Kirenol protects against oxidized low-density lipoprotein induced damages in endothelial cells.

Kirenol (KNL) has recently been reported to have anti-inflammatory properties. Yet, little is known about the potential mechanisms of its anti-inflammatory properties. In HUVECs, we elucidated the anti-inflammatory mechanisms of kirenol. RT-PCR was used to test mRNA of pro-inflammatory mediators produced by Ox-LDL. The viability of cells was measured using MTT. Western blots analyzed protein levels. On Ox-LDL-stimulated HUVECs, KNL significantly inhibited the production of pro-inflammatory mediators such as NO, IL-1ß, iNOS, TNF-α and IL-6. p38, ROS and Nrf2 expression were inhibited by KNL. Inhibition of p38, ROS, and KNL caused nuclear accumulation of Nrf2. KNL attenuated Ox-LDL-induced phosphorylation of ERK1/2 and p38, too. Based on our results, KNL inhibits NF-кB and MAPK signaling in HUVECs by activating Nrf2 signaling. There's a possibility that KNL could be developed into an anti-inflammatory drug.

Syzygium cumini leaf extract protects macrophages against the oxidized LDL-induced toxicity: A promising atheroprotective effect.

Oxidized LDL (oxLDL) plays a pivotal role on atherosclerosis development, mainly in the formation of lipid-laden macrophage "foam cells". As a consequence, substances that can modulate LDL oxidation have a pharmacological and therapeutic relevance. Based in previous findings showing the ability of Syzigium cumini leaf extract (ScExt) in preventing LDL oxidation in vitro, this study was aimed to assess the effects of ScExt on oxLDL-mediated toxicity in murine J774 macrophages-like cells. For biochemical analyses, LDL isolated from fresh human plasma and oxidized with CuSO4 was incubated with ScExt pre-treated macrophages. Our results demonstrated that ScExt was efficient in preventing the overproduction of reactive oxygen/nitrogen species (ROS/RNS), the loss of macrophage's viability and the foam cells formation induced by oxLDL. These protective effects of ScExt make it a promising antioxidant for future trials toward atherogenesis.

Diphenyl diselenide protects endothelial cells against oxidized low density lipoprotein-induced injury: Involvement of mitochondrial function.

Elevated levels of oxidized low density lipoprotein (oxLDL) are considered to be one of the major risk factors for atherosclerosis and cardiovascular morbidity. The early stages of atherosclerosis are initiated by the accumulation of oxLDL and the induction of toxic effects on endothelial cells, resulting in endothelial dysfunction. The aim of this study was to investigate how diphenyl diselenide (DD), an organoselenium compound, protect vascular endothelial cells against the toxic effects of oxLDL in vitro. Our data showed that the treatment of bovine endothelial aortic cells (BAEC) with DD (0.1-1 µM) for 24 h protected from oxLDL-induced reactive species (RS) production and reduced glutathione (GSH) depletion. Moreover, DD (1 µM) per se improved the maximal mitochondrial respiratory capacity and prevented oxLDL-induced mitochondrial damage. In addition, DD could prevent apoptosis induced by oxLDL in BAEC. Results from this study may provide insight into a possible molecular mechanism underlying DD suppression of oxLDL-mediated vascular endothelial dysfunction.

Diphenyl diselenide modulates oxLDL-induced cytotoxicity in macrophage by improving the redox signaling.

It has been reported that oxidized LDLs (oxLDL) are involved in the pathogenesis of atherosclerosis, and that macrophages as well as other cells of the arterial wall can oxidize LDL in vitro, depending on the balance between intracellular prooxidant generation and antioxidant defense efficiency. Because of their potential beneficial role in preventing atherosclerosis and other oxidative stress-related diseases, organoselenium compounds such as diphenyl diselenide (PhSe)2, are receiving increased attention. In the present work, we investigated the mechanisms underlying the protective effect exerted by (PhSe)2 on oxLDL-mediated effects in murine J774 macrophage-like cells. (PhSe)2 pretreatment reduced atherogenic signaling triggered by oxLDL in macrophages in vitro, namely: ROS generation, disturbance of NO homeostasis, activation of matrix metalloproteinase, foam cell formation, and mitochondrial dysfunction. Moreover, the redox signaling effects of (PhSe)2 presented herein were accompanied by a downregulation of NF-κB-binding activity. The relatively strong performance of (PhSe)2 makes it an ideal candidate for further, expanded trials as a new generation of antioxidants for preventing atherosclerotic lesion.

