iridoids and Acute-Lung-Injury

Lider-7-tang, a medicine used for the treatment of respiratory diseases especially pneumonia and fever in Mongolian Traditional Medicine, was selected for this phytochemical and pharmacological study. The objectives of the study were to determine total biological active substances and analyze the effects of Lider-7-tang treatment in rats with acute lung injury (ALI). Quantitative determination of the total active constituents (phenolic, flavonoid, iridoid and alkaloid) of the methanol extract of Lider-7-tang was performed using Folin-Ciocalteu reagent, aluminum chloride reagent, Trim-Hill reagent, and Bromocresol green reagent, respectively. A total of fifty 8-10-week-old male Wistar rats (200-240 g) were randomized into three groups: control group, lipopolysaccharide (LPS) group (7.5 mg/kg) and LPS+Lider-7 group (90 mg/kg Lider-7-tang before LPS administration). The total content of alkaloids was 0.2±0.043%, total phenols 7.8±0.67%, flavonoids 3.12±0.206%, and iridoids 0.308±0.0095%. This study also evaluated the effects of Lider-7 on levels of inflammatory mediators by observing histopathological features associated with LPS-induced ALI. The rats pretreated with Lider-7 had significantly lower levels of IL-6 (at 3 and 6 h), and TNF-α (at 3, 6, 9, and 12 h). The current study showed that Lider-7 exerted a preventive effect against LPS-induced ALI, which appeared to be mediated by inhibiting the release of pro-inflammatory cytokines.

Topics: Acute Lung Injury; Alkaloids; Animals; Enzyme-Linked Immunosorbent Assay; Flavonoids; Indicators and Reagents; Interleukin-6; Iridoids; Lipopolysaccharides; Lung; Male; Molybdenum; Mongolia; Phenols; Phytotherapy; Plants, Medicinal; Protective Agents; Rats, Wistar; Reproducibility of Results; Spectrophotometry; Time Factors; Treatment Outcome; Tumor Necrosis Factor-alpha; Tungsten Compounds

Sepsis-induced acute lung injury (ALI) is a syndrome associated with inflammation. Cornus iridoid glycoside (CIG), a bioactive component isolated from Corni Fructus, exhibits anti-inflammatory activities. However, the function and underlying mechanisms of CIG in mice with sepsis-induced ALI remain elusive.. The sepsis-elicited ALI model of mice was established by the induction of cecal ligation and puncture (CLP). The wet/dry (W/D) ratio of lung tissues was examined, and the pathological alterations were determined by hematoxylin and eosin staining. The. CLP enhanced W/D ratio and aggravated pathological changes and scores in mice, which were obviously alleviated by the two concentrations of CIG treatment. CIG treatment notably decreased the CLP-induced mRNA expressions and serum levels of IL-1β, IL-6, TNF-α, and MDA, but enhanced the decreased concentrations (caused by CLP) of SOD and GSH-Px. Moreover, CIG treatment significantly decreased the ratios of p65/p-p65 and IκBα/p-IκBα caused by CLP, but aggravated the CLP-induced relative protein levels of Nrf2 and HO-1.. CIG obviously ameliorated the sepsis-induced ALI in mice by suppressing inflammation and oxidative stress, which was closely associated with nuclear factor

Topics: Acute Lung Injury; Animals; Cornus; Inflammation; Interleukin-6; Iridoid Glycosides; Iridoids; Mice; NF-E2-Related Factor 2; NF-kappa B; NF-KappaB Inhibitor alpha; RNA, Messenger; Sepsis; Superoxide Dismutase; Tumor Necrosis Factor-alpha

Sepsis is a systemic inflammatory response syndrome resulted from severe infection. Excessive inflammation response plays an important role in sepsis-induced acute lung injury (ALI). Loganin is an iridoid glycoside isolated from Corni fructus and exerts an anti-inflammatory effect in multiple inflammatory diseases; however, the role of loganin in sepsis-induced ALI remains unknown. In the current study, the cecal ligation and puncture (CLP)-induced murine sepsis model was constructed to investigate the anti-inflammatory property of loganin in sepsis-induced ALI. Lipopolysaccharide (LPS)-treated Raw 264.7 cells and primary murine peritoneal macrophages were established to further explore underlying mechanism of loganin. Results showed that intragastrical administration of loganin significantly increased murine survival, reduced the alveolar structure damage and inflammatory cell infiltration. Loganin suppressed the release of the M1 macrophage-associated pro-inflammatory cytokines and induced the activation of M2-type anti-inflammatory cytokines. Besides, loganin dramatically inhibited NLRP3 inflammasome-mediated caspase-1 activation and subsequent IL-1β secretion. Further in vitro studies confirmed that loganin efficiently inhibited M1 macrophage polarization and NLRP3 inflammasome activation by blocking the extra-cellular signal-regulated kinase (ERK) and nuclear factor-kappa B (NF-κB) pathways. Taken together, the anti-inflammatory effect of loganin in sepsis-induced ALI was associated with the ERK and NF-κB pathway-mediated macrophage polarization and NLRP3 inflammasome activation. Our study offers a favorable mechanistic basis to support the therapeutic potential of loganin in anti-inflammatory diseases, such as sepsis-induced ALI.

