-LO expression.

Aneurysmal subarachnoid hemorrhage (aSAH), ischemic stroke (IS), and traumatic brain injury (TBI) are severe conditions impacting individuals and society. Identifying reliable prognostic biomarkers for predicting survival or recovery remains a challenge. Soluble urokinase type plasminogen activator receptor (suPAR) has gained attention as a potential prognostic biomarker in acute sepsis. This study evaluates suPAR and related neuroinflammatory biomarkers in serum for brain injury prognosis. This prospective study included 31 aSAH, 30 IS, 13 TBI, and three healthy controls (n = 77). Serum samples were collected on average 5.9 days post-injury, analyzing suPAR, IL-1β, cyclophilin A, and TNFα levels using ELISA. Outcomes were assessed 90 days post-injury with the modified Rankin Scale (mRS), categorized as favorable (mRS 0-2) or unfavorable (mRS 3-6). Statistical analyses included 2-tailed t-tests, Pearson's correlations, and machine learning linear discriminant analysis (LDA) for biomarker combinations. Elevated suPAR levels were found in brain injury patients compared to controls (p = 0.017). Increased suPAR correlated with unfavorable outcomes (p = 0.0018) and showed prognostic value (AUC = 0.66, p = 0.03). IL-1β levels were higher in the unfavorable group (p = 0.0015). LDA combinatory analysis resulted a fair prognostic accuracy with canonical equation = 0.775[suPAR] + 0.667[IL1-β] (AUC = 0.77, OR 0.296, sensitivity 93.1%, specificity 53.1%, p = 0.0007). No correlation was found between suPAR and CRP or infection status. Elevated suPAR levels in acute brain injury patients were associated with poorer outcomes, highlighting suPAR's potential as a prognostic biomarker across different brain injury types. Combining IL-1β with suPAR improved prognostic accuracy, supporting a multimodal biomarker approach for predicting outcomes.

Acute lung injury (ALI) is characterized by damage to the alveoli and an overabundance of inflammation. Representing a serious inflammatory condition, ALI lacks a precise treatment approach. Despite the recognized benefit impacts of Fibroblast growth factor-10 (FGF10) on ALI, the underlying mechanisms remain unelucidated. To study the role of FGF10 in ALI, C57BL/6 J mice were intratracheally injected with 5 mg/kg Lipopolysaccharide (LPS) with FGF10 (5 mg/kg) or an equal volume of PBS. Inflammatory factors were quantified in bronchoalveolar lavage fluid (BALF) and plasma using ELISA. RNA sequencing of F4/80⁺Ly6G^- macrophages in BALF explored changes in macrophage phenotype and potential mechanisms. Macrophage polarization in BALF was assessed using qRT-PCR, flow cytometry, and Western blot analysis. In vitro, a Transwell co-culture of mouse lung epithelial cells (MLE12) and bone marrow macrophages (BMDM) validated the role of FGF10 in modulating LPS-induced macrophage phenotypic changes. FGF10 ameliorated LPS-induced ALI by diminishing pro-inflammatory factors (IL-1β, TNF-α, and IL-6) and the neutrophil accumulation in BALF. FGF10 also increased the levels of anti-inflammatory factor IL-10. The FGF10 intervention group exhibited enhanced gene expression of macrophage arginine biosynthesis marker (ARG1), and expression of M2-type marker CD206 in monocytes and macrophages. In addition, phosphorylated STAT3 expression increased in isolated monocyte-derived macrophages. Experiments in vitro confirmed that FGF10 could elevate macrophage M2 marker ARG1 expression through the JAK2/STAT3 pathway. FGF10 ameliorates acute LPS-induced lung injury by modulating the polarization of monocyte-derived macrophages recruited in the alveolar space to the M2 type.

Pristimerin is a pentacyclic triterpenoid mainly derived from Celastraceae plants such as Maytenus ilicifolia, which has been traditionally used for the treatment of gastrointestinal disorders. Pharmacological studies have shown that pristimerin exhibited anti-inflammatory, antioxidant, anticancer and antibacterial activities. However, the potential mechanism of pristimerin for the treatment of ulcerative colitis (UC) remains elusive. In the present study, pristimerin could effectively inhibit the NO generation induced by LPS in RAW 264.7 cells and upregulate the decreased expression of tight junction proteins such as occludin and claudin-1. In vivo, oral administration of pristimerin (0.5 mg/kg and 1 mg/kg) could significantly relieve UC symptoms such as body weight loss, disease activity index, shortened colon length and colonic pathological damage. Meanwhile, pristimerin decreased the TNF-α, MPO and MDA levels and increased the levels of IL-10, IL-22, SOD activity, occludin and claudin-1 in colon tissues. Gut microbiota analysis of cecum contents revealed that pristimerin treatment effectively alleviated gut microbiota dysbiosis. Additionally, serum metabolomics showed that 33 potential biomarkers involving lipid and tryptophan metabolism were identified, which may account for the therapeutic effects of pristimerin on UC mice. In conclusion, our findings indicate that pristimerin attenuates UC symptoms in DSS-induced mice through modulating intestinal barrier integrity, gut microbiota composition, lipid and tryptophan metabolism.