Induced Inflammation Mouse Model Research Articles

Vitamin K1 ameliorates lipopolysaccharide-triggered skeletal muscle damage revealed by faecal bacteria transplantation.

Sepsis-associated muscle weakness is common in patients of intensive care units (ICUs), and it is closely associated with poor outcomes. The mechanism of sepsis-induced muscle weakness is unclear. Recent studies have found that gut microbiota and metabolites are involved in the regulation of skeletal muscle mass and metabolism. This study aimed to investigate the effects of gut microbiota and metabolites on sepsis-associated muscle weakness. In a lipopolysaccharide (LPS)-induced inflammation mouse model, mice with different sensitivities to LPS-induced inflammation were considered as donor mice for the faecal microbiota transplantation (FMT) assay, and recipient mice were divided into sensitive (Sen) and resistant (Res) groups. Skeletal muscle mass and function, as well as colonic barrier integrity were tested and gut microbiota and metabolite composition were analysed in both groups of mice. The effect of intestinal differential metabolite vitamin K1 on LPS-triggered muscle damage was investigated, and the underlying mechanism was explored. Recipients exhibited varying LPS-triggered muscle damage and intestinal barrier disruption. Tibialis anterior (TA) muscle of Sen exhibited upregulated expression levels of MuRF-1 (0.825±0.063 vs. 0.304±0.293, P=0.0141) and MAFbx (1.055±0.079 vs. 0.456±0.3, P=0.0092). Colonic tight junction proteins ZO-1 (0.550±0.087 vs. 0.842±0.094, P=0.0492) and occludin (0.284±0.057 vs. 0.664±0.191, P=0.0487) were significantly downregulated in the Sen group. Metabolomic analysis showed significantly higher vitamin K1 in the faeces (P=0.0195) and serum of the Res group (P=0.0079) than those of the Sen group. After vitamin K1 intervention, muscle atrophy-related protein expression downregulated (P<0.05). Meanwhile SIRT1 protein expression were upregulated (0.320±0.035 vs. 0.685±0.081, P=0.0281) and pNF-κB protein expression were downregulated (0.815±0.295 vs. 0.258±0.130, P=0.0308). PI3K (0.365±0.142 vs. 0.763±0.013, P=0.0475), pAKT (0.493±0.159 vs. 1.183±0.344, P=0.0254) and pmTOR (0.509±0.088 vs. 1.110±0.190, P=0.0368) protein expression levels were upregulated in TA muscle. Meanwhile, vitamin K1 attenuated serum inflammatory factor levels. Vitamin K1 might ameliorate LPS-triggered skeletal muscle damage by antagonizing NF-κB-mediated inflammation through upregulation of SIRT1 and regulating the balance between protein synthesis and catabolism.

Metabolomic, Lipidomic and Proteomic Characterisation of Lipopolysaccharide-induced Inflammation Mouse Model

Neuroinflammation is an important feature in the pathogenesis and progression of central nervous system (CNS) diseases including Alzheimer’s disease (AD). One of the widely used animal models of peripherally induced neuroinflammation and neurodegeneration is a lipopolysaccharide (LPS)-induced inflammation mouse model. An acute LPS administration has been widely used for investigation of inflammation-associated disease and testing inflammation-targeting drug candidates. In the present metabolomic, lipidomic and proteomic study, we investigated short-term effects of systemic inflammation induced by LPS administration on the mouse plasma and brain cortical and hippocampal metabolome, lipidome as well as expression of the brain cortical proteins which were shown to be involved in inflammation-associated CNS diseases. From a global perspective, the hippocampus was more vulnerable to the effects of LPS-induced systemic inflammation than the cortex. In addition, the study revealed several brain region-specific changes in metabolic pathways and lipids, such as statistically significant increase in several cortical and hippocampal phosphatidylcholines/phosphatidylethanolamines, and significantly decreased levels of brain cortical betaine after LPS treatment in mice. Moreover, LPS treatment in mice caused significantly increased protein expression of GluN1 receptor in the brain cortex. The revealed perturbations in the LPS-induced inflammation mouse model may give insight into the mechanisms underlying inflammation-associated CNS diseases. In addition, the finding of the study provide important information about the appropriate use of the model during target validation and drug candidate testing.

