Jingyuan Wan

Resolvin D1 protects mice from LPS-induced acute lung injury.

Resolvin D1 (RvD1), an endogenous lipid molecule derived from docosahexaenoic acid (DHA), has been described to promote inflammatory resolution. The present study aimed to determine the protective effects and the underlying mechanisms of RvD1 on lipopolysaccharide (LPS)-induced acute lung injury (ALI). Pretreatment RvD1 to mice 30 min before inducing ALI by LPS decreased the mortality and improved lung pathological changes, inhibited LPS-induced increases in polymorphonulear and mononuclear leukocytes recruitment, total proteins content, tumor necrosis factor (TNF-α) and interleukin-6 (IL-6) production in the bronchoalveolar lavage fluids (BALFs). In addition, RvD1 markedly reduced LPS-induced the expression of cyclooxygenase-2 (COX-2), inducible nitric oxide synthase (iNOS), and adhesion molecules, as well as myeloperoxidase (MPO) activity. Moreover, RvD1 markedly inhibited LPS-induced the activation of mitogen-activated protein kinases (MAPKs) and nuclear factor-κB (NF-κB). Furthermore, pretreatment with Boc, a lipoxin A4 receptor (ALX) antagonist, significantly reversed these beneficial effects of RvD1 on LPS-induced acute lung injury in mice. Taken together, our study showed that RvD1 improved survival rate and attenuated ALI in mice induced by LPS, and the protective mechanisms might be related to selective reaction with ALX, which inhibits MAPKs and NF-κB pathway.

Protective effects of Asiaticoside on acute liver injury induced by lipopolysaccharide/D-galactosamine in mice

Asiaticoside (AS), a triterpenoid product isolated from Centella asiatica, has been described to exhibit anti-in fl ammatory activities in several inflammatory models. However, the effects of AS on liver injury are poorly understood. The present study was undertaken to investigate whether AS is efficacious against Lipopolysaccharide (LPS) /D-galactosamine (D-GalN)-induced acute liver injury in mice and its potential mechanisms. AS (5, 10 and 20 mg/kg/d) was pretreated orally once daily for 3 days before LPS/D-GalN injected in mice. The mortality, hepatic tissue histology, plasma levels of Tumor necrosis factor-alpha (TNF-alpha) and alanine aminotransferase (ALT) and aspartate aminotransferase (AST), hepatic tissue TNF-alpha and caspase-3 activity were measured. Besides, western blotting analysis of phospho-p38 mitogen-activated protein kinase (phospho-p38 MAPK), phospho-c-jun N-terminal kinase (phospho-JNK) and phospho-extracellular signal regulated kinase (phospho-ERK) were determined. As a result, AS showed significant protection as evidenced by the decrease of elevated aminotransferases, hepatocytes apoptosis and caspase-3, alleviation of mortality and improvement of liver pathological injury in a dose-dependent manner. Further, we found that AS dose-dependently reduced the elevation of phospho-p38 MAPK, phospho-JNK, phospho-ERK protein and TNF-alpha mRNA expression in liver tissues and plasma TNF-alpha. These results suggest that AS has remarkable hepatoprotective effects on LPS/D-GalN-induced liver injury and the possible mechanism is related to inhibition of TNF-alpha and MAPKs.

Anti-inflammatory effects of mangiferin on sepsis-induced lung injury in mice via up-regulation of heme oxygenase-1.

Sepsis, a serious unbalanced hyperinflammatory condition, is a tremendous burden for healthcare systems, with a high mortality and limited treatment. Increasing evidences indicated that some active components derived from natural foods have potent anti-inflammatory properties. Here we show that mangiferin (MF), a natural glucosyl xanthone found in both mango and papaya, attenuates cecal ligation and puncture-induced mortality and acute lung injury (ALI), as indicated by reduced systemic and pulmonary inflammatory responses. Moreover, pretreatment with MF inhibits sepsis-activated mitogen-activated protein kinases and nuclear factor kappa-light-chain-enhancer of activated B cells signaling, resulting in inhibiting production of proinflammatory mediators. Notably, MF dose-dependently up-regulates the expression and activity of heme oxygenase (HO)-1 in the lung of septic mice. Further, these beneficial effects of MF on the septic lung injury were eliminated by ZnPP IX, a specific HO-1 inhibitor. Our results suggest that MF attenuates sepsis by up-regulation of HO-1 that protects against sepsis-induced ALI through inhibiting inflammatory signaling and proinflammatory mediators. Thereby, MF may be effective in treating sepsis with ALI.

