Ming-Ling Yang

Rutin decreases lipopolysaccharide-induced acute lung injury via inhibition of oxidative stress and the MAPK-NF-κB pathway.

Acute lung injury (ALI) is a serious disease with unacceptably high mortality and morbidity rates. Up to now, no effective therapeutic strategy for ALI has been established. Rutin, quercetin-3-rhamnosyl glucoside, expresses a wide range of biological activities and pharmacological effects, such as anti-inflammatory, antihypertensive, anticarcinogenic, vasoprotective, and cardioprotective activities. Pretreatment with rutin inhibited not only histopathological changes in lung tissues but also infiltration of polymorphonuclear granulocytes into bronchoalveolar lavage fluid in lipopolysaccharide (LPS)-induced ALI. In addition, LPS-induced inflammatory responses, including increased secretion of proinflammatory cytokines and lipid peroxidation, were inhibited by rutin in a concentration-dependent manner. Furthermore, rutin suppressed phosphorylation of NF-κB and MAPK and degradation of IκB, an NF-κB inhibitor. Decreased activities of antioxidative enzymes such as superoxide dismutase, catalase, glutathione peroxidase, and heme oxygenase-1 caused by LPS were reversed by rutin. At the same time, we found that ALI amelioration by chelation of extracellular metal ions with rutin is more efficacious than with deferoxamine. These results indicate that the protective mechanism of rutin is through inhibition of MAPK-NF-κB activation and upregulation of antioxidative enzymes.

Luteolin Suppresses Inflammatory Mediator Expression by Blocking the Akt/NFκB Pathway in Acute Lung Injury Induced by Lipopolysaccharide in Mice

Acute lung injury (ALI), instilled by lipopolysaccharide (LPS), is a severe illness with excessive mortality and has no specific treatment strategy. Luteolin is an anti-inflammatory flavonoid and widely distributed in the plants. Pretreatment with luteolin inhibited LPS-induced histological changes of ALI and lung tissue edema. In addition, LPS-induced inflammatory responses, including increased vascular permeability, tumor necrosis factor (TNF)-α and interleukin (IL)-6 production, and expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2), were also reduced by luteolin in a concentration-dependent manner. Furthermore, luteolin suppressed activation of NFκB and its upstream molecular factor, Akt. These results suggest that the protection mechanism of luteolin is by inhibition of NFκB activation possibly via Akt.

Protective effect of rutin on LPS-induced acute lung injury via down-regulation of MIP-2 expression and MMP-9 activation through inhibition of Akt phosphorylation.

Lipopolysaccharide (LPS), also called endotoxin, is the important pathogen of acute lung injury (ALI), which is a clinical syndrome that still lacks effective therapeutic medicine. Rutin belongs to vitamin P and possesses various beneficial effects. In this study, we investigate the potential protective effects and the mechanisms of rutin on LPS-induced ALI. Pre-administration with rutin inhibited LPS-induced arterial blood gas exchange and neutrophils infiltration in the lungs. LPS-induced expression of macrophage inflammatory protein (MIP)-2 and activation of matrix metalloproteinase (MMP)-9 were suppressed by rutin. In addition, the inhibitory concentration of rutin on phosphorylation of Akt was similar as MIP-2 expression and MMP-9 activation. In conclusion, rutin is a potential protective agent for ALI via suppressing the blood gas exchange and neutrophil infiltration. The mechanism of rutin is down-regulation of MIP-2 expression and MMP-9 activation through inhibition of Akt phosphorylation.

Protective effect of wogonin on proinflammatory cytokine generation via Jak1/3-STAT1/3 pathway in lipopolysaccharide stimulated BV2 microglial cells.

Wogonin is a flavonoid compound which exhibits antioxidation, anti-inflammation, neuroprotection, and antitumorgenesis functions. However, the mechanism of how wogonin reduces proinflammatory cytokine generation in activated microglia is unclear. At present, we found wogonin inhibited lipopolysaccharide (LPS)-/interferon-γ (INF-γ)-induced generation of interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α). Wogonin exhibited parallel inhibition on LPS-/INF-γ-induced expression of IL-6 and TNF-α messenger RNA at the same concentration range. LPS-/INF-γ-induced phosphorylation of signal transduction and transcription 1 and 3 (STAT1/3) were also inhibited by wogonin. Although wogonin expressed only weak inhibitory effect on LPS-/INF-γ-induced phosphorylation of Janus kinase-2 (Jak-2) and tyrosine kinase (Tyk)-2, it significantly attenuated the phosphorylation of Jak-1 and Jak-3. These results indicated that the blockade of IL-6 and TNF-α production by wogonin in LPS-/INF-γ-stimulated BV2 microglial cells was attributed mainly to the interference in Jak-1/-3-STAT1/3 signaling pathway.