Dietary Hesperidin Suppresses Lipopolysaccharide-Induced Inflammation in Male Mice.

Depressive disorders are partially attributed to chronic inflammation associated with the tryptophan (Trp)-kynurenine (Kyn) pathway. Recent evidence suggests that anti-inflammatory agents may reduce the risk of depression. The present study aimed to elucidate the potential of the citrus flavonoid hesperidin, which exhibits anti-inflammatory activity, in suppressing the Trp-Kyn pathway in the brain, using a lipopolysaccharide (LPS)-induced inflammation mouse model. Dietary hesperidin was found to suppress activation of the Trp-Kyn pathway in the prefrontal cortex. In addition, it reduced systemic LPS-induced signs of illness, such as low skin temperature and enhanced leukocyte count in the blood. However, dietary supplementation with hesperidin did not improve body weight loss, food intake, water intake, or splenic increases in leukocyte numbers in the LPS model. Collectively, the results suggest that dietary hesperidin can partially regulate central and peripheral events linked to inflammation in LPS mouse models.

Anti-inflammatory effect and mechanism of ethanol extract from Saposhnikoviae Radix in LPS-induced inflammation mouse model

This paper aimed to explore the anti-inflammatory effect of ethanol extract from Saposhnikoviae Radix in a lipopolysaccharide(LPS)-induced inflammation mouse model and its regulation of TLR4/NF-κB signaling pathway. The ethanol extract from Saposhnikoviae Radix was separated and purified on the macroporous adsorption resin and its main chemical components were identified by UPLC-QE/MS. The identification results showed that the top ten components of ethanol extract from Saposhnikoviae Radix were mainly chromones and coumarins. A mouse model of inflammation induced by intraperitoneal injection of LPS was used to investigate the anti-inflammatory effects of ethanol extract from Saposhnikoviae Radix after intragastric administration for seven successive days. Mice in all groups except for the control group were treated with intraperitoneal injection of LPS(0.015 g·kg~(-1)) one hour after the last administration, and twelve hours later, the blood was sampled and separated and the broncoalveolar lavage fluid(BALF) was collected. The levels of nitric oxide(NO), tumor necrosis factor-α(TNF-α), interleukin-6(IL-6), and interleukin-1β(IL-1β) in mouse serum and BALF were detected by ELISA. The harvested lung tissue was stained with hematoxylin-eosin(HE) for observing the pathological changes, followed by the detection of protein expression levels of related molecules in TLR4/NF-κB signaling pathway by Western blotting. The results showed that the ethanol extract from Saposhnikoviae Radix significantly ameliorated the pathological conditions in lung tissue of model mice, reversed the increase in NO, TNF-α, IL-6, and IL-1β levels of mouse serum and BALF, down-regulated the protein expression levels of Toll-like receptor 4(TLR4), myeloid differentiation factor(MyD88), and phosphorylated nuclear transcription factor κB-p65/nuclear transcription factor κB-p65(P-NF-κB p65/NF-κB p65), and up-regulated the NF-κB inhibitory protein α(IκBα). The ethanol extract from Saposhnikoviae Radix exhibited a good anti-inflammatory effect in the LPS-induced acute inflammation muse model, which might be related to the inhibition of the activation of TLR4/NF-κB inflammatory signaling pathway. Chromones and coumarins have been proved to be the active components for its anti-inflammatory effects.

Protective Effect and Mechanism of Theanine on Lipopolysaccharide-Induced Inflammation and Acute Liver Injury in Mice.