Metodologia para a determinação da LDL oxidada e sua aplicação como marcador de risco cardiovascular / Assays for measurement of oxidized low density lipoprotein and its application as a marker of cardiovascular risk

Diversos estudos têm evidenciado que as doenças inflamatórias estão fortemente ligadas à condição de estresse oxidativo. Dentre elas, uma das mais estudadas é a aterosclerose. A aterosclerose é uma doença de grande importância mundial, devido à altamortalidade resultante de condições clínicas decorrentes da doença, como o infarto agudo do miocárdio e o acidente vascular cerebral. As lipoproteínas oxidadas, especialmente a lipoproteína de baixa densidade oxidada (LDL-ox), estão presentes no plasma de pacientescom aterosclerose. Estudos demonstram que a modificação da LDL é um fator importante no desenvolvimento da doença. Por isso, a determinaçãoda LDL-ox plasmática é essencial, não apenas para investigar sua relevância para as doenças cardiovasculares, mas, também, como um auxiliar no diagnóstico destas doenças. Estudos sobre a susceptibilidade da LDL à oxidação, dosagens bioquímicas deprodutos da oxidação da LDL, ensaios imunológicos para a pesquisa da LDL-ox e de anticorpos anti LDL-ox têm sido utilizados como marcadores de risco para desenvolvimento de aterosclerose e, conseqüentemente, de eventos cardíacos e vasculares graves.

Efeitos da lipoproteina LDL-oxidada sobre proliferação, motilidade e angiogênese in vitro de células endoteliais de artérias coronárias humanas / Effects of oxidized LDL lipoprotein on proliferation, motility and in vitro angiogenesis in human coronary artery endothelial cells

A lipoproteína de baixa densidade (LDL) está envolvida na aterogênese. A oxidação aumenta a aterogenicidade da LDL. Nós investigamos os efeitos da LDL oxidada (LDL-ox) no endotélio confluente, na proliferação, motilidade e angiogênese in vitro de células endoteliais de artérias coronárias humanas (CEACH). Os efeitos foram determinados para graus variáveis de oxidação de LDL por diferentes métodos de oxidação e comparados entre si e com os efeitos da LDL nativa (LDLn) e da subfração LDL eletronegativa (LDL-) isoladas de plasma humano e do colesterol puro. Nossos resultados sugerem que a LDLn e o colesterol são relativamente inócuos e que a LDL- e a LDL-ox pela ENO e pela SIN-1 apresentam um efeito tóxico significativo para as CEACH em cultura, proporcional à concentração e ao grau de oxidação da LDL / Low-density lipoprotein (LDL) activate a number of processes involved in atherogenesis. Evidence suggests that oxidation increases the atherogenicity of the LDL. We investigated the effects of pure cholesterol and oxidized LDL (ox-LDL) on proliferation, motility and in vitro angiogenesis in human coronary artery endothelial cells (HCAEC) in culture. These effects were compared for various degrees of oxidation of LDL to control, native LDL (n-LDL) and electronegative LDL(LDL-) isolated from a plasma pool of healthy volunteers. Our results strongly suggest that n-LDL and pure cholesterol are not harmful to HCAEC cultures and that LDL- and LDL oxidized by ENO and by SIN-1 present significant toxic effects to HCAEC cultures, directly related to the concentration and the degree of oxidation of the LDL...

High-density lipoprotein aggregated by oxidation induces degeneration of neuronal cells.

We have previously reported that high-density lipoprotein (HDL) exhibits antineuritogenic effects on chicken cerebral cells in culture. In the present study, we show the effects of HDLs, oxidized by UV irradiation or heating, on chicken cerebral neurons in culture. Both treatments produced several physical and chemical changes in the HDLs, i.e., formation of lipid peroxides, enlargement of HDL diameters, an increased exposure of the tryptophan groups of the apolipoprotein A-I to a more hydrophilic environment, formation of bityrosines, and cross-linking of apolipoprotein A-I. When these treatments were performed in the absence of EDTA, most of the modifications described above were more intense and HDLs formed a macroaggregate that displays a rosette-like structure. The aggregated HDLs produced neurodegeneration and death when added to both undifferentiated and differentiated cerebral neurons in culture. This process was accompanied by the disorganization of the cellular microtubular cytoskeleton and hyperphosphorylation of the microtubule-associated protein tau. Native HDL or HDLs treated in the presence of EDTA inhibited the neuritogenesis of undifferentiated neurons but did not show any significant effect on the differentiated neurons in culture. The effects on the cellular cytoskeleton and morphology of aggregated HDLs recall those of the fibrillar beta-amyloid peptide. The present results suggest that aggregated HDLs could participate in neurodegeneration associated with oxidative stress in the CNS.