Topics: Acute Lung Injury; Animals; Anti-Inflammatory Agents; Bronchoalveolar Lavage Fluid; Caspase 1; Inflammasomes; Interleukin-1beta; Iridoids; Lung; Macrophages; Male; MAP Kinase Signaling System; Mice; Mice, Inbred C57BL; NF-kappa B; NLR Family, Pyrin Domain-Containing 3 Protein; RAW 264.7 Cells; Sepsis

The protective effects of genipin against lipopolysaccharide (LPS)-induced acute lung injury (ALI) have been reported; however, the mechanism is unclear. Genipin performs its pharmacological effects via activation of the phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K)/protein kinase B (AKT) signaling pathway. In the present study, we aimed to determine whether the PI3K/AKT pathway is involved in the protective effects of genipin against mitochondrial-dependent apoptosis, endoplasmic reticulum stress (ERS), and inflammation in ALI. We constructed in vivo and in vitro models of LPS-induced ALI. PI3K/AKT signaling was inhibited using LY294002. Pretreatment with genipin increased AKT phosphorylation, indicating that PI3K/AKT signaling was upregulated. Genipin pretreatment prevented LPS-induced histopathological deterioration, increased pulmonary edema, and decreased oxygenation index, all of which were inhibited using LY294002. In addition, genipin pretreatment attenuated LPS-mediated mitochondrial apoptosis, as indicated by improved mitochondrial dysfunction, downregulation of BAX (BCL2 associated X, apoptosis regulator), upregulation of BCL2 (BCL2 apoptosis regulator), inhibited the release of cytochrome c, activation of caspase-3, and cell apoptosis. Genipin pretreatment inhibited the LPS-induced upregulation of AF4/FMR2 family member 4 (CHOP), glucose-regulated protein, 78 kDa (GRP78), and X-box binding protein 1 (XBP1) levels, indicating ERS suppression. Moreover, genipin pretreatment alleviated LPS-induced inflammation, indicating by blockade of nuclear factor kappa b (NF-κB) signaling activation and reduced tumor necrosis factor alpha (TNF-α), interleukin (IL)-1β, and IL-6 levels in the lung and bronchoalveolar lavage fluid. LY294002 could inhibit these genipin-induced protective effects against apoptosis, ERS, and inflammation. Thus, genipin significantly activates PI3K/AKT signaling to ameliorate mitochondria-dependent apoptosis, ERS, and inflammation in LPS-induced ALI.

Topics: A549 Cells; Acute Lung Injury; Animals; Anti-Inflammatory Agents; Apoptosis; Endoplasmic Reticulum Chaperone BiP; Endoplasmic Reticulum Stress; Humans; Iridoids; Lipopolysaccharides; Lung; Male; Mitochondria; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins c-akt; Rats, Sprague-Dawley; Signal Transduction

Although the protective effects of genipin against acute lung injury (ALI) have been described previously, the associated mechanism remains unclear. We have previously reported that genipin exerts its pharmacological effects by regulating autophagy. Here, we hypothesized that the up-regulation of autophagy may contribute to the protective effects exhibited by genipin against ALI. In the present study, ALI was induced by intratracheal LPS administration in rats. Genipin treatment significantly reduced LPS-induced lung injury as evidenced by improved histopathology, decreased lung edema, total cells, and protein concentration in the bronchoalveolar lavage fluid (BALF). This protection was inhibited by 3-methyladenine (3-MA), an inhibitor of autophagy. Genipin treatment reduced the expression of P62 and increased the expression of Beclin-1 and LC3II, indicating increased autophagy. Genipin treatment also alleviated LPS-induced cell apoptosis (down-regulation of Bax, up-regulation of Bcl-2, and decreased number of terminal deoxynucleotidyl transferase dUTP nick end label-positive cells) and oxidative stress (increased SOD and decreased MDA content) in the lung. Furthermore, genipin attenuated LPS-induced production of TNF-α, IL-1β, and IL-6 in the lung and BALF. These protective effects induced by genipin were reversed by 3-MA treatment, indicating that autophagy was involved in the protective effects exerted by genipin against inflammation and apoptosis in ALI. In A549 cells incubated with LPS for 6 h, genipin treatment increased the number of GFP-LC3 punctae. 3-MA prevented the protective effects of genipin against mitochondrial dysfunction and cell death. These findings suggest that genipin protects against apoptosis and inflammation in LPS-induced ALI by promoting autophagy.