BML-111, a lipoxin receptor agonist, modulates the immune response and reduces the severity of collagen-induced arthritis

Abstract.Objective:Lipoxins (LXs) are endogenous antiinflammatory and pro-resolving eicosanoids generated during various inflammatory conditions. Recent research has revealed the novel immunomodulatory function of LXs. The aim of this study is to investigate whether LXs modulate the pathogenesis of collagen-induced arthritis (CIA), a typical chronic immune-mediated inflammatory disease.Methods and results:CIA was induced in DBA/1 mice and BML-111, a lipoxin A4 receptor agonist, was administrated. Results indicated that compared with untreated CIA mice, both clinical disease activity scores and histological destruction of joint were significantly reduced in BML-111-treated CIA mice. The dampened joint injury was accompanied by decreased concentrations of serum pro-inflammatory cytokines tumor necrosis factor α and interleukin-6 in BML-111-treated CIA mice. In addition, proliferation of isolated spleen cells, as well as circulating levels of antibody to type II collagen, were reduced significantly in BML-111-treated CIA mice.Conclusion:BML-111 attenuated CIA in part by negatively regulating the immune response, which implicates the potential pharmacological value of LXs in the treatment of chronic immune-mediated inflammatory diseases such as RA.

Histone Deacetylase Inhibitors Attenuate Acute Lung Injury During Cecal Ligation and Puncture-Induced Polymicrobial Sepsis

BackgroundThe histone deacetylase (HDAC) inhibitors have emerged as the useful reagents that epigenetically modulate the expression of various genes. In the present study, the effects of HDAC inhibitors on the expression of inflammation-related genes and lung injury during sepsis were investigated.MethodsMice were pretreated with two structurally unrelated HDAC inhibitors, Trichostatin A (TSA) and sodium butyrate (SB). Thirty minutes later, mice underwent cecal ligation and puncture (CLP)-induced sepsis. Lung injury and the expression of inflammation-related molecules were determined. In addition, survival was assessed post-CLP.ResultsOur results indicated that administration of TSA or SB alleviated sepsis-induced lung injury. This was accompanied by reduced neutrophil infiltration, decreased intercellular adhesion molecule-1 (ICAM-1) and E-selectin expression in lung tissue, and lower interleukin-6 (IL-6) level in plasma. In addition, treatment with HDAC inhibitors significantly prolonged the survival time of CLP mice.ConclusionsThese data indicated that the HDAC inhibitors, based on modulating the key enzymes linked to acetylation modification, effectively attenuate intrapulmonary inflammatory response, thus significantly alleviating lung injury during sepsis.

Naringin inhibits growth potential of human triple-negative breast cancer cells by targeting β-catenin signaling pathway.

Triple-negative (ER-/PR-/HER2-) breast cancer (TNBC) is a severe clinical problem because of its relatively poorer prognosis, aggressive behavior and lack of targeted therapies. Naringin, a major flavonoid extracted from citrus fruits, has been reported to exert promising anticancer activities. However, the detailed antitumor mechanism of naringin still remains enigmatic. In this study, TNBC cell lines-based in vitro and in vivo models were used to explore the anticancer effect and mechanism of naringin. Our data demonstrated that naringin inhibited cell proliferation, and promoted cell apoptosis and G1 cycle arrest, accompanied by increased p21 and decreased survivin. Meanwhile, β-catenin signaling pathway was found to be suppressed by naringin. In contrast, over-expressing β-catenin by adenoviral vector system in TNBC cells reversed the antitumor activity of naringin, and regulated p21 and survivin. Correspondingly, the antitumor potential of naringin was also observed in naringin-treated MDA-MB-231 xenograft mice, while immunohistochemical analysis of tumors from naringin-treated mice showed higher expression of p21 and lower expression of survivin and active β-catenin. Taken together, these results indicate that naringin could inhibit growth potential of TNBC cells by modulating β-catenin pathway, which suggests naringin might be used as a potential supplement for the prevention and treatment of breast cancer.