Wogonin attenuates endotoxin‐induced prostaglandin E2 and nitric oxide production via Src‐ERK1/2‐NFκB pathway in BV‐2 microglial cells

Microglia are the major component of intrinsic brain immune system in neuroinflammation. Although wogonin expresses anti‐inflammatory function in microglia, little is known about the molecular mechanisms of the protective effect of wogonin against microglia activation. The aim of this study was to evaluate how wogonin exerts its anti‐inflammatory function in BV2 microglial cells after LPS/INFγ administration. Wogonin not only inhibited LPS/ INFγ‐induced PGE2 and NO production without affecting cell viability but also exhibited parallel inhibition on LPS/INFγ‐induced expression of iNOS and COX‐2 in the same concentration range. While LPS/INFγ‐induced expression of P‐p65 and P‐IκB was inhibited by wogonin—only weak inhibition on P‐p38 and P‐JNK were observed, whereas it significantly attenuated the P‐ERK1/2 and its upstream activators P‐MEK1/2 and P‐Src in a parallel concentration‐dependent manner. These results indicated that the blockade of PGE2 and NO production by wogonin in LPS/INFγ‐stimulated BV2 cells is attributed mainly to interference in the Src‐MEK1/2‐ERK1/2‐NFκB‐signaling pathway.

Rutin improves endotoxin‐induced acute lung injury via inhibition of iNOS and VCAM‐1 expression

Endotoxins exist anywhere including in water pools, dust, humidifier systems, and machining fluids. The major causal factor is endotoxins in many serious diseases, such as fever, sepsis, multi‐organ failure, meningococcemia, and severe morbidities like neurologic disability, or hearing loss. Endotoxins are also called lipopolysaccharide (LPS) and are important pathogens of acute lung injury (ALI). Rutin has potential beneficial effects including anti‐inflammation, antioxidation, anti‐hyperlipidemia, and anti‐platelet aggregation. Pre‐treatment with rutin inhibited LPS‐induced neutrophil infiltration in the lungs. LPS‐induced expression of vascular cell adhesion molecule (VCAM)‐1 and inducible nitric oxide synthase (iNOS) was suppressed by rutin, but there was no influence on expression of intercellular adhesion molecule‐1 and cyclooxygenase‐2. In addition, activation of the nuclear factor (NF)κB was reduced by rutin. Furthermore, we found that the inhibitory concentration of rutin on expression of VCAM‐1 and iNOS was similar to NFκB activation. In conclusion, rutin is a potential protective agent for ALI via inhibition of neutrophil infiltration, expression of VCAM‐1 and iNOS, and NFκB activation.

Protective effect of zerumbone reduces lipopolysaccharide-induced acute lung injury via antioxidative enzymes and Nrf2/HO-1 pathway

Abstract Acute lung injury (ALI) is a serious disease with high morbidity and mortality rate. Although there are effective strategies for treatment of ALI; a widely accepted specific pharmacotherapy has not yet established. Zerumbone, the major active phytochemical compound from Zingiber zerumbet Smith, exhibits various beneficial biological and pharmacological activities, such as antioxidation, anti‐inflammation, immunomodulation, and anti‐cancer. We aimed to study the potential protective effects and mechanisms of zerumbone in mouse model of lipopolysaccharide (LPS)‐induced ALI. Pretreatment with zerumbone inhibited the histopatholgical changes such as neutrophils infiltration, increased in alveolar barrier thickness, hemorrhage, and hyaline membrane formation occurred in lungs in LPS‐induced ALI. In addition, not only LPS‐induced activation of myeloperoxidase (MPO) and metallopeptidase‐9 (MMP‐9) was suppressed by zerumbone, but also lipid peroxidation in lungs was inhibited as well. Moreover, pretreatment with zerumbone reversed the antioxidative enzymes activities, including superoxide dismutase, catalase, and glutathione peroxidase, decreased by LPS and enhanced the expression of nuclear factor erythroid 2‐related factor (Nrf2) and heme oxygenase (HO‐1) induced by LPS. These results from present study suggested that the protective mechanisms of zerumbone on LPS‐induced ALI were via up‐regulation of antioxidative enzymes and Nrf2/HO‐1 pathway. Graphical abstract Figure. No Caption available. HighlightsZerumbone inhibited the histopathological changes in LPS‐induced ALI.Zerumbone inhibited LPS‐induced activation of MPO and MMP‐9.Zerumbone inhibited LPS‐induced lipid peroxidation.Zerumbone inhibited LPS‐induced activation of antioxidative enzymes.Zerumbone enhanced LPS‐induced expression of HO‐1 and Nrf‐2.