Theanine, a unique bioactive constituent from tea ( Camellia sinensis) leaves, is widely used as a functional ingredient and dietary supplement. To evaluate the anti-inflammatory and hepatoprotective effects of theanine and its molecular mechanism, the lipopolysaccharide (LPS)-induced inflammation mouse model was employed in this study. The survival rate of mice in the theanine-treated group increased significantly compared with that of LPS-only group mice. Furthermore, ICR male mice were randomly divided into three or four groups: control, LPS (LPS treatment only), LPS + theanine (20 mg/kg/day), and theanine (theanine treatment only). The results showed that compared with the LPS group, the liver damage and oxidative stress of the theanine-treated group decreased significantly, based on plasma alanine aminotransferase (ALT) and aspartate aminotransferase (AST) concentrations, hepatic total superoxide dismutase (T-SOD), and malondialdehyde (MDA) levels, and histological scores and apoptosis [terminal deoxynucleotide transferase-mediated deoxyuridine triphosphate nick end-labeling (TUNEL) staining and caspase-3 activity] in the liver tissues. Furthermore, compared with no treatment, pretreatment with theanine significantly decreased the release of interleukin (IL)-1β and tumor necrosis factor (TNF)-α, inhibited the expression of several inflammatory factors (including IL-1β, TNF-α, and IL-6), and increased the IL-10/interferon (IFN)-γ ratio in the hepatic tissues. In the LPS-induced inflammation model, theanine inhibited the expression of proinflammatory mediators involved in the nuclear factor-kappa B (NF-κB) pathway, such as inducible nitric oxide synthase (iNOS) and matrix metalloproteinase-3 (MMP-3), and attenuated the phosphorylation of NF-κB in the hepatic tissues. Moreover, theanine suppressed the acute-phase response (elevated nitric oxide and C-reactive protein levels). Furthermore, theanine suppressed the LPS-induced inflammatory state by normalizing hypothalamic-pituitary-adrenal (HPA) axis hyperactivity. Taken together, the results suggest that theanine potentially ameliorates LPS-induced inflammation and acute liver injury; molecular mechanism of action may involve normalization of HPA axis hyperactivity and inactivation of the NF-κB signaling pathway.

Abstract 5738: Expression profiling of microRNA and mRNA on hepatic inflammation in high-fat induced murine model

Abstract The inflammation has been identified as a risk factor for cancer and even as a means to prognose/diagnoses cancer at the inception of the inflammatory process. Therefore, it is necessary to discover novel molecules that might play a critical role in the regulation of inflammation, which can be the target of anti-inflammation. Recent reports indicate that microRNAs (miRNAs) have a significant role in the mechanism of inflammation in chronic inflammatory diseases. The goal of this study was to identify and characterize of miRNA in the regulation of inflammatory responses of high-fat induced inflammation mouse model. In this study, we established a mouse model of high-fat-diet-induced inflammation to gain understanding on the biological functions deregulated by aberrant gene expression based on miRNA and mRNA expression profiling analysis. And then we looked for direct miRNA targets by performing pair-wise correlation coefficient analysis on expression levels of mRNAs and by comparing these results with predicted miRNA targets from TargetScan5.1. We used quantitative PCR technology to evaluate the expression of miRNAs and mRNA on liver tissue. Inflammatory foci were observed over 6 months after high-fat induced inflammation mouse. In cDNA microarray analysis, total 2287 genes were differentially expressed between high-fat induced inflammatory group and normal group. Among those genes, the genes related-metabolic pathway were up-regulated at 3 months while those related inflammatory response were up-regulated at late stage of over 6 months in high-fat induced inflammation mouse model. Furthermore, we identified 15 new miRNAs in high-fat induced inflammation model by bioinformatics analysis and further confirmed their expression by stem-loop RT-PCR. GO analysis indicated that many of the identified miRNA targets may function in high-fat induced inflammation model. For three miRNAs (miR-34a, miR-21 and miR-1224), correlated genes were concordant with predicted targets. A gene set enrichment analysis on these genes demonstrated significant enrichment in biological processes related to lipid and glucose metabolism and inflammation. This study represents, to the best of our knowledge, the first integrated analysis of miRNA and mRNA expression in high-fat induced inflammation model. We identified a distinct profile of miRNAs of which expression differed between inflammation and normal, making these miRNAs candidate markers. Supported by the National Research Foundation of Korea (NRF) grant funded by the Korea government (MEST) (No. 2011-0014620). Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5738. doi:1538-7445.AM2012-5738