Topics: A549 Cells; Acute Lung Injury; Animals; Autophagy; Bronchoalveolar Lavage Fluid; Cell Survival; Cytokines; Humans; Iridoids; Lipopolysaccharides; Lung; Male; Protective Agents; Rats, Sprague-Dawley

Genipin has been reported to have anti-inflammatory effect. However, its role on lipopolysaccharide (LPS)-induced acute lung injury (ALI) has not been explored. This study aimed to evaluate the effect of genipin on murine model of acute lung injury induced by LPS. The mice were treated with genipin 1h before LPS administration. 12h later, the myeloperoxidase (MPO) in lung tissues and lung wet/dry ratio were detected. The levels of TNF-α, IL-1β and IL-6 in bronchoalveolar lavage fluid (BALF) were measured by ELISA. Apart from this, we use western blot to detect the protein expression in the NF-κB and NLRP3 signaling pathways. The results showed that the treatment of genipin markedly attenuated the lung wet/dry ratio and the MPO activity. Moreover, it also inhibited the levels of TNF-α, IL-1β, IL-6 in the BALF. In addition, genipin significantly inhibited LPS-induced NF-κB and NLRP3 activation. In conclusion, these results demonstrate that genipin protected against LPS-induced ALI through inhibiting NF-κB and NLRP3 signaling pathways.

Topics: Acute Lung Injury; Animals; Anti-Inflammatory Agents; Cytokines; Inflammation Mediators; Iridoids; Lipopolysaccharides; Lung; Male; Mice; Mice, Inbred BALB C; NF-kappa B; NLR Family, Pyrin Domain-Containing 3 Protein; Peroxidase; Signal Transduction

Geniposide, a main iridoid glucoside component of gardenia fruit, has been shown to possess anti-inflammatory activity. However, its potential use for acute lung injury (ALI) has not yet been studied. The aim of this study was to evaluate the anti-inflammatory properties of geniposide using a mouse ALI model. ALI was induced by intranasal injection of lipopolysaccharide (LPS). Pretreatment of mice with geniposide (20, 40, or 80 mg/kg) resulted in a marked reduction in inflammatory cells and total protein concentration in the bronchoalveolar lavage fluid (BALF) of mice. Levels of inflammatory mediators, including tumour necrosis factor- α (TNF- α), interleukin-6 (IL-6), and interleukin-10 (IL-10), were significantly altered after treatment with geniposide. Histological studies using hematoxylin and eosin (H&E) staining demonstrate that geniposide substantially inhibited LPS-induced alveolar wall changes, alveolar haemorrhage, and neutrophil infiltration in lung tissue, with evidence of reduced myeloperoxidase (MPO) activity. In addition, we investigated potential signal transduction mechanisms that could be implicated in geniposide activity. Our results suggest that geniposide may provide protective effects against LPS-induced ALI by mitigating inflammatory responses and that the compound's mechanism of action may involve blocking nuclear factor-kappaB (NF- κB) and mitogen-activated protein kinases (MAPK) signalling pathway activation.

Topics: Acute Lung Injury; Animals; Anti-Inflammatory Agents; Cytokines; Disease Models, Animal; Dose-Response Relationship, Drug; Fruit; Gardenia; Iridoid Glucosides; Iridoids; Lipopolysaccharides; Lung; Male; Mice; Mice, Inbred BALB C; Mitogen-Activated Protein Kinase Kinases; NF-kappa B; Peroxidase; Plants, Medicinal; Random Allocation; Signal Transduction

The protective effect of iridoid glucosides from Boschniakia rossica (BRI) against carbon tetrachloride (CCl4)-induced liver injury was examined. CCl4 at a dose of 0.5 ml/kg of body weight was given intraperitoneally to rats to induce liver damage. The rats were sacrificed 16 h after the CCl4 injection. The CCl4 challenge caused a marked increase in the levels of serum animotransferases, tumor necrosis factor-alpha (TNF-alpha) and of hepatic inducible nitric oxide synthase (iNOS) protein, depleted reduced glutathione (GSH), and propagated lipid peroxidation. The liver antioxidative defense system, including superoxide dismutase (SOD), glutathione peroxidase (GPx) and glutathione reductase (GR), as well as the cytochrome P450 2E1 (CYP2E1) expression were suppressed, however. Preadministration of BRI reversed the significant changes of all liver function parameters induced by CCl4 and restored the liver CYP2E1 content and function. These results demonstrate that BRI produced a protective action on CCl4-induced acute hepatic injury via reduced oxidative stress, suppressed inflammatory response and improved CYP2E1 function in the liver.

Topics: Acute Lung Injury; Animals; Antioxidants; Carbon Tetrachloride; Cytochrome P-450 CYP2E1; Gene Expression Regulation, Enzymologic; Glutathione; Iridoids; Lipid Peroxidation; Liver; Male; Nitric Oxide Synthase Type II; Orobanchaceae; Oxidative Stress; Rats; Rats, Wistar; Silymarin; Tumor Necrosis Factor-alpha