1-(3-4-dihydroxyphenyl)-3-(2-methoxyphenyl)prop-2-en-1-one and Disease-Models--Animal

Chalcone, a natural product, has a wide range of biological activities. L2H17, a chalcone derivative, was synthesized and screened in our previous study and exhibited excellent anti-inflammatory property in vitro. This study investigated the therapeutic potential of L2H17 on lipopolysaccharide (LPS)-induced acute lung injury (ALI) and the role of heme oxygenase-1 (HO-1).. An ALI animal model was induced by LPS (10 mg/kg) intratracheal instillation. The effect of L2H17 on LPS-induced structural damage was determined using hematoxylin and eosin (HE) staining, and tissue edema extent was examined. Bronchoalveolar lavage fluid (BALF) was harvested to assess the levels of related cytokines by enzyme-linked immunosorbent assay (ELISA), and superoxide dismutase (SOD) activity was also assessed. HO-1 expression was determined using immunohistochemistry and western blotting. The effects of L2H17 on LPS stimulation in RAW 264.7 and the involvement of the HO-1 pathway were investigated.. L2H17 alleviated the histopathological manifestations and tissue edema. Moreover, L2H17 decreased the production of pro-inflammatory factors in BALF and increased SOD activity. In vitro, L2H17 significantly reduced pro-inflammatory cytokine production. Additionally, L2H17 improved the expression of HO-1 in LPS-treated lung tissue and RAW 264.7. We also found that the inhibitory effect of L2H17 on the inflammatory responses was attenuated by an inhibitor of HO-1 activity, Tin protoporphyrin IX (SnPP).. Our data confirmed that L2H17 can exert protective effect on ALI in vitro and in vivo by inhibiting inflammatory responses and modulating the HO-1 pathway.

Topics: Acute Lung Injury; Animals; Anti-Inflammatory Agents; Chalcone; Chalcones; Disease Models, Animal; Gene Expression Regulation; Heme Oxygenase-1; Humans; Inflammation; Lipopolysaccharides; Lung; Macrophages; Male; Membrane Proteins; Metalloporphyrins; Mice; Mice, Inbred C57BL; Protoporphyrins; RAW 264.7 Cells

Retinal ischemia reperfusion (I/R) injury is common in many ophthalmic diseases. Recent studies have shown that toll-like receptor 4 (TLR4) is involved in ischemic retinal injury. Activation of TLRs requires specific accessory proteins such as myeloid differentiation protein 2 (MD2), which facilitate in ligand responsiveness. Therefore, inhibiting MD2 may be a novel approach to modulate TLR4 signaling and deleterious downstream effects in ischemic retinal injury. We used human Müller MIO-M1 cells treated with tert-butyl hydroperoxide (TBHP) to establish an in vitro I/R model of oxidative injury and tested the therapeutic effect of inhibiting MD2. Furthermore, we inhibited MD2 in a mouse model of retinal I/R injury and confirmed the results using MD2 knockout mice. Our studies show that pharmacological inhibition of MD2 prevented TBHP-induced reactive oxygen species (ROS) generation, inflammation and subsequent apoptosis in Müller cells. We also show that retinal I/R injury in mice induced functional deficits, increased ROS levels, inflammation and apoptosis. These pathological changes were not observed in MD2 knockout mice and attenuated when MD2 was inhibited in wildtype mice. In addition, we discovered that the mechanism of these therapeutic effects involved regulation of NADPH oxidase 4 (NOX4)-MD2-TLR4 complex formation. This study provides evidence that MD2 plays a key role in the pathogenesis of retinal I/R damage by participating in TLR4-NOX4 complex formation and elaboration of oxidative and inflammatory damage. Hence, inhibition of MD2 may reduce TLR-dependent damage during retinal I/R injury.

Topics: Animals; Apoptosis; Cell Survival; Chalcones; Disease Models, Animal; Ependymoglial Cells; Humans; Lymphocyte Antigen 96; Mice, Inbred C57BL; Mice, Knockout; NADPH Oxidase 4; Oxidative Stress; Reactive Oxygen Species; Reperfusion Injury; Retinal Diseases; Signal Transduction; tert-Butylhydroperoxide; Toll-Like Receptor 4