Acute lung injury induced by lipopolysaccharide is inhibited by wogonin in mice via reduction of Akt phosphorylation and RhoA activation

Neutrophil infiltration into the lung is the critical characteristic of acute lung injury (ALI), which is a clinical state with acute inflammatory syndrome. Up to now, there is no effective medicine for ALI. Wogonin has been shown to posses serval biological activities including anti‐inflammation, anti‐oxidant and anti‐carcinoma.

Protective effect of wogonin on endotoxin-induced acute lung injury via reduction of p38 MAPK and JNK phosphorylation

Acute lung injury (ALI) is a serious inflammatory disorder which remains the primary cause of incidence and mortality in patients with acute pulmonary inflammation. However, there is still no effective medical strategy available clinically for the improvement of ALI. Wogonin, isolated from roots of Scutellaria baicalensis Georgi, is a common medicinal herb which presents biological and pharmacological effects, including antioxidation, anti‐inflammation, and anticancer. Preadministration of wogonin inhibited not only lung edema but also protein leakage into the alveolar space in murine model of lipopolysaccharide (LPS)‐induced ALI. Moreover, wogonin not only reduced the expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase (COX)−2 but also inhibited the phosphorylation of mitogen‐activated protein kinase (MAPK) induced by LPS. We further found wogonin inhibited the phosphorylation of p38 MAPK and JNK at a concentration lower than ERK. In addition, inhibition of lung edema, protein leakage, expression of iNOS and COX‐2, and phosphorylation of p38 MAPK and JNK were all observed in a parallel concentration‐dependent manner. These results suggest that wogonin possesses potential protective effect against LPS‐induced ALI via downregulation of iNOS and COX‐2 expression by blocking phosphorylation of p38 MAPK and JNK.

Endotoxin‐induced acute lung injury in mice is protected by 5,7‐dihydroxy‐8‐methoxyflavone via inhibition of oxidative stress and HIF‐1α

Up to date, the morbidity and mortality rates of acute lung injury (ALI) still rank high among clinical illnesses. Endotoxin, also called lipopolysaccharide (LPS), induced sepsis is the major cause for ALI. Beneficial biological effects, such as antioxidation, anti‐inflammation, and neuroprotection was found to express by 5,7‐dihydroxy‐8‐methoxyflavone (DHMF). The purpose of present study was to investigate the potential protective effects of DHMF and the possibile mechanisms involved in LPS‐induced ALI. In our experimental model, ALI was induced in mice by intratracheal injection of LPS, and DHMF at various concentrations was injected intraperitoneally for 30 min prior to LPS administration. Pretreatment with DHMF inhibited not only the histolopatholgical changes occurred in lungs but also leukocytes infiltration in LPS‐induced ALI. Decreased activity of antioxidative enzymes (AOE) such as superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx) caused by LPS was reversed by DHMF. LPS‐induced lipid peroxidation HIF‐1α accumulation, NF‐κB phosphorylation, and IκBα degradation were all inhibited by DHMF. In addition, LPS‐induced expression of proinflammatory mediators such as TNF‐α and IL‐1β were also inhibited by 5,7‐dihydroxy‐8‐methoxyflavone. These results suggested that the protective mechanisms of DHMF on endotoxin‐induced ALI might be via up‐regulation of antioxidative enzymes, inhibition of NFκB phosphorylation, and HIF‐1α accumulation.