Mangiferin exerts antitumor activity in breast cancer cells by regulating matrix metalloproteinases, epithelial to mesenchymal transition, and β-catenin signaling pathway

Although mangiferin which is a naturally occurring glucosylxanthone has exhibited promising anticancer activities, the detailed molecular mechanism of mangiferin on cancers still remains enigmatic. In this study, the anticancer activity of mangiferin was evaluated in breast cancer cell line-based in vitro and in vivo models. We showed that mangiferin treatment resulted in decreased cell viability and suppression of metastatic potential in breast cancer cells. Further mechanistic investigation revealed that mangiferin induced decreased matrix metalloproteinase (MMP)-7 and -9, and reversal of epithelial-mesenchymal transition (EMT). Moreover, it was demonstrated that mangiferin significantly inhibited the activation of β-catenin pathway. Subsequent experiments showed that inhibiting β-catenin pathway might play a central role in mangiferin-induced anticancer activity through modulation of MMP-7 and -9, and EMT. Consistent with these findings in vitro, the antitumor potential was also verified in mangiferin-treated MDA-MB-231 xenograft mice where significantly decreased tumor volume, weight and proliferation, and increased apoptosis were obtained, with lower expression of MMP-7 and -9, vimentin and active β-catenin, and higher expression of E-cadherin. Taken together, our study suggests that mangiferin might be used as an effective chemopreventive agent against breast cancer.

Antidiabetic drug metformin alleviates endotoxin-induced fulminant liver injury in mice

Metformin is a first-line antidiabetic drug in type 2 diabetes for its hypoglycemic activity, but recently researches also revealed the anti-inflammatory properties of metformin. In the present study, the pharmacological efficiency of metformin in lipopolysaccharide (LPS)-induced hepatic injury in D-galactosamine (D-Gal)-sensitized mice was investigated. We found that pretreatment with metformin significantly decreased serum ALT and AST levels in LPS/D-Gal-exposed mice. These were accomplished with improved histological alterations in liver sections, decreased myeloperoxidase (MPO) activity, reduced malondialdehyde (MDA) content in liver homogenates and increased survival rate of experimental animals. Metformin also markedly reduced hepatic TNF-α mRNA content and blood TNF-α level. Additional experiment showed that metformin significantly attenuated LPS/D-Gal-induced hepatic apoptosis as evidenced by decreased caspase activities in liver tissues and reduced number of TUNEL-positive cells in liver sections. Furthermore, therapeutic administration of metformin after LPS/D-Gal challenge also improved the survival rate of experimental animal. These results indicated that the hypoglycemic reagent metformin could also provide therapeutic benefits in endotoxin-induced hepatic injury, suggesting its pharmacological potential in inflammation-base disorders.

Tetrandrine attenuates lipopolysaccharide-induced fulminant hepatic failure in D-galactosamine-sensitized mice

Fulminant hepatic failure (FHF) remains an extremely poor prognosis and high mortality; better treatments are urgently needed. Tetrandrine (TET), a traditional anti-inflammatory drug, has been reported to exhibit hepatoprotective activities in several liver injury models. We now investigated the effects and underlying mechanisms of TET on lipopolysaccharide (LPS) and D-galactosamine (D-GalN)-induced FHF in mice. TET (50, 100, and 200 mg/kg) was given intraperitoneally 1h before LPS/D-GalN injection in mice. The mortality and liver injury was evaluated subsequently. The results showed that administering TET to mice reduced mortality and improved liver injury induced by LPS/D-GalN in a dose-dependent manner. In addition, TET dose-dependently inhibited LPS/D-GalN-induced NF-kappaB activation, serum and hepatic tissues tumor necrosis factor-alpha (TNF-alpha) production, caspase-3 activation and hepatocellular apoptosis, myeloperoxidase (MPO) activity, intercellular adhesion molecule-1 (ICAM-1) and endothelial cell adhesion molecule-1 (ECAM-1) expression. Our experimental data indicated that TET might alleviate the FHF induced by LPS/D-GalN through inhibiting NF-kappaB activation to reduce TNF-alpha production.

Protective effects of BML‐111, a lipoxin A4 receptor agonist, on carbon tetrachloride‐induced liver injury in mice

Background:  Lipoxins (LX) are trihydroxytetraene‐containing eicosanoids that display unique anti‐inflammatory and pro‐resolving actions during various inflammatory conditions, but the pathophysiological significance of LX in liver disorders remains unknown.